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ARTICLE: INFLAMMATORY BOWEL DISEASE

Higher Postinduction Infliximab Concentrations Are Associated With Improved Clinical Outcomes in Fistulizing Crohn's Disease: An ACCENT-II Post Hoc Analysis

Papamichael, Konstantinos MD, PhD1; Vande Casteele, Niels PharmaD, PhD2,3; Jeyarajah, Jenny PhD3; Jairath, Vipul MD, PhD3,4; Osterman, Mark T. MD, MS5; Cheifetz, Adam S. MD1

Author Information
The American Journal of Gastroenterology: May 2021 - Volume 116 - Issue 5 - p 1007-1014
doi: 10.14309/ajg.0000000000001111

Abstract

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 1 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 antitumor 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 (iInfliximab; REMICADE Janssen Biotech, Inc,, Malvern, PA) in the Long-term Treatment of Patients with Fistulizing Crohn's Disease) demonstrated superior healing rates after induction and maintenance infliximab treatment when compared with placebo (13).

Unfortunately, even with infliximab, there is a significant rate of primary nonresponse and secondary loss of response (12,13). These negative outcomes might 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). Because 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 might be achieved by using 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 seem 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 multicenter, 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 aged 18 years or older) with CD who had had single or multiple draining fistulas, including perianal fistulas and enterocutaneous fistulas, for at least 3 months. Women with rectovaginal fistulas were included if they had at least 1 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 up 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 crossover to maintenance treatment with 5 mg/kg of infliximab, and patients in the infliximab maintenance group could crossover to treatment with 10 mg/kg of infliximab.

Serum infliximab concentrations were measured with a sandwich enzyme immunoassay (Charles River Laboratories [formerly Tektagen], Wilmington, MA). Antibodies to infliximab were measured with a double-antigen ELISA (Janssen Biotech [formerly Centocor], Malvern, PA) 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, C-reactive protein (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, performed under YODA Project # 2017-1276, used data obtained from the Yale University Open Data Access Project, which has an agreement with Janssen Research & Development, LLC. The interpretation and reporting of research using these data are solely the responsibility of the authors and do not necessarily represent the official views of the Yale University Open Data Access Project or Janssen Research & Development, LLC. This research was performed 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 analyses were 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).

RESULTS

Study population

The study population consisted of 282 patients (men, 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 1 draining fistulas. Demographic and clinical characteristics of the patients 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 of the 139 (25.2%) patients were dose escalated to 10 mg/kg due to loss of response.

Table 1.
Table 1.:
Baseline characteristics of the patients

Fistula response

Fistula response at week 14 was achieved in 195 of 282 (69%) patients. Serum infliximab concentrations at weeks 2, 6, and 14 were numerically higher in patients with fistula response at week 14 when compared with concentrations in 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 summarized 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; see Supplementary Table 3, Supplementary Digital Content, http://links.lww.com/AJG/B812).

Table 2.
Table 2.:
Infliximab concentrations by week 14 therapeutic outcomes status
Figure 1.
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.
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.
Table 3.:
Receiver operating characteristic (ROC) curve analyses of infliximab concentrations by week 14 therapeutic outcomes
Table 4.
Table 4.:
Variables associated with weeks 14 and 54 improved therapeutic outcomes based on multivariable analysis

Fistula response at week 54 was achieved in 51 of 132 (39%) patients. Serum infliximab concentrations at weeks 6 were higher in patients with fistula response at week 54 when compared with concentrations in those without fistula response (see Supplementary Table 1, Supplementary Digital Content, http://links.lww.com/AJG/B812). ROC curve analysis identified an infliximab concentration of ≥9.6 μg/mL at week 6 to be associated with fistula response at week 54 (see Supplementary Table 2, Supplementary Digital Content, http://links.lww.com/AJG/B812). 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; see Supplementary Table 4, Supplementary Digital Content, http://links.lww.com/AJG/B812).

Complete fistula response

Complete fistula response by week 14 was achieved in 144 of 282 (51%) patients. Serum infliximab concentrations at weeks 6 and 14 were statistically significantly higher in patients with complete fistula response at week 14 compared with concentrations in 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; see Supplementary Figure 1, Supplementary Digital Content, http://links.lww.com/AJG/B812). 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; see Supplementary Table 5, Supplementary Digital Content, http://links.lww.com/AJG/B812).

Complete fistula response by week 54 was achieved in 42 of 132 (32%) patients. Serum infliximab concentrations at weeks 6 were higher in patients with complete fistula response at week 54 when compared with those concentrations in without complete fistula response (see Supplementary Table 1, Supplementary Digital Content, http://links.lww.com/AJG/B812). 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 (see Supplementary Table 2, Supplementary Digital Content, http://links.lww.com/AJG/B812). 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; see Supplementary Table 6, Supplementary Digital Content, http://links.lww.com/AJG/B812).

CRP normalization

CRP normalization by week 14 was achieved in 69 of 161 (43%) 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 with concentrations in 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; see Supplementary Figure 2, Supplementary Digital Content, http://links.lww.com/AJG/B812). 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; see Supplementary Table 7, Supplementary Digital Content, http://links.lww.com/AJG/B812).

CRP normalization by week 54 was achieved in 28 of 58 (48%) 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 with concentrations in those without (see Supplementary Table 1, Supplementary Digital Content, http://links.lww.com/AJG/B812). 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 (see Supplementary Table 2, Supplementary Digital Content, http://links.lww.com/AJG/B812). After multivariable analysis, no variables were found to be associated with CRP normalization at week 54 (see Supplementary Table 8, Supplementary Digital Content, http://links.lww.com/AJG/B812).

Composite remission

Composite remission at week 14 was achieved in 36 of 161 (22%) 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 with concentrations in 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; see Supplementary Figure 3, Supplementary Digital Content, http://links.lww.com/AJG/B812). 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; see Supplementary Table 9, Supplementary Digital Content, http://links.lww.com/AJG/B812).

Composite remission at week 54 was achieved in 12 of 58 (21%) 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 with concentrations in those without (see Supplementary Table 1, Supplementary Digital Content, http://links.lww.com/AJG/B812). Higher infliximab concentration quartiles at week 14 were associated with higher proportions of composite remission at week 54 (see Supplementary Figure 4, Supplementary Digital Content, http://links.lww.com/AJG/B812). 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 (see Supplementary Table 2 and Supplementary Figure 5, Supplementary Digital Content, http://links.lww.com/AJG/B812). 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; see Supplementary Table 10, Supplementary Digital Content, http://links.lww.com/AJG/B812).

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 postinduction 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 postinduction infliximab concentration threshold of 2.4 μg/mL to stratify patients achieving long-term composite remission. The discrepancy of the postinduction infliximab concentration thresholds between early and long-term composite remission might be because only a small subset of patients receiving maintenance therapy were followed up until week 54. Moreover, one-quarter of patients were dose escalated to 10 mg/kg for loss of response during the maintenance phase, which might have impacted the association between week 14 exposure and week 54 outcome.

Our findings are in line with previous studies that 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 prospective observational personalized anti-TNF therapy in Crohn's disease study showed that postinduction 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 postinduction 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).

This study also demonstrated that, to achieve more stringent clinical outcomes, such as composite remission, some patients might 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 because 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. (26) 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.

Limitations of our study include the lack of objective magnetic resonance imaging improvement of fistulas (33,34) and the fact that, because of 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 endpoints, and the use of high quality RCT data to investigate the association of infliximab concentrations with therapeutic outcomes in fistulizing CD.

In conclusion, higher postinduction infliximab concentrations are associated with favorable early and long-term therapeutic outcomes in patients with fistulizing CD. Early therapeutic drug monitoring 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 might lead to improved outcomes should be prospectively investigated. The results of this study might help better guide infliximab therapy in patients with fistulizing CD.

CONFLICTS OF INTEREST

Guarantor of the article: Adam S. Cheifetz, MD.

Specific author contributions: The first two authors contributed equally to this work. K.P.: study concept and design, data acquisition, analysis and interpretation, statistical analysis, and manuscript writing. N.V.C.: data analysis and interpretation, statistical analysis, and manuscript critical revision. J.J.: data acquisition, analysis and interpretation, statistical analysis, and manuscript critical revision. V.J.: data interpretation and manuscript critical revision. M.T.O.: study concept and design, data interpretation, and manuscript critical revision. A.S.C.: study concept and design, data analysis and interpretation, and manuscript critical revision. All authors approved the final version of the article.

Financial support: K.P. 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 consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert, and Celltrion; speaker's fees from Takeda, Janssen, Shire, Ferring, Abbvie, and 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.

Study Highlights

WHAT IS KNOWN

  • ✓ There is a positive correlation between anti-TNF therapy concentration and favorable therapeutic outcomes in inflammatory bowel disease.
  • ✓ Preliminary data suggest that higher infliximab concentrations are associated with fistula healing in perianal fistulizing Crohn's disease (CD).
  • ✓ The role of therapeutic drug monitoring for optimizing anti-TNF therapy fistulizing CD is largely unknown.

WHAT IS NEW HERE

  • ✓ Higher postinduction 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.

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