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Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis
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Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis Konstantinos Papamichael,*,‡ Thomas Van Stappen,‡ Niels Vande Casteele,‡ Ann Gils,‡ Thomas Billiet,* Sophie Tops,‡ Karolien Claes,* Gert Van Assche,* Paul Rutgeerts,* Severine Vermeire,* and Marc Ferrante* *KU Leuven, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), and University Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium; and ‡KU Leuven, Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium BACKGROUND & AIMS:
Mucosal healing is an independent predictor of sustained clinical remission in patients with ulcerative colitis (UC) treated with infliximab. We investigated whether infliximab concentrations during induction therapy are associated with short-term mucosal healing (STMH) in patients with UC.
METHODS:
We performed a retrospective, single-center analysis of data collected from a tertiary referral center from 101 patients with UC who received scheduled induction therapy with infliximab at weeks 0, 2, and 6 and had an endoscopic evaluation at baseline and after induction therapy. STMH was defined as Mayo endoscopic sub-score £1, assessed at weeks 10–14, with baseline sub-score ‡2. In a prospective study, infliximab concentrations were evaluated in serum samples collected at weeks 0, 2, 6, and 14 of infliximab therapy by using an enzyme-linked immunosorbent assay we developed.
RESULTS:
Fifty-four patients (53.4%) achieved STMH. Patients with STMH had a higher median infliximab concentration at weeks 2, 6, and 14 than patients without STMH. A receiver operating characteristic (ROC) analysis identified infliximab concentration thresholds of 28.3 (area under the ROC curve [AUROC], 0.638), 15 (AUROC, 0.688), and 2.1 mg/mL (AUROC, 0.781) that associated with STMH at weeks 2, 6, and 14, respectively. Multiple logistic regression analysis identified infliximab concentration ‡15 at week 6 (P [ .025; odds ratio, 4.6; 95% confidence interval, 1.2– 17.1) and ‡2.1 mg/mL at week 14 (P [ .004; odds ratio, 5.6; 95% confidence interval, 1.7–18) as independent factors associated with STMH.
CONCLUSIONS:
In an analysis of data from real-life clinical practice, we associated infliximab concentrations during the induction therapy with STMH in patients with UC.
Keywords: Anti-TNF Agent; Tumor Necrosis Factor; Mucosal Healing; Antibodies to Infliximab.
nti–tumor necrosis factor (anti-TNF) therapy has greatly improved the management of patients with inflammatory bowel disease (IBD), namely Crohn’s disease (CD) and ulcerative colitis (UC).1 Objective therapeutic outcomes such as normalization of C-reactive protein (CRP) and mucosal healing are emerging as primary goals of anti-TNF treatment in IBD.2–4 Mucosal healing is an independent predictor of sustained clinical remission and reduced risk of colectomy and hospitalization in UC patients treated with infliximab.5–8 The role of therapeutic drug monitoring (TDM) in guiding therapeutic decisions in individual patients treated with anti-TNF therapy is increasing.9–11 Exposure-response studies during maintenance therapy
A
of anti-TNF agents showed that higher serum drug concentrations are associated with better therapeutic outcomes, including mucosal healing.5,12–24 Nevertheless, Abbreviations used in this paper: ATI, antibodies to infliximab; AUC, area under the curve; BMI, body mass index; CAI, clinical activity index; CD, Crohn’s disease; CI, confidence interval; CRP, high sensitive C-reactive protein; ELISA, enzyme-linked immunosorbent assay; IBD, inflammatory bowel disease; IMM, immunomodulator; IQR, interquartile range; OR, odds ratio; p-ANCA, perinuclear anti-neutrophil cytoplasmic antibodies; ROC, receiver operating characteristic; SN, sensitivity; SP, specificity; STMH, short-term mucosal healing; TDM, therapeutic drug monitoring; TNF, anti-tumor necrosis factor; UC, ulcerative colitis; ULOQ, upper limit of quantification; VIF, variance inflation factor. © 2016 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.11.014
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there are only limited data regarding the role of TDM during the induction phase, whereas a therapeutic range and relevant thresholds for clinical and biological remission as well as mucosal healing are largely unknown. The main goal of our study was to investigate the relationship of infliximab concentrations during induction therapy with short-term mucosal healing (STMH) in UC patients, and the secondary objective was to identify potential factors associated to STMH.
Materials and Methods Study Design, Definitions, and Patient Population This retrospective, single-center study included UC patients who received infliximab scheduled induction therapy (week 0-2-6) between January 2000 and September 2013 at the University Hospitals Leuven, Belgium, had at least 1 serum sample available at week 2, 6, or 14, and underwent an endoscopic evaluation both at baseline (with a Mayo endoscopic sub-score of 2 or 3) and after induction therapy (week 10-14). STMH was defined as a Mayo endoscopic sub-score of 0 or 1.5 All clinical and endoscopic data were reviewed from the electronic medical records of the patients. Patients gave written informed consent to participate in the Institutional Review Board approved Flemish Study for Research on IBD VLECC registry B322201213950/ S53684. Serum samples were prospectively collected just before an infliximab infusion and stored at –20 C.
Infliximab Concentrations and Antibodies to Infliximab Infliximab concentrations and antibodies to infliximab (ATI) were evaluated in serum samples collected during the induction phase at weeks 0, 2, 6, and 14 after infliximab initiation. Infliximab concentrations were measured by using an in-house developed and clinically validated direct enzyme-linked immunosorbent assay (ELISA).25 The lower limit of detection for infliximab concentrations was 0.3 mg/mL. The upper limit of quantification (ULOQ) by using standard dilutions of 1/150 and 1/300 was 22.5 mg/mL. Samples with a drug concentration above the ULOQ were diluted up to 1/1200 until a result that fell within the linear phase of the standard curve of the assay was obtained. ATI were measured with a recently in-house developed and clinically validated drug-tolerant bridging ELISA by using a monoclonal antibody as calibrator (MA-IFX10F9), which was based on a conversion of the previously described drug-sensitive bridging ELISA26 by using affinity-capture-elution methodology. The cutoff for an ATI-positive sample was 20 ng/mL equivalents, and the upper limit of quantification was 3200 ng/mL.
Figure 1. Flowchart of the study population.
Serology Hemoglobin, CRP, white blood cell count, neutrophils, platelets, albumin, and perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) were measured at baseline before the start of infliximab by standard procedures. Titers of p-ANCA 1/40 were considered as positive.
Statistical Analysis Descriptive statistics were provided with medians and interquartile range (IQR) for continuous variables and frequency and percentage for categorical variables. A receiver operating characteristic (ROC) analysis was performed for infliximab concentrations to trace thresholds associated with STMH. Optimal thresholds were chosen by using the Youden index, which maximizes the sum of the specificity (SP) and sensitivity (SN) of the ROC curve as previously described.24 SN, SP, positive predictive value, and negative predictive value were also calculated. Infliximab concentrations at week 2, 6, and 14 were compared between groups with the Mann-Whitney U test. Serum infliximab concentrations were categorized also into quartiles. Rates of STMH were compared across infliximab serum concentration quartiles at weeks 2, 6, and 14 with the c2 test (linear-by-linear association). The Kruskal-Wallis and the c2 test were used to compare continuous or discrete variables, respectively, across quartile groups. The Mann-Whitney U test and the c2 or the Fisher exact test were used for univariate analysis to identify quantitative or categorical variables associated to STMH, respectively. To determine the independent effects of variables associated to STMH, a multivariable binary
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Table 1. Baseline Characteristics of the Study Population Patients’ characteristics Male (%) Age at diagnosis, median (IQR) (y) Age at infliximab initiation, median (IQR) (y) Disease duration: median (IQR) (y) Disease extension: E3 (pancolitis)a (%) Acute severe UC (%) Prior biological therapy (%) Concomitant CS at infliximab initiation (%) Concomitant IMMsb at infliximab initiation (%) Induction therapy 10 mg/kg (%) Smoking at infliximab initiation (%) Baseline BMI, median (IQR) (kg/m2) (n ¼ 83) Baseline positive p-ANCA (%) Baseline CRP >5 mg/L (%) Biochemical variables at baseline Hemoglobin, median (IQR) (g/dL) (n ¼ 100) WBC, median (IQR) (109/L) (n ¼ 97) Neutrophils, median (IQR) (109/L) (n ¼ 92) Platelets, median (IQR) (109/L) (n ¼ 100) Albumin, median (IQR) (g/L) (n ¼ 98)
N ¼ 101 64 33 43 4.2 63 16 5 36 49 3 12/100 24.9 48/93 53
(63.4) (25–46) (30–53) (1.3–10.2) (62.4) (15.8) (4.9) (35.6) (48.5) (3) (12) (20.8–28.8) (51.6) (52.5)
12.9 8 5.4 343 42
(11.7–14.4) (5.9–10.9) (3.7–7.5) (278–427) (39–44)
CS, corticosteroids; WBC, white blood count. a According to Montreal classification. b Thiopurines.
logistic regression was then performed including variables with a P value <.1 from univariate analysis, which was based on the Backward Wald selection method. The results were expressed as odds ratio (OR) with 95% confidence intervals (95% CIs), followed by the corresponding P value. Multicollinearity between infliximab concentrations at weeks 2, 6, and 14 was assessed on the basis of linear regression analysis and the variance inflation factor (VIF). Results were considered statistically significant when P <.05. All statistical analyses were performed by using the SPSS 22.0 software (SPSS, Chicago, IL) and GraphPad Prism version 5.03 for Windows (GraphPad Software, San Diego, CA).
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Results Study Population The study population consisted of 101 patients (Figure 1). STMH was achieved in 54 of 101 patients (53.4%). The majority of patients were treated with 5 mg/kg infliximab (n ¼ 98, 97%) and were naive to anti-TNF therapy (n ¼ 95, 95.1%). Fifty-three (52.5%) had an elevated baseline CRP (> 5 mg/L), whereas 16 (15.8%) had acute severe UC. Disease and patient characteristics are depicted in Table 1.
Infliximab Concentrations and Short-term Mucosal Healing An ROC curve analysis identified statistically significant infliximab concentration thresholds of 28.3, 15.0, and 2.1 mg/mL at weeks 2, 6, and 14, respectively, associated with STMH (Figure 2). Serum infliximab concentrations at weeks 2, 6, and 14 were higher in patients with STMH compared with those without (Figure 3A). The relationship between serum infliximab concentrations at weeks 2, 6, and 14 and STMH was further analyzed by dividing serum infliximab concentrations into quartiles. The higher infliximab serum concentration quartiles at weeks 2, 6, and 14 were associated with higher rates of STMH (Figure 3B). A summary of factors associated with serum infliximab concentrations quartiles at weeks 2, 6, and 14 is demonstrated in Supplementary Table 1. In general, factors associated with the lowest quartile of infliximab concentrations at different time points during the induction phase were male gender, acute severe UC, pancolitis, a baseline endoscopic Mayo score of 3, absence of concomitant immunomodulators (IMMs) at infliximab initiation, low body mass index (BMI), low albumin levels, high CRP levels, and ATI positivity (Supplementary Table 1).
Figure 2. ROC analysis for infliximab serum concentrations at week 2 (A), week 6 (B), and week 14 (C) stratifying patients with and without STMH.
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transient, because at weeks 6 and 14 they were undetectable, and 4 developed ATI at week 6, 3 of whom had also positive ATI at week 14, whereas for the remaining one no serum sample was available at week 14. After induction at week 14, thirteen patients (19.3%) developed ATI, with a titer ranging from 80 to 2433 ng/mL MA-IFX10F9 equivalents. ATI positivity at week 6 was negatively associated with STMH (P ¼ .043) in contrast to week 2 (P ¼ .460) and week 14 (P ¼ .356). Concomitant IMMs significantly reduced the development of ATI at week 14 compared with infliximab monotherapy (2.5% vs 27.9%, P ¼ .002) and numerically at week 6 (0% vs 7.7%, P ¼ .119).
Factors Associated With Short-term Mucosal Healing
Figure 3. Distribution of serum infliximab concentrations during induction therapy on the basis of STMH. Gray boxes represent infliximab serum concentrations of patients with STMH, and white boxes represent infliximab serum concentrations of patients without STMH. Box plots (5%–95%) show the median (solid line within box), IQR (upper and lower box boundaries), standard deviation (whiskers), and outliers (black dot) (A). Rates of STMH by infliximab serum concentration quartiles at weeks 2, 6, and 14 (P values indicate comparison across quartiles, c2 test (linear-by-linear association) (B). w, week.
Infliximab exposure during the induction therapy, defined as the area under the infliximab concentration curve between time point weeks 0 and 14 (AUCw0-w14), was higher in patients with STMH compared with those without (P ¼ .003) (Figure 4).
Antibodies to Infliximab and Short-term Mucosal Healing During the induction therapy only 5 patients (5%) developed ATI, all of whom did not achieve STMH; 1 developed ATI early at week 2, although probably
Univariate analysis identified female gender (P ¼ .039), concomitant IMMs at start of infliximab (P ¼ .028), ATI at week 6 (P ¼ .043), and infliximab concentrations at week 2 28.3 mg/mL (P ¼ .002), week 6 15 mg/mL (P ¼ .001), and week 14 2.1 mg/mL (P < .001) as variables associated with STMH (Table 2, Supplementary Table 2). No multicollinearity between infliximab concentrations at weeks 2, 6, and 14 was observed (VIF ¼ 2.4<3). Multivariable binary logistic regression analysis retained infliximab concentration 15 (P ¼ .025; OR, 4.6; 95% CI, 1.2–17.1) and 2.1 mg/mL (P ¼ .004; OR, 5.6; 95% CI, 1.7–18) at weeks 6 and 14, respectively, as independent factors associated with STMH (Table 2). To evaluate the predictive value of baseline variables and infliximab serum concentrations at weeks 2 and 6 related to STMH, the same analysis was made excluding the infliximab serum concentration at week 14. Multivariable binary logistic regression analysis retained only infliximab concentration at week 6 15 mg/mL (P ¼ .012; OR, 3.3; 95% CI, 1.3–8.4) as independent factor associated with STMH.
Discussion A treat-to-target approach leading to better clinical outcomes is emerging as a new therapeutic strategy, although relevant serum drug concentrations differ depending on the chosen therapeutic outcome.27–29 We demonstrated that higher infliximab concentrations during the induction therapy are associated with STMH in UC, and we identified infliximab concentration thresholds that are independently associated with STMH. These findings are consistent with previous studies reporting an association between serum antiTNF drug levels and mucosal healing in patients with IBD, although most of them refer to the maintenance therapy.16,18,24,27 Regarding induction therapy, higher plasma concentrations of certolizumab at week 8 were associated with higher rates of endoscopic response
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Figure 4. Total infliximab exposure of patients with and without STMH. Average infliximab concentrations for UC patients with or without STMH are represented by (-) and (), respectively, and AUC 95% CIs are represented by the red and black dotted lines, respectively.
and remission at week 10 in CD patients,17 whereas a post hoc analysis of the ACT-1 and ACT-2 data have shown that higher serum infliximab concentrations were associated with higher rates of mucosal healing at week 8 in UC patients treated with either 5 or 10 mg/kg.24 Moreover, in the same study the presence of an infliximab concentration of approximately 22 mg/mL at week 6 was associated with clinical response at week 8.24 In a retrospective analysis of the ACCENT I trial, median values in the 5 mg/kg maintenance arm were 12.9 and 4.0 mg/mL in CD patients with sustained response compared with 8.8 and 1.9 mg/mL in patients without at weeks 6 and 14, respectively.14 In a recently published post hoc analysis of a multicenter prospective randomized controlled trial regarding UC patients, infliximab concentration 20.7 mg/mL at week 2 was significantly associated with clinical remission on the basis of the clinical activity index (CAI) at week 14 (OR, 2.75; 95% CI, 1.13–6.93; P ¼ .025), whereas week 2 infliximab concentration to CAI ratio was an independent factor associated both with week 14 CAI remission and week 30 mucosal healing.30
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In our study, patients in the lowest infliximab concentration quartile at different time points during the induction phase were found to have a higher baseline inflammatory burden reflective of a more extended (pancolitis) and active disease state (acute severe UC, baseline endoscopic Mayo score of 3, lower baseline BMI and albumin, higher baseline CRP) as well as higher ATI compared with those in the other quartiles, which is in agreement with other studies.17,24,31–33 Thus, it is suggested that patients with a high baseline inflammatory burden and a rapid drug clearance should be treated with accelerated and not standard anti-TNF regiments.34–38 Nevertheless, in this study, although degree of baseline inflammation (eg, CRP, extent of colitis, etc) affected infliximab concentrations, it did not affect the rate of STMH. This probably implies that drug concentrations achieved by standard dosing are within the therapeutic range for the spectrum of inflammatory burden treated in this cohort, and it is not that patients with higher inflammatory burden “need more drug” and fail this standard regimen more often. Besides pharmacokinetics, maybe other factors are also important for achieving STMH or not. In addition, female gender and concomitant IMMs were associated with higher infliximab concentrations as previously shown.5,20,24,28,39,40 The main limitations of this study are its retrospective nature and the lack of fecal calprotectin levels and histologic data,41 because UC patients in clinical and endoscopic remission under infliximab may still have histologic features of inflammation.42 Moreover, high serum infliximab concentrations may not be the reason but rather a consequence of mucosal healing preventing infliximab fecal loss from a leaky gut with severe inflammation.38 In conclusion, this large single-center study, which reflects real-life clinical practice, indicates that infliximab concentrations during induction phase are associated with STMH in UC patients. Nevertheless, before any clinical recommendations can be made, large prospective clinical trials that are based on a treat-to-target therapeutic approach including pharmacokinetic parameters of drug exposure (peak concentration, time
Table 2. Variables Associated With STMH Univariate analysis Prognostic markers Female Concomitant IMMsa at infliximab initiation Infliximab concentration at week 2 28.3 mg/mL Infliximab concentration at week 6 15 mg/mL Infliximab concentration at week 14 2.1 mg/mL ATI at week 6
Multivariate analysis
OR 95% CI P value OR 95% CI P value SN (%) SP (%) PPV (%) NPV (%) 2.5 2.6 6 4.3 9 0.9
1.1–5.8 1.1–5.7 1.9–19.3 1.8–10.2 3.2–25.3 0.8–1
.039 .028 .002 .001 <.001 .043
4.6 1.2–17.1 5.6 1.7–18
.025 .004
60 84
NPV, negative predictive value; PPV, positive predictive value. a Thiopurines.
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Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2015.11.014.
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31. Fasanmade AA, Adedokun OJ, Ford J, et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. Eur J Clin Pharmacol 2009;65:1211–1228.
43. Vande Casteele N, Gils A. Preemptive dose optimization using therapeutic drug monitoring for biologic therapy of Crohn’s disease: avoiding failure while lowering costs? Dig Dis Sci 2015; 60:2571–2573.
32. Ordas I, Feagan BG, Sandborn WJ. Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol Hepatol 2012;10:1079–1087. 33. Dotan I, Ron Y, Yanai H, et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis 2014;20:2247–2259. 34. Yarur AJ, Jain A, Sussman DA, et al. The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study. Gut 2015. 35. Rosen MJ, Minar P, Vinks AA. Review article: applying pharmacokinetics to optimise dosing of anti-TNF biologics in acute severe ulcerative colitis. Aliment Pharmacol Ther 2015; 41:1094–1103. 36. Gibson DJ, Heetun ZS, Redmond CE, et al. An accelerated infliximab induction regimen reduces the need for early colectomy in patients with acute severe ulcerative colitis. Clin Gastroenterol Hepatol 2015;13:330–335. 37. Hendler SA, Cohen BL, Colombel JF, et al. High-dose infliximab therapy in Crohn’s disease: clinical experience, safety, and efficacy. J Crohns Colitis 2015;9:266–275. 38. Brandse JF, van den Brink GR, Wildenberg ME, et al. Loss of infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis. Gastroenterology 2015;149:350–355. 39. Peyrin-Biroulet L, Reinisch W, Colombel JF, et al. Clinical disease activity, Creactive protein normalisation and mucosal healing in Crohn’s disease in the SONIC trial. Gut 2014; 63:88–95. 40. Van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology 2008;134:1861–1868. 41. Hindryckx P, Baert F, Hart A, et al. Clinical trials in ulcerative colitis: a historical perspective. J Crohns Colitis 2015; 9:580–588.
44. Vande Casteele N, Gils A. Pharmacokinetics of anti-TNF monoclonal antibodies in inflammatory bowel disease: adding value to current practice. J Clin Pharmacol 2015;55 (Suppl 3):S39–S50.
Reprint requests Address requests for reprints to: Marc Ferrante, MD, PhD, Department of Gastroenterology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. e-mail: [email protected]; fax: þ3216344419. Acknowledgments The authors thank Vera Ballet and Willem-Jan Wollants for doing an excellent job in maintaining the Leuven IBD patient database (V.B.) and Biobank (W-J.W.)
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Conflicts of interest These authors disclose the following: K. P. received a consultancy fee from MSD Hellas. N. V. C. received consultancy fees from Janssen Biologics MSD, UCB, and Takeda and speaker fees from AbbVie. A. G. received speaker fees from Pfizer, AbbVie, Janssen Biologicals, and MSD and financial support for research from Pfizer. G. V. A received financial support for research from Abbott and Ferring Pharmaceuticals, lecture fees from Janssen, MSD, and Abbott, and consultancy fees from PDL BioPharma, UCB Pharma, SanofiAventis, Abbott, AbbVie, Ferring, Novartis, Biogen Idec, Janssen Biologics, NovoNordisk, Zealand Pharma A/S, Millenium/Takeda, Shire, Novartis, and Bristol Mayer Squibb. P. R. received research grants from Abbott, AbbVie, Prometheus, MSD, and UCB Pharma and lecture and consultant fees from Abbott, AbbVie, MSD, UCB Pharma, Genentech Inc, Millenium, Neovacs, Actogenics, Amgen, Prometheus, Bristol-Myers Squibb, Falk Pharma, and Tillotts. S. V. received financial support for research from MSD, AbbVie, and UCB Pharma, lecture fees from Abbott, AbbVie, MSD, Ferring Pharmaceuticals, and UCB Pharma, and consultancy fees from Pfizer, Ferring Pharmaceuticals, Shire Pharmaceuticals Group, MSD, and AstraZeneca Pharmaceuticals. M. F. received financial support for research from Janssen Biologics, lecture fees from MSD, Ferring Pharmaceuticals Inc, Chiesi, MSD, Tillotts, Janssen Biologics, Abbott Laboratories, and AbbVie, and consultancy fees from Abbott Laboratories, AbbVie, MSD, and Janssen Biologics. The remaining authors disclose no conflicts.
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Funding Supported in part by the Research Foundation-Flanders (FWO), Belgium (grant number G.0617.12). Serological factors were analyzed by Prometheus Laboratories, San Diego, CA, which also provided additional research support funding. K. P. received a fellowship grant from the Hellenic Gastroenterology Society and the European Crohn’s and Colitis Organization (ECCO). N.V.C. is a Postdoctoral Fellow and S.V., G.V.A., and M.F. are Senior Clinical Investigators of the Research Foundation – Flanders (FWO), Belgium.
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Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis Konstantinos Papamichael,*,‡ Thomas Van Stappen,‡ Niels Vande Casteele,‡ Ann Gils,‡ Thomas Billiet,* Sophie Tops,‡ Karolien Claes,* Gert Van Assche,* Paul Rutgeerts,* Severine Vermeire,* and Marc Ferrante* *KU Leuven, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), and University Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium; and ‡KU Leuven, Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium BACKGROUND & AIMS:
Mucosal healing is an independent predictor of sustained clinical remission in patients with ulcerative colitis (UC) treated with infliximab. We investigated whether infliximab concentrations during induction therapy are associated with short-term mucosal healing (STMH) in patients with UC.
METHODS:
We performed a retrospective, single-center analysis of data collected from a tertiary referral center from 101 patients with UC who received scheduled induction therapy with infliximab at weeks 0, 2, and 6 and had an endoscopic evaluation at baseline and after induction therapy. STMH was defined as Mayo endoscopic sub-score £1, assessed at weeks 10–14, with baseline sub-score ‡2. In a prospective study, infliximab concentrations were evaluated in serum samples collected at weeks 0, 2, 6, and 14 of infliximab therapy by using an enzyme-linked immunosorbent assay we developed.
RESULTS:
Fifty-four patients (53.4%) achieved STMH. Patients with STMH had a higher median infliximab concentration at weeks 2, 6, and 14 than patients without STMH. A receiver operating characteristic (ROC) analysis identified infliximab concentration thresholds of 28.3 (area under the ROC curve [AUROC], 0.638), 15 (AUROC, 0.688), and 2.1 mg/mL (AUROC, 0.781) that associated with STMH at weeks 2, 6, and 14, respectively. Multiple logistic regression analysis identified infliximab concentration ‡15 at week 6 (P [ .025; odds ratio, 4.6; 95% confidence interval, 1.2– 17.1) and ‡2.1 mg/mL at week 14 (P [ .004; odds ratio, 5.6; 95% confidence interval, 1.7–18) as independent factors associated with STMH.
CONCLUSIONS:
In an analysis of data from real-life clinical practice, we associated infliximab concentrations during the induction therapy with STMH in patients with UC.
Keywords: Anti-TNF Agent; Tumor Necrosis Factor; Mucosal Healing; Antibodies to Infliximab.
nti–tumor necrosis factor (anti-TNF) therapy has greatly improved the management of patients with inflammatory bowel disease (IBD), namely Crohn’s disease (CD) and ulcerative colitis (UC).1 Objective therapeutic outcomes such as normalization of C-reactive protein (CRP) and mucosal healing are emerging as primary goals of anti-TNF treatment in IBD.2–4 Mucosal healing is an independent predictor of sustained clinical remission and reduced risk of colectomy and hospitalization in UC patients treated with infliximab.5–8 The role of therapeutic drug monitoring (TDM) in guiding therapeutic decisions in individual patients treated with anti-TNF therapy is increasing.9–11 Exposure-response studies during maintenance therapy
A
of anti-TNF agents showed that higher serum drug concentrations are associated with better therapeutic outcomes, including mucosal healing.5,12–24 Nevertheless, Abbreviations used in this paper: ATI, antibodies to infliximab; AUC, area under the curve; BMI, body mass index; CAI, clinical activity index; CD, Crohn’s disease; CI, confidence interval; CRP, high sensitive C-reactive protein; ELISA, enzyme-linked immunosorbent assay; IBD, inflammatory bowel disease; IMM, immunomodulator; IQR, interquartile range; OR, odds ratio; p-ANCA, perinuclear anti-neutrophil cytoplasmic antibodies; ROC, receiver operating characteristic; SN, sensitivity; SP, specificity; STMH, short-term mucosal healing; TDM, therapeutic drug monitoring; TNF, anti-tumor necrosis factor; UC, ulcerative colitis; ULOQ, upper limit of quantification; VIF, variance inflation factor. © 2016 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.11.014
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there are only limited data regarding the role of TDM during the induction phase, whereas a therapeutic range and relevant thresholds for clinical and biological remission as well as mucosal healing are largely unknown. The main goal of our study was to investigate the relationship of infliximab concentrations during induction therapy with short-term mucosal healing (STMH) in UC patients, and the secondary objective was to identify potential factors associated to STMH.
Materials and Methods Study Design, Definitions, and Patient Population This retrospective, single-center study included UC patients who received infliximab scheduled induction therapy (week 0-2-6) between January 2000 and September 2013 at the University Hospitals Leuven, Belgium, had at least 1 serum sample available at week 2, 6, or 14, and underwent an endoscopic evaluation both at baseline (with a Mayo endoscopic sub-score of 2 or 3) and after induction therapy (week 10-14). STMH was defined as a Mayo endoscopic sub-score of 0 or 1.5 All clinical and endoscopic data were reviewed from the electronic medical records of the patients. Patients gave written informed consent to participate in the Institutional Review Board approved Flemish Study for Research on IBD VLECC registry B322201213950/ S53684. Serum samples were prospectively collected just before an infliximab infusion and stored at –20 C.
Infliximab Concentrations and Antibodies to Infliximab Infliximab concentrations and antibodies to infliximab (ATI) were evaluated in serum samples collected during the induction phase at weeks 0, 2, 6, and 14 after infliximab initiation. Infliximab concentrations were measured by using an in-house developed and clinically validated direct enzyme-linked immunosorbent assay (ELISA).25 The lower limit of detection for infliximab concentrations was 0.3 mg/mL. The upper limit of quantification (ULOQ) by using standard dilutions of 1/150 and 1/300 was 22.5 mg/mL. Samples with a drug concentration above the ULOQ were diluted up to 1/1200 until a result that fell within the linear phase of the standard curve of the assay was obtained. ATI were measured with a recently in-house developed and clinically validated drug-tolerant bridging ELISA by using a monoclonal antibody as calibrator (MA-IFX10F9), which was based on a conversion of the previously described drug-sensitive bridging ELISA26 by using affinity-capture-elution methodology. The cutoff for an ATI-positive sample was 20 ng/mL equivalents, and the upper limit of quantification was 3200 ng/mL.
Figure 1. Flowchart of the study population.
Serology Hemoglobin, CRP, white blood cell count, neutrophils, platelets, albumin, and perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) were measured at baseline before the start of infliximab by standard procedures. Titers of p-ANCA 1/40 were considered as positive.
Statistical Analysis Descriptive statistics were provided with medians and interquartile range (IQR) for continuous variables and frequency and percentage for categorical variables. A receiver operating characteristic (ROC) analysis was performed for infliximab concentrations to trace thresholds associated with STMH. Optimal thresholds were chosen by using the Youden index, which maximizes the sum of the specificity (SP) and sensitivity (SN) of the ROC curve as previously described.24 SN, SP, positive predictive value, and negative predictive value were also calculated. Infliximab concentrations at week 2, 6, and 14 were compared between groups with the Mann-Whitney U test. Serum infliximab concentrations were categorized also into quartiles. Rates of STMH were compared across infliximab serum concentration quartiles at weeks 2, 6, and 14 with the c2 test (linear-by-linear association). The Kruskal-Wallis and the c2 test were used to compare continuous or discrete variables, respectively, across quartile groups. The Mann-Whitney U test and the c2 or the Fisher exact test were used for univariate analysis to identify quantitative or categorical variables associated to STMH, respectively. To determine the independent effects of variables associated to STMH, a multivariable binary
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Table 1. Baseline Characteristics of the Study Population Patients’ characteristics Male (%) Age at diagnosis, median (IQR) (y) Age at infliximab initiation, median (IQR) (y) Disease duration: median (IQR) (y) Disease extension: E3 (pancolitis)a (%) Acute severe UC (%) Prior biological therapy (%) Concomitant CS at infliximab initiation (%) Concomitant IMMsb at infliximab initiation (%) Induction therapy 10 mg/kg (%) Smoking at infliximab initiation (%) Baseline BMI, median (IQR) (kg/m2) (n ¼ 83) Baseline positive p-ANCA (%) Baseline CRP >5 mg/L (%) Biochemical variables at baseline Hemoglobin, median (IQR) (g/dL) (n ¼ 100) WBC, median (IQR) (109/L) (n ¼ 97) Neutrophils, median (IQR) (109/L) (n ¼ 92) Platelets, median (IQR) (109/L) (n ¼ 100) Albumin, median (IQR) (g/L) (n ¼ 98)
N ¼ 101 64 33 43 4.2 63 16 5 36 49 3 12/100 24.9 48/93 53
(63.4) (25–46) (30–53) (1.3–10.2) (62.4) (15.8) (4.9) (35.6) (48.5) (3) (12) (20.8–28.8) (51.6) (52.5)
12.9 8 5.4 343 42
(11.7–14.4) (5.9–10.9) (3.7–7.5) (278–427) (39–44)
CS, corticosteroids; WBC, white blood count. a According to Montreal classification. b Thiopurines.
logistic regression was then performed including variables with a P value <.1 from univariate analysis, which was based on the Backward Wald selection method. The results were expressed as odds ratio (OR) with 95% confidence intervals (95% CIs), followed by the corresponding P value. Multicollinearity between infliximab concentrations at weeks 2, 6, and 14 was assessed on the basis of linear regression analysis and the variance inflation factor (VIF). Results were considered statistically significant when P <.05. All statistical analyses were performed by using the SPSS 22.0 software (SPSS, Chicago, IL) and GraphPad Prism version 5.03 for Windows (GraphPad Software, San Diego, CA).
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Results Study Population The study population consisted of 101 patients (Figure 1). STMH was achieved in 54 of 101 patients (53.4%). The majority of patients were treated with 5 mg/kg infliximab (n ¼ 98, 97%) and were naive to anti-TNF therapy (n ¼ 95, 95.1%). Fifty-three (52.5%) had an elevated baseline CRP (> 5 mg/L), whereas 16 (15.8%) had acute severe UC. Disease and patient characteristics are depicted in Table 1.
Infliximab Concentrations and Short-term Mucosal Healing An ROC curve analysis identified statistically significant infliximab concentration thresholds of 28.3, 15.0, and 2.1 mg/mL at weeks 2, 6, and 14, respectively, associated with STMH (Figure 2). Serum infliximab concentrations at weeks 2, 6, and 14 were higher in patients with STMH compared with those without (Figure 3A). The relationship between serum infliximab concentrations at weeks 2, 6, and 14 and STMH was further analyzed by dividing serum infliximab concentrations into quartiles. The higher infliximab serum concentration quartiles at weeks 2, 6, and 14 were associated with higher rates of STMH (Figure 3B). A summary of factors associated with serum infliximab concentrations quartiles at weeks 2, 6, and 14 is demonstrated in Supplementary Table 1. In general, factors associated with the lowest quartile of infliximab concentrations at different time points during the induction phase were male gender, acute severe UC, pancolitis, a baseline endoscopic Mayo score of 3, absence of concomitant immunomodulators (IMMs) at infliximab initiation, low body mass index (BMI), low albumin levels, high CRP levels, and ATI positivity (Supplementary Table 1).
Figure 2. ROC analysis for infliximab serum concentrations at week 2 (A), week 6 (B), and week 14 (C) stratifying patients with and without STMH.
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transient, because at weeks 6 and 14 they were undetectable, and 4 developed ATI at week 6, 3 of whom had also positive ATI at week 14, whereas for the remaining one no serum sample was available at week 14. After induction at week 14, thirteen patients (19.3%) developed ATI, with a titer ranging from 80 to 2433 ng/mL MA-IFX10F9 equivalents. ATI positivity at week 6 was negatively associated with STMH (P ¼ .043) in contrast to week 2 (P ¼ .460) and week 14 (P ¼ .356). Concomitant IMMs significantly reduced the development of ATI at week 14 compared with infliximab monotherapy (2.5% vs 27.9%, P ¼ .002) and numerically at week 6 (0% vs 7.7%, P ¼ .119).
Factors Associated With Short-term Mucosal Healing
Figure 3. Distribution of serum infliximab concentrations during induction therapy on the basis of STMH. Gray boxes represent infliximab serum concentrations of patients with STMH, and white boxes represent infliximab serum concentrations of patients without STMH. Box plots (5%–95%) show the median (solid line within box), IQR (upper and lower box boundaries), standard deviation (whiskers), and outliers (black dot) (A). Rates of STMH by infliximab serum concentration quartiles at weeks 2, 6, and 14 (P values indicate comparison across quartiles, c2 test (linear-by-linear association) (B). w, week.
Infliximab exposure during the induction therapy, defined as the area under the infliximab concentration curve between time point weeks 0 and 14 (AUCw0-w14), was higher in patients with STMH compared with those without (P ¼ .003) (Figure 4).
Antibodies to Infliximab and Short-term Mucosal Healing During the induction therapy only 5 patients (5%) developed ATI, all of whom did not achieve STMH; 1 developed ATI early at week 2, although probably
Univariate analysis identified female gender (P ¼ .039), concomitant IMMs at start of infliximab (P ¼ .028), ATI at week 6 (P ¼ .043), and infliximab concentrations at week 2 28.3 mg/mL (P ¼ .002), week 6 15 mg/mL (P ¼ .001), and week 14 2.1 mg/mL (P < .001) as variables associated with STMH (Table 2, Supplementary Table 2). No multicollinearity between infliximab concentrations at weeks 2, 6, and 14 was observed (VIF ¼ 2.4<3). Multivariable binary logistic regression analysis retained infliximab concentration 15 (P ¼ .025; OR, 4.6; 95% CI, 1.2–17.1) and 2.1 mg/mL (P ¼ .004; OR, 5.6; 95% CI, 1.7–18) at weeks 6 and 14, respectively, as independent factors associated with STMH (Table 2). To evaluate the predictive value of baseline variables and infliximab serum concentrations at weeks 2 and 6 related to STMH, the same analysis was made excluding the infliximab serum concentration at week 14. Multivariable binary logistic regression analysis retained only infliximab concentration at week 6 15 mg/mL (P ¼ .012; OR, 3.3; 95% CI, 1.3–8.4) as independent factor associated with STMH.
Discussion A treat-to-target approach leading to better clinical outcomes is emerging as a new therapeutic strategy, although relevant serum drug concentrations differ depending on the chosen therapeutic outcome.27–29 We demonstrated that higher infliximab concentrations during the induction therapy are associated with STMH in UC, and we identified infliximab concentration thresholds that are independently associated with STMH. These findings are consistent with previous studies reporting an association between serum antiTNF drug levels and mucosal healing in patients with IBD, although most of them refer to the maintenance therapy.16,18,24,27 Regarding induction therapy, higher plasma concentrations of certolizumab at week 8 were associated with higher rates of endoscopic response
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Figure 4. Total infliximab exposure of patients with and without STMH. Average infliximab concentrations for UC patients with or without STMH are represented by (-) and (), respectively, and AUC 95% CIs are represented by the red and black dotted lines, respectively.
and remission at week 10 in CD patients,17 whereas a post hoc analysis of the ACT-1 and ACT-2 data have shown that higher serum infliximab concentrations were associated with higher rates of mucosal healing at week 8 in UC patients treated with either 5 or 10 mg/kg.24 Moreover, in the same study the presence of an infliximab concentration of approximately 22 mg/mL at week 6 was associated with clinical response at week 8.24 In a retrospective analysis of the ACCENT I trial, median values in the 5 mg/kg maintenance arm were 12.9 and 4.0 mg/mL in CD patients with sustained response compared with 8.8 and 1.9 mg/mL in patients without at weeks 6 and 14, respectively.14 In a recently published post hoc analysis of a multicenter prospective randomized controlled trial regarding UC patients, infliximab concentration 20.7 mg/mL at week 2 was significantly associated with clinical remission on the basis of the clinical activity index (CAI) at week 14 (OR, 2.75; 95% CI, 1.13–6.93; P ¼ .025), whereas week 2 infliximab concentration to CAI ratio was an independent factor associated both with week 14 CAI remission and week 30 mucosal healing.30
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In our study, patients in the lowest infliximab concentration quartile at different time points during the induction phase were found to have a higher baseline inflammatory burden reflective of a more extended (pancolitis) and active disease state (acute severe UC, baseline endoscopic Mayo score of 3, lower baseline BMI and albumin, higher baseline CRP) as well as higher ATI compared with those in the other quartiles, which is in agreement with other studies.17,24,31–33 Thus, it is suggested that patients with a high baseline inflammatory burden and a rapid drug clearance should be treated with accelerated and not standard anti-TNF regiments.34–38 Nevertheless, in this study, although degree of baseline inflammation (eg, CRP, extent of colitis, etc) affected infliximab concentrations, it did not affect the rate of STMH. This probably implies that drug concentrations achieved by standard dosing are within the therapeutic range for the spectrum of inflammatory burden treated in this cohort, and it is not that patients with higher inflammatory burden “need more drug” and fail this standard regimen more often. Besides pharmacokinetics, maybe other factors are also important for achieving STMH or not. In addition, female gender and concomitant IMMs were associated with higher infliximab concentrations as previously shown.5,20,24,28,39,40 The main limitations of this study are its retrospective nature and the lack of fecal calprotectin levels and histologic data,41 because UC patients in clinical and endoscopic remission under infliximab may still have histologic features of inflammation.42 Moreover, high serum infliximab concentrations may not be the reason but rather a consequence of mucosal healing preventing infliximab fecal loss from a leaky gut with severe inflammation.38 In conclusion, this large single-center study, which reflects real-life clinical practice, indicates that infliximab concentrations during induction phase are associated with STMH in UC patients. Nevertheless, before any clinical recommendations can be made, large prospective clinical trials that are based on a treat-to-target therapeutic approach including pharmacokinetic parameters of drug exposure (peak concentration, time
Table 2. Variables Associated With STMH Univariate analysis Prognostic markers Female Concomitant IMMsa at infliximab initiation Infliximab concentration at week 2 28.3 mg/mL Infliximab concentration at week 6 15 mg/mL Infliximab concentration at week 14 2.1 mg/mL ATI at week 6
Multivariate analysis
OR 95% CI P value OR 95% CI P value SN (%) SP (%) PPV (%) NPV (%) 2.5 2.6 6 4.3 9 0.9
1.1–5.8 1.1–5.7 1.9–19.3 1.8–10.2 3.2–25.3 0.8–1
.039 .028 .002 .001 <.001 .043
4.6 1.2–17.1 5.6 1.7–18
.025 .004
60 84
NPV, negative predictive value; PPV, positive predictive value. a Thiopurines.
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Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at http://dx.doi.org/10.1016/j.cgh.2015.11.014.
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Reprint requests Address requests for reprints to: Marc Ferrante, MD, PhD, Department of Gastroenterology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. e-mail: [email protected]; fax: þ3216344419. Acknowledgments The authors thank Vera Ballet and Willem-Jan Wollants for doing an excellent job in maintaining the Leuven IBD patient database (V.B.) and Biobank (W-J.W.)
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Conflicts of interest These authors disclose the following: K. P. received a consultancy fee from MSD Hellas. N. V. C. received consultancy fees from Janssen Biologics MSD, UCB, and Takeda and speaker fees from AbbVie. A. G. received speaker fees from Pfizer, AbbVie, Janssen Biologicals, and MSD and financial support for research from Pfizer. G. V. A received financial support for research from Abbott and Ferring Pharmaceuticals, lecture fees from Janssen, MSD, and Abbott, and consultancy fees from PDL BioPharma, UCB Pharma, SanofiAventis, Abbott, AbbVie, Ferring, Novartis, Biogen Idec, Janssen Biologics, NovoNordisk, Zealand Pharma A/S, Millenium/Takeda, Shire, Novartis, and Bristol Mayer Squibb. P. R. received research grants from Abbott, AbbVie, Prometheus, MSD, and UCB Pharma and lecture and consultant fees from Abbott, AbbVie, MSD, UCB Pharma, Genentech Inc, Millenium, Neovacs, Actogenics, Amgen, Prometheus, Bristol-Myers Squibb, Falk Pharma, and Tillotts. S. V. received financial support for research from MSD, AbbVie, and UCB Pharma, lecture fees from Abbott, AbbVie, MSD, Ferring Pharmaceuticals, and UCB Pharma, and consultancy fees from Pfizer, Ferring Pharmaceuticals, Shire Pharmaceuticals Group, MSD, and AstraZeneca Pharmaceuticals. M. F. received financial support for research from Janssen Biologics, lecture fees from MSD, Ferring Pharmaceuticals Inc, Chiesi, MSD, Tillotts, Janssen Biologics, Abbott Laboratories, and AbbVie, and consultancy fees from Abbott Laboratories, AbbVie, MSD, and Janssen Biologics. The remaining authors disclose no conflicts.
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Funding Supported in part by the Research Foundation-Flanders (FWO), Belgium (grant number G.0617.12). Serological factors were analyzed by Prometheus Laboratories, San Diego, CA, which also provided additional research support funding. K. P. received a fellowship grant from the Hellenic Gastroenterology Society and the European Crohn’s and Colitis Organization (ECCO). N.V.C. is a Postdoctoral Fellow and S.V., G.V.A., and M.F. are Senior Clinical Investigators of the Research Foundation – Flanders (FWO), Belgium.
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