Median Infliximab Trough Levels Research Articles

Effectiveness of Switching to Subcutaneous Infliximab in Pediatric Inflammatory Bowel Disease Patients on Intravenous Maintenance Therapy.

No real-world data are available on subcutaneous infliximab (SC-IFX) in pediatric inflammatory bowel disease (PIBD). We report a single-center cohort experience of an elective switching program from biosimilar intravenous infliximab to SC-IFX, 120 mg fortnightly, as maintenance. Clinical and laboratory data were collected for 7 patients with infliximab trough levels collected prior and at 6 and 40 weeks after the switch. High treatment persistence was registered with a single patient discontinuing the treatment due to high IFX antibodies, already present before switching. All patients remained in clinical remission with no significant changes in laboratory markers and median infliximab trough levels (12.3 µg/mL at baseline; 13.9 and 14.0 µg/mL at 6 and 40 weeks respectively). No newly-developed IFX antibodies were detected and no adverse reactions or rescue therapies were recorded. Our real-world data support the feasibility of an elective switch to SC-IFX in PIBD as maintenance with potential advantages concerning medical resources and patient satisfaction.

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<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.

P081 Therapeutic Drug Monitoring of infliximab in Crohn’s Disease: Cut-off points during maintenance therapy

Abstract Background Therapeutic drug monitoring of infliximab in Crohn’s disease is necessary to optimize treatments. However, infliximab serum levels are not well defined. The aim of the study was to find our cut-off of infliximab serum levels in Crohn’s disease patients in remission in clinical practice. Furthermore, we tried to identify other predictors of long-term benefit of infliximab therapy. Methods Observational, retrospective and single-center study of patients diagnosed with Crohn’s disease on maintenance therapy with infliximab from January 2019 to July 2020. Infliximab trough levels and antibodies to infliximab were measured at least three times, after 6 months of treatment. The tests were performed using enzyme linked immunosorbent assay. Clinical remission was defined using the Harvey Bradshaw index ≤4. The interpretation of data was by ROC analysis. Results 105 Crohn’s disease patients were included in the study, 57.1% men, with a median age at diagnosis of 26 years. The rest of the characteristics are in table 1. The best infliximab level cut-off point classifying patients in clinical remission was 4 μg/ml with an area under the curve of 0.801 (figure 1 and 2). Median infliximab trough levels were significantly higher when patients achieved clinical remission [4.8 (3–8) μg/ml] versus [0.59 (0.1–2.4) μg/ml]. In the multivariate analysis we observed that the variables age, time on infliximab treatment and time of disease evolution were associated with non-remission (table 2). Conclusion Infliximab levels are an objective parameter related to clinical remission in maintenance therapy in patients with Crohn’s disease. Our cut-off point associated with clinical remission was 4 μg/ml.

P339 Effect of antinuclear antibodies on pharmacokinetics of anti-TNF therapy in patients with Inflammatory Bowel Disease

Abstract Background The detection of antinuclear antibodies (ANA) in serum of patients with inflammatory bowel disease (IBD) has been associated with a worse response to anti-TNF therapy and the development of cutaneous or arthritic manifestations. The aim of this study was to investigate a possible association of serum ANA with infliximab (IFX) and adalimumab (ADA) trough levels (TLs) and anti-drug antibodies in IBD patients treated with IFX or ADA. Methods Consecutive IBD patients under maintenance therapy with IFX or ADA in whom there was at least one available measurement of anti-TNF TLs, antibodies to IFX or ADA, and ANA in serum were included. The cut off of therapeutic TLs for both IFX and ADAs was, 5μg/ml. For anti-drug antibodies the cut off of, 10 AU/ml for IFX and, 3 AU/ml for ADA (as positivity of anti-drug antibodies was defined) was applied. The correlation of ANA positivity with demographics, clinical characteristics, treatment, TLs and anti-drug antibodies, of all patients was analyzed. Results A total of, 102 IBD patients [mean age (SD), 43.4 (13.8) years, females, 40 (39%), Crohn’s Disease, 85 (84%), under IFX, 50 (49%), under combination therapy with immunomodulator, 36 (35%), median duration of treatment (IQR), 33 (21–81.8) months] were included. Among them, 53 (52%) were ANA positive with, 28 (27.5%) positive also to anti-ds-DNA in serum. In the univariate analysis ANA positivity (ANA greater than, 1:80) was found to be correlated with age (P=0.008), female gender (P=0.03), duration of treatment (P=0.06), arthralgias (P=0.04) and TLs (P=0.007). In multivariate logistic regression analysis only age and TLs remained significantly associated with the presence of ANA positivity (P=0.04 and P=0.003 respectively). Studying separately IFX and ADA treated patients, the median IFX TLs of ANA(+) group (N=28) was, 3.51 (1.2–7.12) μg/ml significantly lower than the median IFX TLs of ANA(-) group [7.38 (4.83–10.3) μg/ml, N=22], P=0.017. The median antibodies to IFX of ANA(+) group was, 2.65 (2.4–3.24) AU/ml, significantly higher than the median antibodies to IFX of ANA(-) group [2.53 (2.11–2.83) AU/ml, P=0.03]. Regarding ADA treated patients, the median TLs of ANA(+) and ANA(-) group was, 7.33 (2.03–9.85) VS, 9.32 (6.17–10.05) μg/m (P=0.14), while antibodies to ADA in ANA(+) and ANA(-) group was, 1.42 (1.40–1.43) VS, 1.41 (1.40–1.43) AU/ml (P=0.52). No significant association of ANA positivity with the development of cutaneous or rheumatological manifestations was found. Conclusion In IBD patients under maintenance therapy with anti-TNF ANA positivity is associated with lower TLs, more remarkably with IFX TLs. The clinical significance of this finding remains to be defined in future larger prospective studies.

An observational study of switching infliximab biosimilar: no adverse impact on inflammatory bowel disease control or drug levels with first or second switch.

Biologics account for a significant cost in inflammatory bowel disease (IBD) management; however, switching from infliximab originator to its biosimilars has enabled cost saving without compromising disease control. The effects on IBD activity and infliximab trough levels of a second switch to another biosimilar are, however, uncertain. To assess the effects on disease activity and infliximab trough levels associated with switching from infliximab biosimilar CT-P13 to another biosimilar SB2 and compare outcomes in those switching for the first and second time. IBD patients on CT-P13, including some previously switched from originator, were prospectively followed during a switch to SB2. C-reactive protein (CRP), trough infliximab level and clinical disease activity indices were collected at baseline, Infusion 3 or 4 ('early' after switch), and 1year. One hundred eighty-six patients (n=99 second switch) on stable infliximab dosing underwent switching. Compared with baseline, there was no significant change in CRP, clinical disease activity scores or median trough infliximab level at the early time point among first-switch (baseline vs early: 5.7 vs 6.6µg/mL, P=0.05) and second-switch (4.3 vs 4.9µg/mL, P=0.07) patients nor at 1year (median infliximab trough levels, baseline vs 1year, in first-switch [5.7 vs 5.7µg/mL, P=0.37] and second-switch [4.3 vs 4.7µg/mL, P=0.06] patients). The proportion of patients in clinical remission did not significantly change at the early (92% vs 91% at baseline, P=0.75) or 1year (95% vs 91% at baseline, P=0.16) time points. There was no significant difference in time to loss of response between patients switching for the first or second time (P=0.69). Switching from one infliximab biosimilar to another had no adverse impact on infliximab trough levels, and clinical and biochemical disease activity, regardless of whether switching for the first or second time.

P505 Early therapeutic drug monitoring after induction therapy with infliximab: correlation with intestinal ultrasound

Abstract Background Therapeutic drug monitoring (TDM) in patients receiving infliximab (IFX) has a role in assessing treatment and managing outcomes. Infliximab trough levels (ITL) have been suggested as useful markers for treatment optimization in Crohn’s disease (CD).Our goals were: to assess the relationship between ITL and transmural inflammation as assessed by intestinal ultrasound(IUS), following induction therapy with IFX; to assess which clinical, laboratorial or IUS parameters better predicted adequate levels by the end of induction therapy. Methods Prospective multicentric cohort study including patients with active CD starting IFX therapy. Clinical disease activity assessed using the Harvey-Bradshaw index (HBI), C-reactive protein (CRP), fecal calprotectin (FC) were measured at week 0 and after induction therapy (week 14). IUS was performed at week 0 and 14, bowel wall thickness (BWT) from the worst segment was selected for analysis. Ileocolonoscopy was performed at W0 and SES-CD was registered. ITL were measured at W14. Results We included 36 patients with CD (61% male; median age 30 years (range 16–73)). According to Montreal classification, most patients were A2 (69%), had ileocolonic disease (L3 56%) and an inflammatory phenotype (B1 58%).Perianal disease was present in 42%. Combination therapy was used in 61%. After induction therapy, 81% were in clinical remission (HBI <5) and 43% had laboratorial remission (normal CRP and FC). IUS response (decrease >25% in BWT) was observed in 24% of patients and remission (BWT normalization) in 11%. Median ITL were 4.3 (IQR 2.3–8.1) and 64% had ITL >3 ug/ml. There was a good negative correlation between ITL and SES-CD (r=-0.492, p=0.003). Adequate ITL were associated with lower HBI (1.5 vs 4.5, p=0.052), laboratory remission (61% vs 15%, p=0.014), lower BWT (4 vs 5.5 mm, p=0.009) and sonographic response (39% vs 0%, p=0.014) at W14. At the end of induction, we found a fair to good correlation between ITL and HBI (r=-0.430, p=0.009),CRP (r=-0,510, p=0.001), FC (r=-0.590, p=0.001) and BWT (R=-0.506, p=0.002). Receiver operating characteristic (ROC) curve analysis showed that FC at W14 had the largest area under the curve (AUC) in predicting adequate ITL (0.813 vs 0.716 vs 0.739 vs 0.772, p<0.05). Conclusion Patients with higher disease burden measured by ileocolonoscopy at baseline had lower ITL after induction. Adequate ITL were associated with laboratorial remission and sonographic response at the end of induction, with a good correlation with clinical, laboratorial and sonographic parameters. These findings suggest that adequate IFX levels after induction are associated with a better control of inflammation in IBD, so early proactive TDM during induction may be helpful in treatment management.

Long-term effectiveness, safety and immunogenicity of the biosimilar SB2 in inflammatory bowel disease patients after switching from originator infliximab.

Background:Long-term data on inflammatory bowel disease (IBD) patients switched from originator to biosimilar infliximab SB2 are lacking. The aim of the conducted study was to investigate the effectiveness, immunogenicity and safety of a large prospectively followed-up IBD patient cohort that was entirely switched from originator infliximab to biosimilar SB2 treatment.Methods:This was a prospective, single-center, longitudinal, observational study describing clinical outcomes in IBD patients, over an 80-week period following switch from originator infliximab to SB2. Primary outcome measures were change of disease activity [Harvey-Bradshaw Index for Crohn’s disease (CD), partial Mayo Score for ulcerative colitis (UC)], C-reactive protein (CRP), infliximab trough levels (TLs), anti-drug antibodies (ADAs) and adverse events.Results:One hundred and forty-four IBD patients (94 CD, 50 UC), with median duration of 30.5 months’ (range 2–110) treatment with originator infliximab were evaluated. Mean change of disease activity compared with baseline was −0.9 (SD 2.6), –0.4 (2.2) and –0.4 (2.0) in CD; 0.1 (1.1), 0.1 (1.1) and 0.1 (1.3) in UC patients at weeks 24, 48 and 72. Median infliximab TLs were 6.2 µg/ml (interquartile range 2.3–12.2), 5.0 µg/ml (2.7–10.0), 6.6 µg/ml (3.5–12.4) and 5.1 µg/ml (2.7–10.9) at baseline and weeks 24, 48 and 72. Median CRP levels were within normal ranges throughout the study. After the switch, 9.8% of the patients developed new ADAs. Persistence on SB2 was 90% (95% confidence interval 0.85–0.95), 79% (0.72–0.86), 72% (0.64–0.80) at weeks 26, 52 and 78. Serious adverse events occurred in 11 patients.Conclusion:Over the individual patient follow-up of 80 weeks, switch to biosimilar SB2 from originator infliximab does not result in increased disease activity or changed immunogenicity patterns. The switch to SB2 was well tolerated.

Is there a correlation between infliximab trough levels and the development of adverse events in patients with inflammatory bowel disease?

Background/AimsThe measurement of infliximab trough levels (IFX-TLs) in patients with inflammatory bowel disease (IBD) is performed to optimize treatment. However, the association between the development of adverse events (AEs) and IFX-TLs has not been sufficiently studied thus far. To investigate the possible association of IFX-TLs with AEs in Greek patients with IBD receiving maintenance treatment with IFX.MethodsA retrospective analysis of the registry data of the Gastroenterology Department of the University Hospital of Heraklion, from IBD patients with at least one available IFX-TL measurement during the years 2016 to 2017 was conducted. AEs reported 4 months before and 4 months after the measured IFX-TLs were recorded. The IFX-TLs of patients with or without AEs were compared.ResultsOf a total of 83 IBD patients (61 Crohn’s disease [73%]; 52 men [63%]; mean age ± standard deviation, 43.3 ± 16.0 years), 147 measurements of IFX-TLs were available (median 4.69 μg/mL [1.32–9.16]), and 99 AEs (67.3%, 14 severe) were registered. The median IFX-TL of patients with AEs was 5.79 μg/mL (1.36–10.25), higher than the median IFX-TL of patients without AEs (3.40 μg/mL [1.30–5.92]), but the difference was not significant (P=0.97). The presence of infections or dermatologic reactions was not correlated with IFX-TLs. There was no difference in the prevalence of the total AEs (66.7% vs. 73.3%, P=0.77) or in the analysis of AEs by group between patients with IFX-TLs ≥ 15 μg/mL and patients with IFX-TLs < 15 μg/mL.ConclusionsIFX-TLs are not significantly associated with the development of AEs in IBD patients receiving maintenance treatment with IFX.

P408 Long-term impact of the decrease of infliximab trough levels on the disease course in Inflammatory Bowel Disease patients under maintenance treatment with infliximab

Abstract Background The measurement of infliximab trough levels (IFX-TLs) has been suggested as an important biomarker for the optimisation of treatment in patients with inflammatory bowel disease (IBD). We have previously reported that IFX-TLs of patients under maintenance treatment with IFX show decreasing patterns associated with an increasing pattern of CRP levels1. We aimed to study the clinical impact of this observation by recording the treatment changes that became necessary during a three year follow-up. Methods Consecutive asymptomatic patients on maintenance treatment with IFX were included. Two different measurements of IFX-TLs were made (ELISA, Eagle BioSciences) with a ten-month interval using serum samples drained before IFX infusion. After the second measurement patients were followed up for three years and all treatment modifications including IFX intensification, change of biologic agent or IBD-related surgical intervention were assessed. Results Among a total of 86 IBD patients under maintenance treatment with IFX, 64 [49 CD, 15 UC, 42 men, mean age 44.2 ± 15.2 years, 41 in combination therapy with immunomodulator, 6 in intensified dose], with 2 available measurements of IFX-TLs (A and B) were included in the study. Median levels of IF-TLs were 5.07 (IQR 1.60–12.73) μg/ml in measurement A and 4.68 (1.19–7.83) μg/ml in measurement B (p &amp;lt; 0.0001). Treatment was intensified in 8 patients after measurement A. Patients with stable IFX dose showed a significant reduction in median IFX-TLs from 5.65 to 3.8 μg/ml (p &amp;lt; 0.0001). Moreover, CRP levels were significantly increased in measurement B compared with measurement A [0.33 (03–4.4) mg/dl vs. 0.31 (0.3–3.8) mg/dl, p = 0.02]. During a 3 year follow-up, 22 (34%) patients needed treatment optimisation (6 IFX intensification, 7 change of agent, 6 surgery, 3 change of agent plus surgery). In three patients IFX was stopped for safety reasons. Fifty-eight hospitalisations in 19 patients were also recorded. The decrease of IFX-TLs between the two measurements was significantly more in patients with treatment optimisation compared with patients without treatment optimisation (p = 0.03). Conclusion IBD patients who are on maintenance treatment with infliximab showing decreasing patterns of IFX-TLs often need treatment optimisation during the follow-up due to clinical or endoscopic activity. These results probably suggest the importance of the proactive therapeutic drug monitoring and early treatment optimisation in these patients References

P389 Post induction infliximab trough levels predict long-term endoscopic remission in paediatric patients with inflammatory bowel disease

Abstract Background Although higher infliximab (IFX) trough levels (TL) have been associated with better outcomes, the ideal predictive sampling time and cut-points to achieve endoscopic remission remain unclear in children with inflammatory bowel disease (IBD). Therefore, we evaluated the pharmacokinetics of IFX during induction to predict long-term outcome of IFX. Methods All children with Crohn’s disease (CD) or ulcerative colitis (UC) starting IFX therapy (5 mg/kg at weeks 0–2–6–12) for active luminal disease from May 2017 till May 2019 were followed prospectively. IFX levels were measured by Ridascreen IFX Monitoring ELISA (TL at weeks 2–6–12, peak at weeks 0–2–6 and intermediate at weeks 1–4). IFX levels and cumulative drug exposure (area under the curve (AUC) till week 12) were correlated with the outcome at month 6. Clinical remission was defined as PUCAI/PCDAI &amp;lt;10, biochemical remission as CRP ≤5 mg/l + ESR ≤20 mm/h, endoscopic remission as SES-CD &amp;lt;3 or Mayo endoscopic sub-score = 0 and deep remission if both clinical + endoscopic remission. Results were analysed using Mann–Whitney U-test (presented as median [IQR]). Results A total of 252 serum induction levels were included from 32 patients (20 CD and 12 UC; 38% male; median age at start of IFX 13.8 years [11.3–14.9]; 84% on concomitant thiopurines). Clinical remission was achieved in 24 (75%) patients and 18 (56%) were in endoscopic remission (all in deep remission) at month 6. Endoscopic remission at month 6 was associated with significantly higher median IFX TL at week 4 (38.8 µg/ml [24.3–46.0] vs. 23.5 µg/ml [10.5–36.6], p = 0.017), at week 6 (19.9 µg/ml [10.1–26.3] vs. 11.1 µg/ml [3.7–19.9], p = 0.031), at week 12 (9.6 µg/ml [5.5–11.9] vs. 3.5 µg/ml [2.7–7.2], p = 0.004; fig1.) and higher AUC week 0–12 (4574.7 µg*day/ml [3783.0–5160.8] vs. 3722.9 µg*day/ml [3102.2–3991.9], p = 0.008). Median IFX TL at week 12 were significantly higher in children with clinical remission (8.6 µg/ml [5.1–12.0] vs. 4.3 µg/ml [3.1–5.9], p = 0.033), but not for biological remission (6.7 µg/ml [4.0–12.0] vs. 4.3 µg/ml [1.2–7.2], p = 0.250; Figure 2) at month 6. ROC analysis identified an IFX TL at week 12 ≥ 5.0 µg/ml and an AUC weeks 0–12 ≥ 4056.0 µg*day/ml as minimal target to achieve endoscopic remission at mo. 6 (AUROC: 0.796 [95% CI: 0.62–0.97] and AUROC: 0.778 [95% CI: 0.61–0.94], respectively; Figure 3.). Height, haemoglobin and PCDAI score at start of IFX therapy, significantly correlated with week 12 IFX TL. Conclusion Adequate IFX exposure during induction in paediatric IBD patients is associated with significantly better clinical, endoscopic and deep remission rates at month 6. Model-informed precision dosing can assist physicians to achieve optimal exposure during induction more precisely (and rapidly) what is essential for an optimal outcome.

Infliximab trough levels are decreasing over time in patients with inflammatory bowel disease on maintenance treatment with infliximab.

Infliximab trough levels (IFX-TLs) and antibodies to infliximab (ATIs) have been suggested as useful markers for the optimization of treatment in inflammatory bowel disease (IBD). We aimed to estimate the patterns over time of IFX-TLs and ATIs in IBD patients on maintenance treatment with IFX. Two different measurements of IFX-TLs and ATIs were performed (ELISA; Eagle BioSciences) at a 10-month interval using serum samples of consecutive patients on maintenance treatment with IFX. Certain biomarkers [hemoglobin, erythrocyte sedimentation rate, C-reactive protein (CRP), platelets, albumin] measured at the same time as well as clinical disease activity and quality of life were assessed. Among a total of 86 IBD patients under maintenance treatment with IFX, 64 [49 Crohn's disease, 15 ulcerative colitis (UC), 42 men, mean age 44.2±15.2 years, 41 in combination therapy with immunomodulator, six in intensified dose], with two available measurements of IFX-TLs and ATIs (A and B), were included in the study. The median levels of IF-TLs were 5.07 (interquartiles range: 1.60-12.73) μg/ml in measurement A and 4.68 (1.19-7.83) μg/ml in measurement B (P<0.0001). Patients whose dose was intensified after the first measurement showed an increase in their median IFX-TLs from 1.47 to 8.5 μg/ml, whereas patients with stable IFX dose showed a significant reduction in the median IFX-TLs from 5.65 to 3.8 μg/ml (P<0.0001). In the logistic regression analysis, the decrease in IFX-TL was correlated significantly and independently with the increase in CRP [odds ratio 5.2 (1.4-19.0), P=0.01]. IBD patients on maintenance treatment with IFX show decreasing patterns of IFX-TLs over time associated with increasing patterns of CRP levels.

P447 Infliximab trough levels are decreasing overtime in patients with inflammatory bowel disease on maintenance treatment with infliximab

The measurement of infliximab trough levels (IFX-TLs) and antibodies to infliximab (ATIs) has been suggested as an important parameter for the optimisation of treatment in patients with inflammatory bowel disease (IBD). We aimed to estimate the patterns overtime of IFX-TLs and ATIs in IBD patients on maintenance treatment with IFX. Consecutive patients on maintenance treatment with IFX were included. Two different measurements of IFX-TLs και ATIs were made (ELISA, Eagle BioSciences) with a 10-month interval using serum samples drained before IFX infusion. From the same samples certain biomarkers (haemoglobin, ESR, CRP, platelets, albumin) were measured and at the same time quality of life (SIBDQ) and clinical disease activity [Harvey-Bradshaw index (HBI) for Crohn’s disease (CD), simple colitis activity index (SCAI) for ulcerative colitis (UC)] were assessed. Among a total of 86 IBD patients under maintenance treatment with IFX, 64 [49 CD, 15 UC, 42 men, mean age 44.2 ± 15.2 years, 41 in combination therapy with immunomodulator, 6 in intensified dose], with two available measurements (A and B) of IFX-TLs and ATIs were included. Forty-seven patients (73.4 %, 2 after dose de-escalation) had lower IFX-TLs in measurement B compared with A. Median levels of IF-TLs were 5.07 (IQR 1.60–12.73) μg/ml in measurement A and 4.68 (1.19–7.83) μg/ml in measurement B (p < 0.0001). Patients whose dose was intensified after the first measurement increased their median IFX-TLs from 1.47 to 8.5 μg/ml, whereas patients with stable IFX dose showed a significant reduction (from 5.65 to 3.8 μg/ml, p < 0.0001). Six IBD patients (9.4%) had positive ATIs (>10 AU/ml) in measurement A 4 of which were neutralised in measurement B (2 after dose intensification), while ATIs were positive in two patients at measurement B although they were negative at the initial one. Regarding the biomarkers only CRP levels were significantly increased in measurement B compared with measurement A [0.33 (03–4.4) mg/dl vs. 0.31 (0.3–3.8) mg/dl, p = 0.02]. No significant differences in the two measurements of the other biomarkers, clinical activity indices and SIBDQ were found. The reduction of IFX-TLs among the two measurements was significantly correlated with the increase of CRP levels (r = 0.29, p = 0.02). No other correlations of the examined parameters including the use of immunomodulators was found (all p > 0.05). IBD patients on maintenance treatment with infliximab show decreasing patterns of IFX-TLs overtime associated with increasing CRP levels. These results probably provide an underlying mechanism for the known loss of efficacy of IFX in many patients and suggest the need for early treatment optimisation.

Infliximab trough levels and persistent vs transient antibodies measured early after induction predict long-term clinical remission in patients with inflammatory bowel disease

BackgroundThe use of therapeutic drug monitoring has been proposed as a useful tool in the management of patients with loss of response to biological therapy in patients with inflammatory bowel disease. AimsTo evaluate whether early, post-induction anti-tumor necrosis factor trough levels and the presence of different types of anti-drug antibodies may impact long-term clinical remission in patients with inflammatory bowel disease. MethodsWe prospectively assessed anti-tumor necrosis factor trough levels and both persistent and transient anti-drug antibodies. The Harvey–Bradshaw Index and the partial Mayo score were evaluated at each visit or in case of relapse. ResultsAt week 14, median infliximab trough levels were significantly lower in patients who experienced loss of response at week 48 as compared to patients in stable remission (1.3mcg/mL [range 0–10.2mcg/mL] vs. 10.1mcg/mL[range 0–42.8mcg/mL], P<0.0004). ROC curve identified an infliximab trough levels of 6.2mcg/mL as the cut-off value with the highest accuracy (c-index=0.864) for loss of response at week 48. At week 14 we observed a correlation between anti-drug antibodies concentration and infliximab trough levels (rs=−0.513, P=0.04). ConclusionsThe results highlight the usefulness of assessing early biological TL in order to predict patients’ long-term outcome.

Infliximab Trough Levels at Induction to Predict Treatment Failure During Maintenance.

Infliximab (IFX) is indicated for the treatment of inflammatory bowel diseases (IBD). Nevertheless, loss of response (LOR) to IFX is reported in up to 10% to 30% of patients within the first year of treatment. Our objective was to evaluate the impact of the pharmacokinetics of IFX at induction on treatment failure. This is a longitudinal cohort study on 269 patients with IBD treated with IFX in a single center. A total of 2331 blood samples were prospectively collected from 2007 until March 2015 with a retrospective analysis of clinical data. IFX trough levels (TLs) were measured by enzyme-linked immunosorbent assay. Antibodies to IFX were measured by drug-sensitive bridging assay. During follow-up, patients were defined according to treatment outcome. At week 6, median IFX TL in patients requiring a switch to another treatment due to LOR (LOR switched group) (2.32 μg/mL [0.12-19.93 μg/mL]) was lower than in patients with long-term response (long-term responders) (8.66 μg/mL [0.12-12.09 μg/mL], P = 0.007) and in patients responding to optimization (LOR optimized group) (7.28 μg/mL [0.17-14.91 μg/mL], P = 0.021). At week 2, median IFX TL was lower in the LOR switched group (5.7 μg/mL [0.15-12.09 μg/mL]) compared with the long-term responders (11.92 μg/mL [0.14-19.93 μg/mL], P = 0.041) but no significant difference was reached with the LOR optimized group (11.91 μg/mL [0.23-12.09 μg/mL], P = 0.065). In the LOR switched group, median IFX TL at induction (weeks 2 and 6) was significantly lower when patients had been previously exposed to anti-tumor necrosis factor compared with naive patients (0.91 μg/mL [0.12-4.4 μg/mL] versus 6.6 μg/mL [0.15-19.93 μg/mL], P = 0.044). This study suggests that patients who do not respond to any optimization strategy have lower IFX TLs during induction at week 6. IFX TLs measured early on at induction might predict treatment failure to IFX during maintenance.

Clinical correlations of infliximab trough levels and antibodies to infliximab in South Korean patients with Crohn's disease.

AIMTo investigate the clinical implications of infliximab trough levels (IFX-TLs) and antibodies to infliximab (ATI) levels in Crohn’s disease (CD) patients in Asian countries.METHODSIFX-TL and ATI level were measured using prospectively collected samples obtained with informed consent from CD patients being treated at Asan Medical Center, South Korea. We analyzed the correlations between IFX-TLs/ATI levels and the clinical activity of CD (quiescent vs active disease) based on the CD activity index, C-reactive protein level, and physician’s judgment of patients’ clinical status at enrollment. The impact of concomitant immunomodulators was also investigated.RESULTSThis study enrolled 138 patients with CD (84 with quiescent and 54 with active disease). In patients with quiescent and active diseases, the median IFX-TLs were 1.423 μg/mL and 0.163 μg/mL, respectively (P < 0.001) and the median ATI levels were 8.064 AU/mL and 11.209 AU/mL, respectively (P < 0.001). In the ATI-negative and -positive groups, the median IFX-TLs were 1.415 μg/mL and 0.141 μg/mL, respectively (P < 0.001). In patients with and without concomitant immunomodulator use, there were no differences in IFX-TLs (0.632 μg/mL and 1.150 μg/mL, respectively; P = 0.274) or ATI levels (8.655 AU/mL and 9.017 AU/mL, respectively; P = 0.083).CONCLUSIONIFX-TL/ATI levels were well correlated with the clinical activity in South Korean CD patients. Our findings support the usefulness of IFX-TLs/ATI levels in treating CD patients receiving IFX in clinical practice.

P-012 YI Decisions to Dose Optimize Infliximab Using Pre-adjustment Therapeutic Drug Monitoring Result in Higher Trough Concentrations and Improved Endoscopic Outcomes

Increasingly, adequate infliximab (IFX) dosing is associated with improved outcomes in inflammatory bowel disease (IBD). Individualized therapeutic drug monitoring (TDM) to guide dose adjustment is cost-effective may offer clinical improvement. However, the effect of TDM-guided dose escalation on subsequent endoscopic outcomes remains unclear. We retrospectively evaluated the impact of TDM-driven dose adjustment on endoscopic remission. Data from primary responders to IFX who underwent dose escalation between 2008 and 2014 (interval reduction, dose increase or both) were reviewed. Patients with documented active endoscopic disease (ileal or colonic) <3 months prior to dose adjustment were included. 2 cohorts were examined: those with TDM-based decision to escalate and those with empiric decision. Outcomes recorded at median 6 months post- adjustment included endoscopic remission (Mayo <1, SES-CD <3), CRP, clinical remission and IBD-specific healthcare utilization (emergency visits, hospitalizations, steroid use, flares). TDM was performed using a homogenous mobility shift assay. Post-adjustment IFX and ATI concentration most discriminant for endoscopic remission were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission. Three hundred twelve dose optimization events were examined (149 TDM –based decision, 163 empiric). Patient demographics were not significantly different between groups apart from CRP ([mean ± SE] TDM: 23 ± 1.2; non-TDM: 11 ± 0.8 mg/L, P < 0.01). 63% of TDM group attained endoscopic remission compared to 48% non-TDM group (P < 0.05). 69% of the TDM group had significant clinical response compared to 57% non-TDM (P < 0.01) and also had fewer hospitalizations including ED visits (22% TDM versus 35% non-TDM group, P = 0.025). UC patients had a shorter time to optimization from first infusion (10 versus 20 months, P < 0.0001) and in the TDM group, had higher rates of endoscopic healing (64% compared to 46% CD) though this was not statistically significant. Median IFX trough levels increased significantly after TDM- based adjustment (from 1.5(pre) to 11 μg/mL (post); P < 0.0001) and were significantly higher than post-adjustment levels available in the empiric cohort (6.5 μg/mL, P = 0.015). Post-adjustment infliximab concentration of >4.5 μg/mL (area under the curve (AUC) = 0.8; 95% CI 0.71 to 0.88) and ATI concentration of <2.3 U/mL (AUC = 0.70; 95% CI 0.63 to 0.81) were associated with endoscopic remission. Multivariable analysis showed that IFX concentration (OR 1.2; [95% CI 1.1–1.3]; P < 0.0001) remained an independent predictor of endoscopic remission. TDM -guided dose adjustment is associated with higher post-adjustment trough levels, fewer ATI and in turn, higher endoscopic remission rates and fewer relapses.

The association of infliximab trough levels with disease activity in pediatric inflammatory bowel disease

Objective. Low serum trough levels (TLs) of infliximab (IFX) and antibodies to IFX (ATIs) are associated with the loss of therapeutic response in adults with inflammatory bowel disease (IBD) receiving IFX. Until now, pediatric data are scarce. Therefore, we aimed to cross-sectionally investigate the association between ATIs and IFX TLs, and clinical and biochemical disease activity in children receiving IFX for IBD. Material and methods. Children aged <18 years receiving IFX maintenance treatment for Crohn’s disease (CD) or ulcerative colitis (UC) at three Dutch hospitals were included. Prior to two consecutive IFX infusions, IFX TLs and ATI levels were measured. Clinical disease activity was determined by Pediatric Crohn’s Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI), for CD and UC, respectively. Biochemical disease activity was assessed by serum C-reactive protein (CRP) and fecal calprotectin (FC). Clinical remission was defined as a PUCAI or PCDAI score of <10. Therapeutic range of IFX was considered 3–7 µg/ml. Results. Thirty-nine patients were included (31 CD; 16 females). Median age was 15 years. Median IFX TL was 3.5 µg/ml [IQR 2–7]. Subtherapeutic and supratherapeutic TLs were found in 38% and 23% of children, respectively. ATIs were detected in four patients. A correlation was found between IFX TL and CRP [rs = −0.51; p < 0.01] and FC [rs = −0.49; p < 0.01]. However, when only clinical disease activity was considered, no difference in median TL was found between remission and active disease (resp. 3.5 µg/ml [IQR 2–5] and 2.3 µg/ml [IQR 0.3–4.6]; p = 0.2). Conclusions. IFX TLs are related to biochemical markers of disease activity. This could provide a rationale for monitoring TLs in children receiving IFX for IBD.

Knowledge of Fecal Calprotectin and Infliximab Trough Levels Alters Clinical Decision-making for IBD Outpatients on Maintenance Infliximab Therapy.

Infliximab is an effective therapy for inflammatory bowel disease (IBD). However, more than 50% of patients lose response. Empiric dose intensification is not effective for all patients because not all patients have objective disease activity or subtherapeutic drug level. The aim was to determine how an objective marker of disease activity or therapeutic drug monitoring affects clinical decisions regarding maintenance infliximab therapy in outpatients with IBD. Consecutive patients with IBD on maintenance infliximab therapy were invited to participate by providing preinfusion stool and blood samples. Fecal calprotectin (FCP) and infliximab trough levels (ITLs) were measured by enzyme linked immunosorbent assay. Three decisions were compared: (1) actual clinical decision, (2) algorithmic FCP or ITL decisions, and (3) expert panel decision based on (a) clinical data, (b) clinical data plus FCP, and (c) clinical data plus FCP plus ITL. In secondary analysis, Receiver-operating curves were used to assess the ability of FCP and ITL in predicting clinical disease activity or remission. A total of 36 sets of blood and stool were available for analysis; median FCP 191.5 μg/g, median ITLs 7.3 μg/mL. The actual clinical decision differed from the hypothetical decision in 47.2% (FCP algorithm); 69.4% (ITL algorithm); 25.0% (expert panel clinical decision); 44.4% (expert panel clinical plus FCP); 58.3% (expert panel clinical plus FCP plus ITL) cases. FCP predicted clinical relapse (area under the curve [AUC] = 0.417; 95% confidence interval [CI], 0.197-0.641) and subtherapeutic ITL (AUC = 0.774; 95% CI, 0.536-1.000). ITL predicted clinical remission (AUC = 0.498; 95% CI, 0.254-0.742) and objective remission (AUC = 0.773; 95% CI, 0.622-0.924). Using FCP and ITLs in addition to clinical data results in an increased number of decisions to optimize management in outpatients with IBD on stable maintenance infliximab therapy.