Abstract
OBJECTIVES:
There are only limited data regarding the role of therapeutic drug monitoring in fistulizing Crohn’s disease (CD). We investigated the association between both induction and maintenance serum infliximab concentrations and favorable therapeutic outcomes in patients with fistulizing CD.
METHODS:
This was a post-hoc analysis of the ACCENT-II trial evaluating patients with fistulizing CD receiving induction (n=282) and maintenance infliximab therapy (n=139). Investigated therapeutic outcomes at both week 14 and week 54 included fistula response, complete fistula response, C-reactive protein (CRP) normalization (≤5 mg/L) in patients with an elevated baseline CRP and a more stringent outcome of composite remission, defined as combined complete fistula response and CRP normalization. Associations between serum infliximab concentrations and outcomes were assessed by multivariable logistic regression models.
RESULTS:
Higher week 14 infliximab concentrations were independently associated with week 14 fistula response [odds ratio (OR): 1.16; 95% confidence interval (CI): 1.02-1.32; p=0.019], and composite remission (OR: 2.32; 95%CI: 1.55-3.49; p<0.001). Higher week 14 infliximab concentrations were also independently associated with week 54 composite remission (OR: 2.05; 95%CI: 1.10-3.82; p=0.023). Based on receiver operating characteristic curve analysis, week 14 infliximab concentrations thresholds with combined maximal sensitivity and specificity of ≥20.2 μg/mL at week 2, ≥15 μg/mL at week 6, and ≥7.2 μg/mL at week 14 were associated with week 14 composite remission.
CONCLUSIONS:
Higher post-induction infliximab concentrations are associated with early and long-term favorable therapeutic outcomes in patients with fistulizing CD.
Keywords: infliximab, fistulizing Crohn’s disease, perianal fistulas, therapeutic drug monitoring, drug concentrations
INTRODUCTION
Fistulas, particularly perianal, develop in a significant number of patients with Crohn’s disease (CD) and are associated with poor long-term prognosis.1–3 In a recent population-based inception cohort of CD, one-fifth of patients were diagnosed with at least one perianal or rectovaginal fistula.2 These complications lead to impaired quality of life and an increased rate of hospitalizations and surgeries.1 Treatment of fistulizing CD is challenging and necessitates a multidisciplinary approach of both pharmacological and surgical therapy.4–7 The cornerstone of pharmacological therapy is anti-tumor necrosis factor (anti-TNF) therapy, specifically infliximab.8–13 The pivotal randomized-controlled trial (RCT) ACCENT-II [A Randomized, Double-blind, Placebo-controlled Trial of Anti-TNFα Chimeric Monoclonal Antibody (Infliximab, REMICADE®) in the Long-term Treatment of Patients with Fistulizing Crohn’s Disease] demonstrated superior healing rates after induction and maintenance infliximab treatment when compared to placebo.13
Unfortunately, even with infliximab there is a significant rate of primary non-response and secondary loss of response.12, 13 These negative outcomes may be related to increased drug clearance and inadequate exposure to drug.14 Several studies suggest that early drug exposure is associated with both early and long-term outcomes in CD.15–17 As pharmacological treatment options in patients with fistulizing CD are limited, emphasis should be given to rational decision-making and prevention of treatment failure and drug discontinuation.18–20 It is possible that improved fistula healing rates may be achieved by utilizing an early proactive therapeutic drug monitoring-based approach for optimization of anti-TNF therapy.21
Several exposure-response relationship studies demonstrate a positive correlation between serum anti-TNF drug concentrations and favorable objective therapeutic outcomes in inflammatory bowel disease.22–25 Most studies suggest that higher drug concentrations are associated with more objective and stringent outcomes.23 In particular, higher drug concentrations appear to be associated with fistulizing CD.26 However, these association data come mostly from small retrospective studies that included patients on maintenance infliximab therapy.26–30.
We aimed to investigate the association between both induction and maintenance infliximab serum concentrations and favorable therapeutic outcomes using the ACCENT-II patient population.
MATERIAL AND METHODS
Study design and outcomes
This was a post-hoc analysis of the ACCENT-II RCT.13 This was a multi-center, randomized, double-blind trial. The first patient was enrolled on January 21, 2000, and the last completed visit occurred on October 17, 2001. Eligible patients included men and women (patients 18 years of age or older) with CD who had had single or multiple draining fistulas, including perianal fistulas and enterocutaneous fistulas. for at least three months. Women with rectovaginal fistulas were included if they had at least one other enterocutaneous draining fistula. Setons were permitted at screening but were required to be removed by week 2. Concurrent therapies for CD, including stable doses of 5-aminosalicylates, oral corticosteroids, azathioprine, mercaptopurine, mycophenolate mofetil, methotrexate, and antibiotics, were permitted. Patients were excluded from the study if they had a stricture or abscess for which surgery might be indicated or if they had previously been treated with infliximab. All eligible patients received an intravenous infusion of infliximab at a dose of 5 mg/kg at weeks 0, 2, and 6. At week 14, those with a response were randomly assigned to receive an infusion of either placebo 5 mg/kg of infliximab at weeks 14, 22, 30, 38, and 46 and were followed until week 54. Patients without a response were also randomly assigned to a maintenance regimen of either placebo or infliximab to permit a secondary analysis of the proportion of patients who had a response to continued treatment after having had no response to the initial treatment. Beginning at week 22, patients receiving placebo maintenance who had a loss of response were eligible to cross over to maintenance treatment with 5 mg/kg of infliximab, and patients in the infliximab maintenance group could cross over to treatment with 10 mg/kg of infliximab.
Serum infliximab concentrations were measured with a sandwich enzyme immunoassay (Charles River Laboratories, Inc (formerly Tektagen, Inc), Wilmington, Massachusetts, USA). Antibodies to infliximab (ATI) were measured with a double-antigen ELISA (Janssen Biotech, Inc (formerly Centocor, Inc), Malvern, Pennsylvania, USA) at weeks 14, 30, and 54.
Investigated therapeutic outcomes included fistula response, defined as a reduction of at least 50% of draining fistulas from baseline, complete fistula response, defined as absence of draining fistulas, CRP normalization in patients with an elevated baseline CRP of >0.5 mg/dL and composite remission, defined as a combined complete fistula response and CRP normalization and were assessed both early (at week 14) and at long-term (at week 54).
This study, carried out under YODA Project # 2017-1276, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH & DEVELOPMENT, L.L.C. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH & DEVELOPMENT, L.L.C. This research was done without patient or public involvement.
Statistical analysis
Descriptive statistics were provided with medians and interquartile range for continuous variables and frequencies and percentages for categorical variables. Receiver-operating characteristic (ROC) curve analysis was performed to identify infliximab concentration thresholds associated with the investigated therapeutic outcomes. Optimal thresholds were chosen using the Youden index, which is the point with highest sum of the specificity and sensitivity along the ROC curve. Sensitivity, specificity, positive predictive value and negative predictive value were also calculated. Infliximab concentrations were compared between the patients who achieved and those who did not achieve the therapeutic outcomes with a 2-sided Wilcoxon–Mann–Whitney 2-sample rank-sum test. Serum infliximab concentrations were also categorized into quartiles. Proportions of investigated therapeutic outcomes were compared across infliximab trough concentration quartiles using the Fisher exact test.
To determine the independent effects of variables associated with the investigated therapeutic outcomes, univariable and multivariable logistic regression analysis was performed. Multivariable logistic regression analysis with backward elimination method was used to select the significant variables from univariable analysis with the p-value less than 0.1. Results were considered statistically significant when p value <0.05. All statistical analyses were performed using the R studio software (version 1.1.456) and GraphPad Prism (version 5.03) for Windows (GraphPad Software, San Diego CA, USA).
RESULTS
Study population
The study population consisted of 282 patients [male, n=144 (51.1%)] with active fistulizing CD who received induction infliximab therapy at a dose of 5 mg/kg at weeks 0, 2, and 6 and were evaluated at week 14. Most patients had perianal fistulizing CD (n=246, 87.2%) and 160 patients (56.7%) had more than one draining fistulas. Patients’ demographic and clinical characteristics are depicted in Table 1. A subgroup of these patients (n=139) received also infliximab maintenance therapy and were evaluated for long-term therapeutic outcomes assessed at week 54. Thirty-five out of the 139 (25.2%) patients were dose escalated to 10 mg/kg due to loss of response.
Table 1:
Baseline characteristics of the patients.
| Patients’ characteristics | Total (n=282) |
|---|---|
| Male, (%) | 144 (51.1) |
| Age, median [interquartile range (IQR)], years | 38 (29.5-48) |
| Involved intestinal area, (%) | |
| ileum | 48 (17) |
| colon | 92 (32.6) |
| ileum and colon | 142 (50.4) |
| Previous segmental resection, (%) | 156 (55.3) |
| CRP, median (IQR), mg/dl | 0.7 (0.3-1.9) |
| CRP > 0.5 mg/dl, (%) | 161 (57.1%) |
| Perianal fistula locationa, (%) | 246 (87.2) |
| Draining fistulas >1, (%) | 160 (56.7) |
| Smoking history, (%) | |
| Current smoker | 106 (37.6) |
| Former smoker | 69 (24.5) |
| Nonsmoker | 107 (37.9) |
| IMMb as prior medication (%) | 209 (74.1) |
| Concomitant medication, (%) | |
| Corticosteroids | 81 (28.7) |
| IMMb | 97 (34.4) |
Abdominal fistulas (n=39), rectovaginal fistulas (n=25);
Thiopurines or methotrexate.
CRP: C-reactive protein; IMM: immunomodulators; IQR: interquartile range; CDAI: Crohn’s disease activity index.
Fistula response
Fistula response at week 14 was achieved in 195/282 (69%) of the patients. Serum infliximab concentrations at weeks 2, 6, and 14 were numerically higher in patients with fistula response at week 14 when compared to those without fistula response (Table 2). Higher infliximab concentration quartiles at weeks 6 (Figure 1A) and 14 (Figure 2A) were associated with higher proportions of fistula response at week 14. ROC curve analysis of infliximab concentrations at weeks 2, 6, or 14 associated with fistula response at week 14 is shown in Table 3. In multivariable analysis, infliximab concentration at week 14 was identified as the only variable associated with fistula response at week 14 [Odds ratio (OR): 1.16; 95% confidence interval (CI): 1.02-1.32, p=0.019] (Table 4, supplementary Table 3).
Table 2.
Infliximab concentrations by week 14 therapeutic outcomes status.
| Infliximab concentration time point | Median (IQR) infliximab concentration per week 14 therapeutic outcome | |||
|---|---|---|---|---|
| Achieved, (%) | Not achieved, (%) | p-value | ||
| Week 2 | Fistula response | 25.6 (19.5-34.7) | 24.3 (19.5-31.9) | 0.228 |
| Complete fistula response | 25.8 (21.2-33.1) | 24.3 (18.8-33.5) | 0.240 | |
| CRP normalization | 24.0 (20.3-32.5) | 23.0 (18.1-34.5) | 0.542 | |
| Composite remission | 24.8 (22.1-33.0) | 23.0 (17.7-33.0) | 0.070 | |
| Week 6 | Fistula response | 17.9 (11.3-28.3) | 14.9 (8.3-24.2) | 0.060 |
| Complete fistula response | 18.4 (12.7-27.8) | 15.2 (9.1-26.0) | 0.038 | |
| CRP normalization | 17.5 (11.3-27.6) | 15.1 (7.8-24.1) | 0.225 | |
| Composite remission | 22.3 (16.0-34.7) | 13.9 (7.2-22.7) | 0.001 | |
| Week 14 | Fistula response | 5.7 (2.1-9.0) | 4.0 (1.0-8.4) | 0.050 |
| Complete fistula response | 6.4 (2.3-10.8) | 3.7 (1.5-7.3) | 0.002 | |
| CRP normalization | 5.9 (2.3-11.1) | 3.7 (0.8-7.2) | 0.004 | |
| Composite remission | 9.3 (4.9-16.2) | 3.2 (1.1-7.0) | <0.001 | |
IQR: interquartile range, CRP: C-reactive protein.
Figure 1.
Rates of week 14 therapeutic outcomes by week 6 infliximab concentration quartiles regarding fistula response (A), complete fistula response (B), CRP normalization (C) and composite remission (D).
CRP: C-reactive protein.
Figure 2.
Rates of week 14 therapeutic outcomes by week 14 infliximab concentration quartiles for fistula response (A), complete fistula response (B), CRP normalization (C) and composite remission (D).
CRP: C-reactive protein.
Table 3.
Receiver operating characteristic (ROC) curve analyses of infliximab concentrations by week 14 therapeutic outcomes.
| Week 14 therapeutic outcome | Infliximab concentration time point (week) | Threshold (μg/mL) | SN (%) | SP (%) | PPV (%) | NPV (%) | AUROC (95% CI) | P-value |
|---|---|---|---|---|---|---|---|---|
| Fistula response | 2 | 29.1 | 40 | 72 | 76 | 34 | 0.54 (0.47-0.62) | 0.220 |
| 6 | 10.1 | 80 | 36 | 74 | 45 | 0.57 (0.49-0.64) | 0.068 | |
| 14 | 1.7 | 82 | 36 | 74 | 48 | 0.57 (0.50-0.65) | 0.059 | |
| Complete fistula response | 2 | 21.8 | 73 | 41 | 57 | 60 | 0.54 (0.47-.061) | 0.244 |
| 6 | 15 | 67 | 50 | 59 | 59 | 0.57 (0.51-0.64) | 0.036 | |
| 14 | 6.1 | 52 | 69 | 63 | 58 | 0.61 (0.54-0.68) | 0.001 | |
| CRP normalization | 2 | 20.2 | 76 | 39 | 48 | 69 | 0.53 (0.44-0.62) | 0.534 |
| 6 | 7 | 91 | 24 | 46 | 79 | 0.56 (0.47-0.65) | 0.216 | |
| 14 | 2 | 83 | 42 | 52 | 76 | 0.63 (0.55-0.72) | 0.003 | |
| Composite remission | 2 | 20.2 | 94 | 40 | 30 | 96 | 0.60 (0.51-0.69) | 0.029 |
| 6 | 15 | 83 | 54 | 34 | 92 | 0.68 (0.59-0.77) | <0.001 | |
| 14 | 7.2 | 63 | 77 | 44 | 88 | 0.76 (0.68-0.85) | <0.001 |
SN: sensitivity, SP: specificity, PPV: positive predictive value, NPV: negative predictive value, AUROC: area under ROC curve, CI: confidence interval, CRP: C-reactive protein.
Table 4.
Variables associated with week 14 and 54 improved therapeutic outcomes based on multivariable analysis.
| Variables | OR | 95%CI | P-value |
|---|---|---|---|
| Week 14 therapeutic outcome | |||
| Fistula response | |||
| Week 14 infliximab concentration | 1.16 | 1.02-1.32 | 0.019 |
| Complete fistula response | |||
| Week 14 infliximab concentration | 1.18 | 1.03-1.35 | 0.019 |
| Draining fistulas >1 | 0.30 | 0.18-0.50 | <0.001 |
| Perianal fistula location | 2.60 | 1.19-5.68 | 0.016 |
| CRP normalization | |||
| Week 14 infliximab concentration | 1.46 | 1.18-1.80 | <0.001 |
| Perianal fistula location | 3.95 | 1.22-12.78 | 0.022 |
| Composite remission | |||
| Week 14 infliximab concentration | 2.32 | 1.55-3.49 | <0.001 |
| Week 54 therapeutic outcome | |||
| Fistula response | |||
| Concomitant IMM | 0.26 | 0.08-0.81 | 0.020 |
| Complete fistula response | |||
| Draining fistulas >1 | 0.43 | 0.21-0.92 | 0.030 |
| Composite remission | |||
| Week 14 infliximab concentration | 2.05 | 1.10-3.82 | 0.023 |
OR: odds ratio, CI: confidence interval, CRP: C-reactive protein; IMM: immunomodulators
Fistula response at week 54 was achieved in 51/132 (39%) of the patients. Serum infliximab concentrations at weeks 6 were higher in patients with fistula response at week 54 when compared to those without fistula response (supplementary Table 1). ROC curve analysis identified an infliximab concentration of ≥9.6 μg/mL at week 6 to be associated with fistula response at week 54 (supplementary Table 2). In multivariable analysis, concomitant immunomodulators (OR: 0.26; 95%CI: 0.08-0.81), p=0.020] was identified as the only variable associated with complete fistula response at week 54 (Table 4, supplementary Table 4).
Complete fistula response
Complete fistula response by week 14 was achieved in 144/282 (51%) of the patients. Serum infliximab concentrations at weeks 6 and 14 were statistically significantly higher in patients with complete fistula response at week 14 compared to those without (Table 2). Higher infliximab concentration quartiles at weeks 6 (Figure 1B) and 14 (Figure 2B) were associated with higher proportions of complete fistula response at week 14. ROC curve analysis identified an infliximab concentration of ≥15 μg/mL at week 6 and ≥6.1 μg/mL at week 14 to be associated with complete fistula response at week 14 (Table 3, supplementary Figure 2). In multivariable analysis, infliximab concentration at week 14 (OR: 1.18; 95%CI: 1.03-1.35; p=0.019), perianal fistula location (OR: 2.60; 95%CI: 2.19-5.68; p=0.016) and draining fistulas >1 at baseline (OR: 0.30; 95%CI: 0.18-0.50), p<0.001] were identified as the only variables associated with complete fistula response at week 14 (Table 4, supplementary Table 5).
Complete fistula response by week 54 was achieved in 42/132 (32%) of the patients. Serum infliximab concentrations at weeks 6 were higher in patients with complete fistula response at week 54 when compared to those without complete fistula response (supplementary Table 1). ROC curve analysis identified an infliximab concentration of ≥9.6 μg/mL at week 6 to be associated with complete fistula response at week 54 (supplementary Table 2). In multivariable analysis, draining fistulas >1 at baseline (OR: 0.43; 95%CI: 0.21-0.92), p=0.020] was identified as the only variable associated with complete fistula response at week 54 (Table 4, supplementary Table 6).
CRP normalization
CRP normalization by week 14 was achieved in 69/161 (43%) of the patients with elevated CRP at baseline. Serum infliximab concentrations at week 14 were statistically significantly higher in patients with CRP normalization at week 14 compared to those without (Table 2). Higher infliximab concentration quartiles at week 14 were associated with higher proportions of CRP normalization at week 14 (Figure 2C). ROC curve analysis identified an infliximab concentration of ≥2 μg/mL at week 14 to be associated with CRP normalization (Table 3, supplementary Figure 2). In multivariable analysis, infliximab concentration at week 14 (OR 1.46; 95%CI: 1.18-1.80; p<0.001) and perianal fistula location (OR 3.95; 95%CI: 1.22-12.78; p=0.022) were identified as the only variables associated with CRP normalization at week 14 (Table 4, supplementary Table 7).
CRP normalization by week 54 was achieved in 28/58 (48%) of the patients with elevated CRP at baseline. Serum infliximab concentrations at week 30, 46 and 54 were statistically significantly higher in patients with CRP normalization at week 54 compared to those without (supplementary Table 1). ROC curve analysis identified an infliximab concentration of ≥2.9 μg/mL at week 30, ≥1.7 μg/mL at week 46 and ≥4.4 μg/mL at week 54 to be associated with CRP normalization (supplementary Table 2). Following multivariable analysis, no variables were found to be associated with CRP normalization at week 54 (supplementary Table 8).
Composite remission
Composite remission at week 14 was achieved in 36/161 (22%) of the patients with elevated CRP at baseline. Serum infliximab concentrations at weeks 6 and 14 were statistically significantly higher in patients with composite remission at week 14 compared to those without (Table 2). Higher infliximab concentration quartiles at weeks 6 (Figure 1D) and 14 (Figure 2D) were associated with higher proportions of composite remission at week 14. ROC analysis identified an infliximab concentration of ≥20.2 μg/mL at week 2, ≥15 μg/mL at week 6, and ≥7.2 μg/mL at week 14 to be associated with composite remission at week 14 (Table 3, supplementary Figure 3). In multivariable analysis, infliximab concentration at week 14 was identified as the only variable associated with composite remission (OR: 2.32; 95%CI 1.55-3.49; p<0.001) (Table 4, supplementary Table 9).
Composite remission at week 54 was achieved in 12/58 (21%) of the patients with elevated CRP at baseline. Serum infliximab concentrations at weeks 14 and 54 were statistically significantly higher in patients with composite remission at week 54 compared to those without (supplementary Table 1). Higher infliximab concentration quartiles at week 14 were associated with higher proportions of composite remission at week 54 (supplementary Figure 4). ROC analysis identified an infliximab concentration of ≥2.4 μg/mL at week 14 and ≥1.8 μg/mL at week 54 to be associated with composite remission at week 54 (supplementary Table 2, supplementary Figure 5). In multivariable analysis, infliximab concentration at week 14 was identified as the only variable associated with composite remission at week 54 (OR: 2.05; 95%CI 1.10-3.82; p=0.024) (Table 4, supplementary Table 10).
DISCUSSION
In this post-hoc analysis of the ACCENT-II RCT, higher serum infliximab concentrations during and early after induction therapy were associated with both early and long-term improved therapeutic outcomes in patients with fistulizing CD, including a stringent composite outcome of biological and clinical remission. This is notable because deep remission has been related to a higher flare-free survival and lower rates of surgery and hospitalization in patients with perianal fistulizing CD.31
We found that higher post-induction infliximab concentrations are associated with early fistula response, complete fistula response and CRP normalization and most importantly with both early and long-term composite remission. We also identified an infliximab concentration threshold of 20.2 μg/ml at week 2, 15 μg/ml at week 6, and 7.2 μg/ml at week 14 to stratify patients achieving the robust outcome of early composite remission. Moreover, we identified a post-induction infliximab concentration threshold of 2.4 μg/ml to stratify patients achieving long-term composite remission. The discrepancy of the post-induction infliximab concentration thresholds between early and long-term composite remission may be because only in a small subset of patients receiving maintenance therapy were followed until week 54. Moreover, one quarter of patients were dose-escalated to 10 mg/kg for loss of response during the maintenance phase, which may have impacted the association between week 14 exposure and week 54 outcome.
Our findings are in line with prior studies which demonstrated a positive correlation between infliximab concentrations and favorable objective clinical outcomes in fistulizing CD.26–30 The same holds true for active luminal CD. The recent PANTS (prospective observational personalized anti-TNF therapy in Crohn’s disease study) study, showed that post-induction infliximab concentration >7 mg/L was associated with remission at both weeks 14 and 54.15 A post-hoc analysis of the ACCENT-I (A Crohn’s Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen) RCT showed that post-induction infliximab concentrations of ≥3.5 mg/mL were associated with durable sustained response in patients with moderate to severe CD receiving 5 mg/kg of infliximab.32
Our study also demonstrated that to achieve more stringent clinical outcomes, such as composite remission, some patients may require even higher early drug concentrations. In fact, infliximab concentrations of ≥26.1 μg/ml at week 6 and ≥8.7 μg/ml at week 14 were associated with the highest rates of early composite remission (36% and 48%, respectively) and infliximab concentrations ≥11.3 μg/ml at week 14 were associated with the highest rate (33%) of long-term composite remission. These findings are important as infliximab is the cornerstone of treatment for fistulizing CD and because of limited efficacy and safety data on other biologics for the treatment of fistulizing CD, clinicians should first optimize infliximab before switching therapies. Previously, Yarur et al. proposed that although infliximab concentrations >10.1 μg/mL during maintenance therapy are associated with fistula healing, targeting even higher concentrations (>20.2 μg/mL) should be considered before changing to other therapeutic options.26
Limitations of our study include the lack of objective magnetic resonance imaging improvement of fistulas33, 34 and the fact that due to the design of the study only an association between higher serum infliximab concentrations and improved therapeutic outcomes can be established rather than causality. Strengths of our study include the large sample size, the use of stringent end-points and the use of high quality RCT data to investigate the association of infliximab concentrations with therapeutic outcomes in fistulizing CD.
In conclusion, higher post-induction infliximab concentrations are associated with favorable early and log-term therapeutic outcomes in patients with fistulizing CD. Early TDM can indicate in individual patients with fistulizing CD whether therapeutic drug exposure is achieved or not and guide subsequent rational treatment decisions to achieve rapid fistula closure. However, whether, accelerated dosing in some patients with subtherapeutic drug exposure may lead to improved outcomes should be prospectively investigated. The results of this study may help better guide infliximab therapy in patients with fistulizing CD.
Supplementary Material
STUDY HIGHLIGHTS.
WHAT IS KNOWN?
There is a positive correlation between anti-TNF therapy concentration and favorable therapeutic outcomes in IBD.
Preliminary data suggest that higher infliximab concentrations are associated with fistula healing in perianal fistulizing CD.
The role of therapeutic drug monitoring for optimizing anti-TNF therapy fistulizing CD is largely unknown.
WHAT IS NEW HERE?
Higher post-induction infliximab concentrations are associated with early and long-term composite remission in patients with fistulizing CD.
A week 6 infliximab concentration threshold of 15 μg/ml stratified patients with fistulizing CD achieving early composite remission.
A week 14 infliximab concentration threshold of 7.2 μg/ml stratified patients with fistulizing CD achieving early composite remission.
Acknowledgments
Financial support: KP is supported by the Ruth L. Kirschstein NRSA Institutional Research Training Grant 5T32DK007760-18.
Potential competing interests: K.P. received a lecture fee from Mitsubishi Tanabe Pharma; N.V.C. received research and consulting support from Takeda and UCB, research support from R-Biopharm and consulting support from Janssen, Pfizer, Progenity and Prometheus. V.J received has received has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert, Celltrion; speaker’s fees from Takeda, Janssen, Shire, Ferring, Abbvie, Pfizer M.T.O: received consultancy fees from Janssen, AbbVie, UCB, Takeda, Pfizer, Merck, and Lycera, and received research grant support from UCB; A.S.C: received consultancy fees from AbbVie, Janssen, Takeda, EMD Serono, Arena pharmaceuticals, Alfasigma, Arsanis, Bacainn, Grifols, Prometheus, Samsung, and Pfizer, and research support from Inform Diagnostics; the remaining authors disclose no conflicts of interest.
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