What Is Known
- Loss of response to anti-tumor necrosis factor is a big concern in inflammatory bowel disease management and especially among pediatric patients in whom treatment options are limited.
- Therapeutic drug monitoring has been recommended in order to optimize the long-term outcome, however these approaches consider only adaptations during the maintenance phase of the treatment.
What Is New
- Adequate infliximab exposure during induction therapy is essential for a long and durable clinical and/or biological remission.
- Patients with a lower weight and hemoglobin level are especially at risk for lower infliximab trough levels and may benefit from higher infliximab doses.
Infliximab (IFX), a chimeric monoclonal antibody directed against tumor necrosis factor alpha, greatly improved the outcome of children with inflammatory bowel disease (IBD) (1–5). Despite its excellent efficacy in induction as well as maintenance of remission, a proportion of IBD patients who initially respond to IFX will lose response over time (6–8). One of the main reasons for loss of response is the immunogenicity of the drug and altered pharmacokinetic profile of patients. Recent studies have shown that earlier introduction of IFX (9–11) and the use of combination therapy can improve long-term outcome (12). While, the predictive value of other factors (younger age (13,14), extensive disease (14,15) and higher inflammatory burden (16)) and their relative contribution to each other are poorly investigated in children.
Therapeutic drug monitoring (TDM) has been recommended to optimize the long-term outcome of IFX (17,18). Although reactive TDM is well implemented in current IBD management, the role of proactive TDM is still under investigation. Most of the TDM approaches consider solely adaptations during the maintenance phase of the treatment (19–27). Only limited data are available on IFX exposure during induction and the impact on long-term outcomes in children (28). Data from adult literature suggest that adequate drug exposure during induction is essential for a favorable long-term outcome (29–35).
We hypothesized that IFX trough levels measured immediately after induction therapy at first trough are predictive for IFX efficacy at week 52 in pediatric patients with IBD. We also explored if other clinical or biological parameters influenced long-term outcomes in children.
Patients and Study Design
The study population originated from all children age younger than 18 years with Crohn disease (CD) or ulcerative colitis (UC) receiving maintenance IFX therapy for active luminal disease at our center between May 2012 and May 2018. Only patients with IFX trough levels available at first maintenance infusion and a follow-up of at least 52 weeks after IFX initiation were included retrospectively.
Patients were treated with standard intravenous IFX 5 mg/kg at weeks 0, 2, and 6, although infusions could be intensified at the discretion of the treating physician based on disease severity and not on drug concentration. Only patients with evidence of response continued maintenance treatment and were included in the study. Primary nonresponders to IFX were defined as patients with a decrease in Paediatric Crohn Disease Activity Index (PCDAI) <12.5 for patients with CD (36) and a decrease in Paediatric Ulcerative Colitis Activity Index (PUCAI) <20 points for patients with UC (37) and this in association with therapeutic IFX trough levels (>3 μg/mL) just before 4th IFX dose (38,39). All children received standard proactive drug monitoring during maintenance treatment and dose adaptations were made aiming to target a therapeutic window between 3 and 7 μg/mL (conform adult studies (40)). This is explained in Supplemental Digital Content 1 (https://links.lww.com/MPG/B557). The Ethical Committee of our university hospital approved the study (Approval No: S59870, April 10, 2017).
Baseline patient characteristics were prospectively registered and retrieved from electronic medical records. These included age, sex, IBD type, Paris classification at diagnosis, comorbidity, and concomitant treatment. At each patient visit, disease activity was recorded using PCDAI for CD (36) and the PUCAI for UC (37). IFX doses and intervals were recorded along with patients’ biometrics (body weight and height) and age.
Standard laboratory tests were measured prior to each IFX infusion and included hemoglobin, platelet count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, and serum IFX trough levels. The latter were determined by Ridascreen IFX monitoring enzyme-linked immunosorbent assay (R-Biopharm, Darmstadt, Germany), which has a lower limit of quantification of 0.3 μg/mL and a higher limit of quantification of 12 μg/mL using a 1/100 serum dilution. Anti-IFX antibodies (ATI) were determined by an in house developed drug sensitive anti-IFX bridging assay (41).
Endoscopic evaluation was performed only in a subset of patients and at varying time points. We included the first available endoscopic evaluation beyond 1 year of IFX therapy (as this would best reflect the long-term IFX efficacy). If this endoscopic outcome was, however, not available, then the endoscopic evaluation between 6 and 12 months after IFX initiation was used. Endoscopic evaluation was performed in case of disease flare or to evaluate mucosal healing typically 6 and 12 months after starting IFX therapy.
Primary outcome was evaluated at week 52 after IFX initiation for clinical and biological remission. Clinical remission was defined as a PCDAI/PUCAI <10 (42,43). Biological remission was defined as CRP ≤5 mg/L in combination with an ESR ≤20 mm/h, in patients with elevated inflammatory markers at start of IFX therapy (19). Patients were considered in combined clinical and biological remission if both criteria were met. Endoscopic remission was evaluated at heterogeneous time points and was defined as absence of ulcerations (19,44). For patients with CD, endoscopic remission was assessed by both gastroscopy and ileocolonoscopy, whereas for UC patients it could be either sigmoidoscopy or colonoscopy. If these strict criteria were not met, the patients were considered to have lack of response.
IBM SPSS 25.0 software (SPSS Inc, Chicago, IL) was used to perform all statistical analyses. Continuous variables are presented as medians with interquartile ranges (IQRs) and categorical variables as frequencies and percentages. For the univariable analysis of unpaired continuous variables, an independent 2-group Mann-Whitney U test was used and for paired continuous variables, a Wilcoxon signed rank test. To quantify correlation, the Spearman rank correlation coefficient (rs) was calculated. For the univariable analysis of discrete variables, the Fisher exact test or Chi-square test was used where appropriate. Receiver operating characteristics (ROC) analysis was used to define the optimal cut-off value for each of the outcomes based on the Youden J statistic. A binary logistic regression analysis was performed to assess associations between predefined outcomes and all studied variables using a backward Wald method. Except for variables with high collinearity (Variance Inflation Factor > 5), only one of these variables was retained in the model. These results are reported as odds ratios and 95% confidence intervals (95% confidence interval [CI]). P values were calculated 2-tailed and the threshold for significance was set at 0.05.
Eighty-two pediatric patients with IBD received maintenance IFX therapy at our center between May 2012 and 2018. Forty-nine of them were eligible for the study as they had an IFX trough levels at their first maintenance infusion available of which 35 were followed up for at least 52 weeks after IFX initiation. Of the 33 patients without an available trough levels, 19 of them (58%) were already on maintenance therapy before the availability to test these levels in our center and in 4 of them (12%) IFX therapy was started elsewhere. One patient was lost to follow-up and 13 patients are still in their first year of IFX therapy (Fig. 1).
CD was diagnosed in 23 patients (65.7%) and 12 patients (34.3%) had UC. Patient characteristics are displayed in Table 1. Median age at start of IFX therapy was 12.7 years (10.2–14.6), with a median disease duration before starting IFX of 6.0 months (3.0–11.0). Two patients discontinued IFX treatment before week 52 due to loss of response (despite adequate IFX trough levels) and were reported as treatment failures at week 52 (5.7%).
Data on Infliximab Trough Concentration and Dosages
First maintenance infusion (5 mg/kg) was started at week 14 in 21 patients (60.0%). By following the standard induction schedule, we uncovered low IFX trough levels at week 14 in most patients. Therefore, in the past year, the start of maintenance therapy was expedited to week 12 instead of 14 to increase these levels and hopefully the long-term outcome. Seven patients of this cohort (20%) were subject to this expedited scheme (with a first maintenance dose of 5 mg/kg). The time point of first maintenance infusion (week 14 or earlier) was taking into account in the further analysis. In addition, induction therapy was intensified based on disease severity in 7 patients (20.0%). A more detailed report can be consulted in Supplemental Table 1 (Supplemental Digital Content 2 https://links.lww.com/MPG/B558). The overall median IFX trough level before the first maintenance infusion was 3.2 μg/mL (2.1–6.0) with subtherapeutic levels (<3 μg/mL) observed in 42.9% of the individuals. Three patients had undetectable levels (<0.3 μg/mL), but no patient had measurable ATIs. These 3 patients started the maintenance phase at week 14. Six patients (17.1%) had levels above the limit of quantification.
Predictive Value of Postinduction Infliximab Trough Level
Clinical remission was achieved in 24 of 35 patients at week 52 (68.6%). The median IFX trough level at first maintenance infusion was significantly higher in children who were in clinical remission at week 52 (4.6 μg/mL [2.7–11.8]) versus those who were not (1.5 μg/mL [0.9–3.0], P = 0.001; Fig. 2).
Biological remission was reported in 20 of 31 patients at week 52 (64.5%). Median IFX trough level at first maintenance infusion was significantly higher in children who were in biological remission (4.6 μg/mL [2.5–10.3]) at week 52 versus those who were not (2.6 μg/mL [0.3–3.2], P = 0.002; Fig. 2). Early normalization of baseline biomarkers (time between IFX initiation and moment of CRP and ESR normalization) correlated well with the postinduction trough levels (rs = −0.493; P = 0.005).
A total of 18 of 35 patients were in combined clinical and biological remission at week 52 (51.4%). Median IFX trough level at first maintenance infusion was significantly higher in this subgroup (6.0 μg/mL [3.2–12.0]) compared with children who did not achieve this endpoint (2.6 μg/mL [1.1–3.2], P < 0.0001; Fig. 2).
Endoscopic evaluation was performed in 32 of 35 patients (91.4%) with a median duration on IFX therapy before endoscopy of 14.0 months (7.5–18.2). Median IFX trough level at first maintenance infusion was significantly higher in patients achieving endoscopic remission (3.6 μg/mL [2.4–12.0]) compared with children who did not (2.2 μg/mL [0.3–3.9], P = 0.039; Fig. 3).
An ROC analysis was performed to determine the threshold of these postinduction trough levels that best predicts remission (see Suppl Fig. 1, Supplemental Digital Content 3 https://links.lww.com/MPG/B559). The best area under the ROC curve for IFX trough level was seen for combined clinical and biological remission (0.856 [95% CI: 0.731–0.982]). This resulted in an optimal cut-off level for IFX trough concentration of 4.6 μg/mL with a sensitivity of 66.7% and a specificity of 100% (positive predictive value of 100.0% and negative predictive value of 73.9%).
Impact of Other Covariates on Infliximab Efficacy at Week 52
Demographic covariates (body weight, height, body mass index, body surface area [BSA], age, disease severity, sex, IBD subtype, and concomitant immunosuppression use) and blood chemistry covariates (CRP, ESR, albumin level, hemoglobin, and platelet count) at start of IFX therapy, in addition time of the first maintenance infusion (week 14 or earlier) and the IFX trough level before first maintenance infusion were considered as potential factors to influence outcomes at week 52. Binary logistic regression identified only IFX trough level as independent predictor for clinical and/or biological remission with an odds ratio of 2.083 (95% CI: 1.085–3.998; P = 0.027); 2.203 (95% CI: 1.101–4.408; P = 0.026) and 2.264 (95% CI: 1.096–4.680; P = 0.027), respectively. This was not the case for endoscopic remission, in which only body weight was identified as an independent predictor for mucosal healing with an odds ratio of 1.123 (95% CI: 1.025–1.232; P = 0.013).
No significant difference in clinical outcome at week 52 was found based on disease severity (PCDAI: P = 0.213 and or PUCAI: P = 0.209) and biomarkers of inflammation (CRP: P = 0.847, ESR: P = 0.472 and albumin: P = 0.334) at start of IFX therapy or other patients’ characteristics (see Suppl Table 2, Supplemental Digital Content 4 https://links.lww.com/MPG/B560), including age of the patient. Patients with a lower weight (46.1 kg [32.6–60.8] vs 31.5 kg [24.2–49.7], P = 0.030), height (162.7 cm [150.5–172.2] vs 136.5 cm [124.6–157.0], P = 0.005), and BSA (1.435 m2 [1.153–1.715] vs 1.090 m2 [0.920–1.500], P = 0.027) at start of IFX therapy were, however, more likely to have a worse clinical outcome. The median standardized IFX dose that was administered during the total maintenance phase was significantly lower in patients with clinical remission at week 52 (7.4 mg/kg [5.0–9.6]) compared to lack of responders (10.0 mg/kg [8.0–20.0], P = 0.025).
Correlation Between Infliximab Trough Levels at First Maintenance Infusion and Potential Covariates
On univariate analysis, the same covariates, collected at week 0 (start of IFX treatment) and at start of maintenance therapy, were considered as potential factors to influence IFX trough levels at first maintenance infusion. At week 0, weight (rs = 0.341; P = 0.045), BSA (rs = 0.341; P = 0.045), and hemoglobin (rs = 0.340; P = 0.045) were significantly correlated with these IFX trough levels. At start of maintenance, biometrics of patients (weight [rs = 0.355; P = 0.037] and BSA [rs = 0.373; P = 0.028]) and biomarkers of inflammation (CRP [rs = −0.609; P < 0.0001], ESR [rs = −0.519; P = 0.001], albumin [rs = 0.335; P = 0.049], hemoglobin [rs = 0.524; P = 0.001], and platelet count [rs = −0.447; P = 0.007]) were significantly associated with these IFX trough levels. Interestingly, no difference in median IFX trough levels at start of maintenance therapy was seen in patients on mono- versus combo-therapy with immunosuppressants (3.8 μg/mL [2.4–5.9] vs 3.1 μg/mL [1.5–9.8], P = 0.517).
The present study assessed the impact of postinduction IFX trough levels and other variables on the long-term outcome to IFX in pediatric patients with IBD.
We showed that patients achieving clinical and/or biological remission at week 52 already demonstrated significantly higher IFX trough levels at start of maintenance therapy. Similar results were found for endoscopic remission, although performed at heterogeneous time points. In fact, these IFX trough levels were the only independent predictor for clinical and/or biological remission. No other factors such as concomitant immunosuppression, disease severity or biomarkers of inflammation at baseline were found to have an impact on the 1-year outcome.
Our data underscore the fact that adequate drug exposure during induction therapy is essential for a long and durable remission. Our results confirm those of a prospective study in 46 patients with IBD (81% CD) younger than 21 years of age reported by Singh et al (28), where IFX trough levels at week 14 together with CRP levels, predicted clinical remission at week 54. In the former study, the median CRP levels at baseline were significantly lower in patients with persistent clinical remission at week 54. Patients with higher CRP levels and therefore probably also higher disease burden are more likely to have lower IFX trough levels, as the inflamed tissue acts as a sink for anti-tumor necrosis factor (45). In our study, no difference was found in baseline disease burden between patients who achieved clinical remission and lack of response and still postinduction levels remained the sole predictor for remission at week 52. In addition, Stein et al (46) reported higher IFX levels at week 10 in patients who were still on IFX therapy at 1 year compared to patients not able to sustain this therapy. However, 30% of the patients continuing on IFX had still active disease making the primary outcome in this study different from our study (namely clinical remission). Finally, our data lend support to previous adult studies that examined predictors of long-term outcome. Most of these studies set the minimal threshold for postinduction IFX trough levels at least >3.0 μg/mL (29–33). In our study, a postinduction IFX trough level of 4.6 μg/mL was identified as the minimal target to achieve combined clinical and biological remission, with a sensitivity of 66.7% and specificity of 100%.
We uncovered as many as 42.9% of patients with an IFX trough levels <3.0 μg/mL at first maintenance infusion. Therefore, identifying covariates at baseline that influence postinduction IFX trough levels are of utmost importance to improve outcome. We identified weight, BSA, and hemoglobin to be significantly associated with these levels. Patients with lower body weight are probably more likely to have lower IFX levels because of the nonlinear association between body weight and volume of distribution in the peripheral compartment (47). Low hemoglobin levels are probably a surrogate marker for more severe disease with a leaky gut. It has been shown previously in adults that lower hemoglobin levels at the start of IFX therapy were a predictor of primary nonresponse (48,49).
Therefore, patients with a lower weight and hemoglobin would probably benefit from higher IFX doses and a more rigorous TDM approach. Especially since patients with a lower weight at start of IFX therapy were more likely to have a worse clinical outcome at week 52 and weight was the only independent predictor for mucosal healing. Hence, appropriated weight-based cut-off dosing schemes should be determined and validated to improve long-term outcome.
The strength of our study is that we could investigate the impact of multiple variables on the long-term IFX efficacy in a well phenotyped cohort, although this cohort was relatively heterogeneous and small of sample size. In addition, the induction scheme could be intensified based on disease severity and time of start of maintenance infusion differs among patients. A more uniform induction scheme might lead to the identification of other covariates (eg, disease severity) influencing the IFX trough levels. Nevertheless, we believe that a more personalized medicine is necessary when dealing with this vulnerable population based on the knowledge of the pharmacokinetics of IFX (40). Hence, our policy has changed during the years by expediting the maintenance phase (at week 12) and in case of higher disease burden by intensifying the induction scheme, although these strategies are not validated. Thirdly, due to the retrospective design of the study, endoscopy was performed only in a subset of patients and at varying time points. By still including this hard endpoint we can, however, strengthen our results.
Prospective studies are now warranted to assess the usefulness of early TDM and dose adaptation based on these postinduction serum levels and other baseline characteristics (ie, weight) in predicting the long-term efficacy of IFX.
Paediatric patients with IBD with adequate exposure during induction therapy have a better chance for clinical and/or biological remission at week 52. Patients with a lower weight and hemoglobin level are especially at risk for lower IFX trough levels and may benefit from higher IFX doses and a more rigorous TDM approach.
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