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Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0b013e3182a77b41
Original Clinical Articles

Therapeutic Drug Monitoring of Infliximab and Mucosal Healing in Inflammatory Bowel Disease: A Prospective Study

Paul, Stephane PhD*; Del Tedesco, Emilie MD; Marotte, Hubert MD, PhD; Rinaudo-Gaujous, Melanie MD*; Moreau, Amelie MD*; Phelip, Jean-Marc MD, PhD; Genin, Christian MD, PhD*; Peyrin-Biroulet, Laurent MD, PhD§; Roblin, Xavier MD, PhD

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*Immunology and Immunomonitoring Department, Laboratoire d’Immunologie et d’Immunomonitoring, CHU de Saint-Etienne, Saint-Étienne, France;

Service de Gastrologie-Entérologie-Hépatologie, CHU de Saint-Etienne, Saint-Étienne, France;

Service de Rhumatologie, CHU de Saint-Etienne, Saint-Étienne, France; and

§Service de Gastroenterologie, CHU Nancy, Nancy, France.

Reprints: Xavier Roblin, MD, PhD, Department of Gastroenterology, CHU de Saint-Etienne, 42023 Saint-Etienne, France (e-mail: xavier.roblin@chu-st-etienne.fr).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

L. Peyrin-Biroulet, lecture and consulting fees from Merck; X. Roblin, lecture and consulting fees from Merck and Theradiag. The other authors have no conflicts of interest to disclose.

Received July 09, 2013

Accepted July 30, 2013

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Abstract

Background: Data on the value of therapeutic drug monitoring of infliximab (IFX) to predict mucosal healing (MH) in inflammatory bowel diseases (IBD) are scarce.

Methods: All consecutive patients with IBD receiving ongoing IFX (5 mg/kg) treatment and developing secondary failure to IFX were enrolled in a prospective study between June 2010 and May 2011. IFX trough levels, antibodies to IFX concentrations, C-reactive protein levels, and fecal calprotectin were measured before IFX optimization and at week 8. A proctosigmoidoscopy was performed on the day of first IFX optimization and at week 8 in all patients with ulcerative colitis (UC). MH was defined by fecal calprotectin <250 μg/g stools in Crohn's disease (CD) and by an endoscopic Mayo score of 0 or 1 in UC.

Results: This study included 52 patients with IBD: 34 patients with CD (mean Crohn's Disease Activity Index, 300; mean C-reactive protein, 28 ± 10 mg/L; mean fecal calprotectin, 705 ± 300 μg/g) and 18 patients with UC (mean Simple Clinical Colitis Activity Index, 7; mean Mayo endoscopic score, 3). After IFX dose intensification, half of CD and UC patients achieved MH. Increase in IFX trough levels (called “delta IFX” in micrograms per milliliter) was associated with MH in both CD and UC (P = 0.001). A delta IFX >0.5 μg/mL was associated with MH (sensitivity [se], 0.88; specificity [sp], 0.77; P = 0.0001, area under the receiver operating characteristic curve, 0.89). On multivariate analysis, the only factor associated with MH after IFX optimization was a delta IFX >0.5 µg/mL (likelihood ratio = 2.02; 95% confidence interval, 1.01–4.08; P = 0.048) in patients with IBD.

Conclusions: Therapeutic drug monitoring of IFX strongly predicts the likelihood of achieving MH following IFX dose intensification in both CD and UC.

Anti–tumor necrosis factor (TNF) agents (e.g., infliximab [IFX] and adalimumab) have changed the way patients with inflammatory bowel disease (IBD) are treated. However, only one-third of patients with IBD who are administered IFX or adalimumab will be in clinical remission at 1 year.1 In addition, secondary loss of response is relatively frequent with all anti-TNF agents.2,3 As our therapeutic armamentarium is still limited in patients with IBD refractory to standard medications, it is highly desirable to optimize both initial response and long-term continuation of TNF antagonists.4 One of the most well-characterized factors associated with loss of response to these agents is the development of immunogenicity, whereby the production of neutralizing anti-drug antibodies accelerates drug clearance leading to subtherapeutic drug concentrations and, finally, to treatment failure.1,3,4

In 2009, a systematic review concluded that there is no clear evidence that antibodies to IFX (ATIs) have an impact on efficacy nor a need to measure or prevent them in clinical practice and that circulating drug concentration may be a more relevant measure of immunogenicity.5 Overall, data are scarce and conflicting in IBD, but most available data come from retrospective studies.6 Post hoc analyses from placebo-controlled trials with TNF antagonists and some recent studies have suggested that the use of IFX trough levels and ATI is correlated with clinical efficacy.7,8 Over the past years, mucosal healing (MH) has emerged as a major therapeutic goal in clinical trials in IBD. Accumulating evidence indicates that MH may change the natural course of the disease by decreasing the need for surgery and reducing hospitalization rates in both ulcerative colitis (UC) and Crohn's disease (CD).9 The relationships between IFX trough levels and ATI and MH are unknown in IBD.

We therefore first conducted a cross-sectional and observational study to research a cutoff of trough residual level of IFX associated with clinical remission and ATI levels associated with loss of response to IFX. In a second part, in a prospective and interventional study, we explored the clinical utility of therapeutic drug monitoring of IFX and notably these isolated cutoffs in predicting clinical remission and MH rates following IFX dose intensification for flare-up in patients with IBD.

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MATERIALS AND METHODS

Study Population
Cohort 1

All consecutive patients with IBD receiving scheduled IFX treatment at Saint-Etienne University Hospital were enrolled in a prospective observational study between June 2010 and May 2011. All patients with IBD were treated with a scheduled IFX strategy (IFX infusion every 8 wk at 5 mg/kg) and presented a primary response to IFX defined by a clinical remission after induction treatment.

A total of 103 patients with IBD were included in this prospective study. Standard operating procedures for infusions of IFX are used in our IBD unit. The infusion unit was staffed by the same nurses since several years and direct medical supervision was always available. Similarly to all patients treated in the Saint-Etienne IBD unit, all patients received a routine prophylactic premedication by intravenous corticosteroids (200 mg of hydrocortisone) before IFX treatment.

All adult patients with an established diagnosis of CD or UC for at least 3 months were eligible for inclusion in the study (study 2012-007, Clinical Investigation Center and Health Ministry).

Exclusion criteria were as follows: patients' refusal to enter the study, exclusive active perianal CD, IFX maintenance regimen at a dose above 5 mg/kg, and primary nonresponders to IFX therapy. Clostridium difficile toxin results were negative in all included patients, and all patients with UC were also negative for cytomegalovirus by PCR on inflamed tissues at the time of inclusion as routinely done in our center.

At every IFX infusion, the Crohn's Disease Activity Index (CDAI) for patients with CD10–12 and the Simple Clinical Colitis Activity Index (SCCAI) for patients with UC13 were calculated.

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Definitions

Loss of response to IFX was defined as an active disease after primary response to at least the first 4 IFX infusions as judged by the physician. Active disease was defined by a CDAI score >220 associated with a C-reactive protein concentration >10 mg/L and fecal calprotectin level >450 µg/g stools for patients with CD, and by a SCCAI ≥3 associated with an endoscopic Mayo score above 1 for UC and indeterminate colitis patients.14 A clinical remission was defined by a CDAI <150 for patients with CD and by a SCCAI <3 for both UC and indeterminate colitis patients.15

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Cohort 2

Between November 2010 and May 2011, 52 patients with IBD requiring IFX optimization for active disease with indirect (high fecal calprotectin level) or direct (endoscopic disease activity) signs of mucosal lesions (CDAI >220 and calprotectin >450 µg/g stools for CD, SCCAI >3, and Mayo score endoscopic >1 for UC) while receiving IFX maintenance treatment with 5 mg/kg every 8 weeks for at least 6 months were prospectively followed.

We included only primary responders to IFX who have responded for at least 6 months to IFX and without any dose optimization or loss of response to IFX at the time of inclusion. Dose optimization was decided by the treating physician in case of loss of response. Accordingly, no patient with IBD enrolled lost response before inclusion in the study. Of note, we included only patients with CD with normal calprotectin level <250 µg/g before study inclusion to reduce the number of patients with false-positive results for fecal calprotectin. Only patients with stable concomitant medications during 3 months before IFX were included in the analysis. Other exclusion criteria were as follows: patients' refusal to enter the study (study 2012-007, Clinical Investigation Center and Health minister), exclusive active perianal CD, IFX maintenance regimen at a dose above 5 mg/kg, and primary nonresponders to IFX therapy. Research of toxin of C. difficile toxin was negative in all included patients, and all patients with UC were also negative for cytomegalovirus by PCR on inflamed tissues at the time of inclusion as routinely done in our center.

All patients were optimized with IFX 10 mg/kg every 8 weeks. Clinical activity (CDAI for CD, SCCAI for UC) and direct or indirect mucosal lesions (fecal calprotectin in CD and endoscopic Mayo score) were reported for all included patients at week 8.

A clinical remission was defined by a CDAI <150 for patients with CD and by a SCCAI <3 for both UC and indeterminate colitis patients.15 MH was defined by fecal calprotectin <250 µg/g stools in CD16 and by an endoscopic Mayo score of 0 or 1 in UC. The endoscopist (E.D.T. or X.R.) who performed the second proctosigmoidoscopy was masked to the first endoscopic findings and to the results of therapeutic drug monitoring of IFX.

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Therapeutic Drug Monitoring of IFX

Serum samples are routinely and systematically collected just before each IFX infusion for all patients with IBD in our center blindly of clinical data and stored at −20°C. TNF, IFX and ATI concentrations were all measured using the Lisa-Tracker Premium Infliximab enzyme linked immunoassay (ELISA) kit (Theradiag, Marne La vallée, France). This assay has been developed to reduce low affinity binding of immune complexes or interfering molecules such as the rheumatoid factor. The use of specific buffers for both binding and washing steps allows a very efficient capture of free molecules. IFX trough levels were measured immediately before IFX infusion. Fecal calprotectin was measured in stools using the Quantum Blue Calprotectin assay (Buhlmann Laboratories, Schonenbuch, Switzerland).

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Statistical Analysis

Continuous variables were expressed as mean and SD, and categorical variables were expressed as percentage. The χ2 test and the Mann–Whitney test were used to compare categorical and quantitative variables. When considering trough levels of IFX and ATI, a receiver operating characteristic (ROC) curve analysis was performed using clinical remission as a classification variable to calculate the sensitivity (Se), specificity (Sp), likelihood ratio (LHR), and area under the ROC curve (AUROC) with the associated P value. In the intensification part, delta IFX was defined by IFX trough level after optimization minus IFX trough level before optimization. Se, Sp, LHR, and AUROC were determined for clinical remission and mucosal healing. All reported P values were 2-sided, and P < 0.05 was considered statistically significant. A logistic regression analysis was performed to estimate odds ratio of mucosal healing and clinical remission. Statistical analysis was performed using IBM SPSS 20.0.0 (IBM, Somers, NY).

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RESULTS

Clinical Remission Rates According to Therapeutic Drug Monitoring of IFX (Cohort 1) (N = 103)

The baseline demographic and clinical characteristics of the 103 patients included between June and October 2010 in this cross-sectional study are reported in Table, Supplemental Digital Content 1, http://links.lww.com/IBD/A279.

For CD (N = 55), the mean age was 35.5 ± 12.2 years and sex ratio (M/F) was 1. The mean disease duration was 7.5 ± 4.3 years and mean IFX therapy duration was 13.9 ± 8.4 months. Twenty patients (41%) were receiving concomitant thiopurine treatment. At study inclusion, 15 patients (28%) had active disease with a mean CDAI of 280 ± 35. The mean C-reactive protein level was 33 ± 33 mg/L. Eight patients (13%) had previous exposure to adalimumab.

For UC (N = 48), the mean age was 42.4 ± 16.1 years, with a sex ratio (M/F) of 1.4. The mean disease duration was 8.4 ± 3.2 years and the mean duration of IFX therapy was 12.5 ± 9.5 months. Twenty-three patients (44%) were receiving concomitant thiopurine treatment. No patients were on methotrexate and 20% in patients with UC were on 5 aminosalicylates. Effectively in our center, patients are not treated by both anti-TNF and 5 aminosalicylates because there is no clear evidence on the association of these 2 drugs. Twenty-two patients (46%) had active luminal disease with a mean SCCAI of 8.2 ± 2.6. The mean C-reactive protein level was 25 ± 24 mg/L.

The mean IFX trough level was higher in patients with CD in clinical remission (2.2 versus 0.8 μg/mL for patients with active disease; P < 0.0001) and in patients with UC in clinical remission (1.9 versus 0.9 μg/mL; P = 0.01) (Fig., Supplemental Digital Content 2, http://links.lww.com/IBD/A280). A total of 34 (32.8%) patients with IBD had detectable ATI when using a cutoff of 10 ng/mL (25.4% for CD and 41.5% for UC); this percentage increased to 65.3% when using a cutoff of 5 ng/mL (Table, Supplemental Digital Content 3, http://links.lww.com/IBD/A281).

Median ATI level was 43 ng/mL (range, 5–300 ng/mL). ATI level was lower in patients with IBD in clinical remission than in those with active disease (P = 0.017; Fig. A, Supplemental Digital Content 4, http://links.lww.com/IBD/A282). A cutoff of 200 ng/mL for ATI could discriminate responders to IFX from patients who lost response to IFX with a low sensitivity (22%) but a high specificity (93.5% LHR = 2.8; P = 0.032; AUROC = 0.61). Half of patients with detectable IFX trough levels had ATI levels above 10 ng/mL (62.5% for CD and 40% for UC; see Table, Supplemental Digital Content 5, http://links.lww.com/IBD/A283).

Of note, TNF-α concentration was not correlated with clinical activity in patients with CD and UC (data not shown). A threshold of less than 2 μg/mL for IFX trough level was strongly associated with the absence of clinical remission in both patients with CD and patients with UC (Se = 76%; Sp = 82.3%; LHR = 4.7; P = 0.017; AUROC = 0.68).

Rates of clinical remission were not influenced by concomitant use of immunomodulators. The median levels of ATI and IFX trough levels were similar in patients with and without immunomodulators (37.3 versus 49.3 ng/mL; P = 0.9 for ATI and 2.4 versus 2.1 μg/mL; P = 0.41 for IFX trough levels).

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Impact of Therapeutic Drug Monitoring of IFX on Clinical Remission with Dose Intensification (Cohort 2) (N = 52)

A total of 52 patients were included (34 patients with CD and 18 patients with UC). The mean age was 34 years, with a sex ratio (M/F) of 0.8. About two-thirds of patients were receiving concomitant treatment with azathioprine. No patients were receiving methotrexate or mesalamine. The characteristics of these 52 patients are summarized in Table 1.

Table 1
Table 1
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Thirty patients with IBD (58%) were in clinical remission 8 weeks after IFX therapy optimization. IFX trough level before optimization was lower in patients with IBD who responded to IFX optimization (1.4 versus 2.9 μg/mL for those who did not respond to IFX optimization; P = 0.62). Mean ATI levels did not differ between responders and nonresponders to IFX dose intensification (15 ng/mL for both groups). Mean ATI levels were higher in patients with IFX trough levels <2 μg/mL than in those with IFX trough levels >2 μg/mL before IFX optimization (48 versus 11 ng/mL; P = 0.91).

Only 12 of 30 patients who responded to IFX optimization had detectable ATI levels before dose intensification (see Table, Supplemental Digital Content 6, http://links.lww.com/IBD/A284). Among the 33 patients with IBD with an IFX trough level <2 μg/mL before dose intensification, 26 patients had ATI levels <200; 25 patients (96%) achieved clinical remission at week 8 (Fig. 1A).

Figure 1
Figure 1
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ATI levels were undetectable in 20 patients and >10 ng/mL but <200 ng/mL in 25 patients. All 7 patients with IBD with ATI levels >200 ng/mL and IFX trough levels <2 μg/mL did not respond to IFX optimization.

Among the 19 patients with IBD with an IFX trough level >2 µg/mL before dose intensification, only 5 patients (26.2%) were in clinical remission at week 8 (Fig. 1A). Twelve of 13 patients with IFX trough levels >2 μg/mL and ATI levels >10 ng/mL did not respond to IFX optimization, and 2 of 6 patients with IFX trough levels >2 μg/mL did not respond to IFX optimization despite undetectable ATI levels (see Table, Supplemental Digital Content 7, http://links.lww.com/IBD/A284). A trough level of IFX <2 μg/mL associated with ATI <200 ng/mL was strongly predictive of clinical remission for both CD and UC (Se = 0.85 and 0.7; Sp = 0.87 and 1; positive predictive value [PPV] = 0.89 and 1; negative predictive value [NPV] = 0.89 and 0.72, respectively).

IFX trough levels were also measured after dose intensification. An increase in IFX trough (considered as a positive Delta IFX) was strongly associated with clinical remission rates after IFX optimization (P = 0.0001), with similar results for CD and UC (Fig. 1B).

Percentages of clinical remission increased in parallel with delta IFX. The rate of clinical remission was 7% in patients with IBD with a percentage of delta IFX under 0; 25% of clinical remission if percentage of delta IFX was between 0% and 50%, 78% of clinical remission if percentage of delta IFX was between 50% and 100%, and 84% of MH for values of delta IFX higher than 100%. None of the patients with a “delta IFX” higher than 100% and who achieved clinical remission at week 8 (N = 14) had IFX trough levels >2 μg/mL before IFX dose intensification (Fig. 1C).

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Impact of the Percentage of Increase in IFX Trough Levels on Mucosal Healing Rates (Cohort 2)

Twenty-six of 52 patients with IBD achieved MH 8 weeks after IFX optimization. Mean IFX trough levels before optimization were comparable in patients with IBD with and without MH (2.6 versus 3.2 μg/mL; P = 0.6), with similar results for CD and UC. Mean ATI levels before optimization did not differ between patients with MH after optimization and those who did not achieve MH (22 versus 35 ng/mL; P = 0.11).

An increase in IFX trough levels after dose intensification (considered as a positive delta IFX, in micrograms per milliliter) was strongly associated with MH in patients with IBD (P < 0.0001). Similar results were obtained for CD (P = 0.0003) and UC (P = 0.0027) (Fig. 2A). The analysis of quartiles of delta IFX showed a parallel increase between IFX trough levels and MH rates (Fig. 2B). The median delta IFX was higher in patients with IBD who achieved MH than in those who did not achieve MH (2.2 versus 0.2 μg/mL, respectively; P < 0.001), with similar results for CD (+2.5 versus −0.01, P = 0.0003) and UC (+2.65 versus −0.9, P = 0.027) (Fig. 2A).

Figure 2
Figure 2
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ROC curve analysis identified 0.5 μg/mL as the optimal cutoff for delta IFX to predict MH for patients with IBD (N = 52) (Fig. 3A). These results were broadly similar for patients with UC (N = 18), with Se = 70%, Sp = 100%, PPV = 100%, and NPV = 72% (Fig. 3A), and patients with CD (N = 34), with Se = 94%, Sp = 76%, PPV = 80%, and NPV = 92%.

Figure 3
Figure 3
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The median delta IFX was similar in patients with and without concomitant immunomodulators (1.3 versus 0.9 μg/mL; P = 0.09).

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Impact of Therapeutic Drug Monitoring of IFX on Mucosal Healing Rates (Cohort 2)

Among the 33 patients with IBD with an IFX trough level <2 µg/mL before dose intensification, 22 of 26 patients with ATI levels <200 ng/mL (69%) achieved MH at week 8. All 7 patients with IBD with ATI levels >200 ng/mL and IFX trough levels <2 μg/mL did not respond to IFX optimization. Among the 19 patients with IBD with an IFX trough level >2 μg/mL before dose intensification, only 4 patients (21%) achieved MH at week 8. Eleven of 12 patients (n = 12) with IFX trough levels >2 μg/mL and ATI levels >10 ng/mL did not respond to IFX optimization (Fig. 3B). A threshold of trough levels of IFX <2 μg/mL associated with ATI <200 ng/mL was strongly predictive of MH for patients with CD (P = 0.004) and UC (P = 0.015) (Se = 88% and 80%; Sp = 76% and 87%; PPV = 78% and 88%; and NPV = 86% and 77%, respectively).

Percentages of mucosal healing increased in parallel with delta IFX: the rate of MH was 0% in patients with IBD with a % delta IFX under 0; 40% of MH if % delta IFX was between 0% and 50%; 85% of MH if % delta IFX was between 50% and 100%; and 77% of MH for values of delta IFX >100%. None of the patients with a delta IFX >100 and who achieved MH at week 8 (N = 11) had IFX trough levels >2 before IFX dose intensification.

Only 2 of 19 patients with trough levels >2 μg/mL before optimization had an increase of 50% to 100% of delta IFX. Conversely, 19 of 26 patients with trough levels <2 μg/mL before optimization had an increase of delta IFX higher than 50% (Fig. 3C).

The median levels of ATI and IFX trough levels before optimization were similar in patients with and without concomitant immunomodulator (35.3 versus 46.5 ng/mL; P = 0.9 for ATI trough levels and 2.2 versus 1.9 μg/mL; P = 0.52 for IFX trough levels).

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Baseline Factors Associated with Clinical Remission and Mucosal Healing Following IFX Dose Intensification (Cohort 2)

In univariate analysis, 3 factors were associated with clinical remission after optimization: IFX <2 μg/mL before optimization (P = 0.03), a delta IFX >0.5 μg/mL (P = 0.02), and IFX <2 μg/mL with ATI < 200 ng/mL (P = 0.03). In our results, UC was not significantly associated with clinical remission in univariate analysis (P = 0.085), but this factor was included in our logistic regression. Concomitant immunomodulators use was not associated with clinical remission (P = 0.9).

In multivariate analysis, 2 factors were independently associated with clinical remission after optimization: IFX <2 μg/mL before optimization (LHR, 10.3; 95% confidence interval [CI], 1.24–82.6; P = 0.031) and a delta IFX >0.5 μg/mL (LHR, 2.34; 95% CI, 1.03–5.2; P = 0.044). The type of IBD was not associated with clinical remission (UC, LHR = 0.87; P = 0.82; Fig. 4A).

Figure 4
Figure 4
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In univariate analysis, 3 factors were associated with MH after optimization: IFX <2 μg/mL before optimization (P = 0.04), a delta IFX >0.5 μg/mL (P = 0.02), and IFX <2 μg/mL with ATI <200 ng/mL (P = 0.05). In our results, UC was not significantly associated with MH in univariate analysis (P = 0.09), but this factor was included in our logistic regression. Concomitant immunomodulators use was not associated with MH (P = 0.8).

In multivariate analysis, only a delta IFX >0.5 μg/mL after optimization was independently associated with MH (LHR, 2.02; 95% CI, 1.01–4.06; P = 0.048). There was a trend for an association between IFX <2 μg/mL before optimization and MH (LHR, 5.28; 95% CI, 0.82–34.3; P = 0.08). The type of IBD was not associated with MH (UC: LHR, 3.1; P = 0.267; Fig. 4B).

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DISCUSSION

This is the first prospective study investigating the clinical utility of therapeutic drug monitoring of IFX following dose intensification in both CD and UC to predict clinical remission and MH.

In a first cohort of patients with IBD, we first demonstrated that both patients with UC and patients with CD in clinical remission had significantly higher IFX trough levels than those with active disease, thus confirming previous reports.17–23 The clinical utility of therapeutic drug monitoring of IFX outside an acute setting was poorly known in UC.22

We also found that ATI levels were associated with loss of response to IFX. The ELISA used in our study was able to assess ATI levels independently from IFX trough concentrations. This may partly explain the discrepancy between our results and previous reports.17,19–25

In a second cohort of patients with IBD, we prospectively evaluated the impact of therapeutic drug monitoring of IFX on response to dose intensification in patients with IBD, who lost response to IFX. All patients with ATI levels >200 ng/mL did not respond to IFX optimization, whereas all patients with IFX trough levels <2 μg/mL and ATI levels <200 ng/mL responded to IFX dose intensification.

Two recent studies provided conflicting results.17,20 However, no definite conclusions could be drawn from these studies because of their retrospective study design and the lack of evaluation of clinical disease activity using validated tools, such as CDAI. In addition, cutoff values were determined by the manufacturers, and the authors could not analyze the clinical utility of evaluating ATI levels in combination with IFX trough levels. Finally, some patients had inconclusive tests because of the method used for therapeutic drug of IFX in both studies.17,20 The study by Vande Casteele et al26 recently compared homogenous mobility shift assay (HMSA) and ELISA techniques. In the presence of IFX, the HMSA seems to be more sensitive in detecting ATI than ELISA: 1 patient was classified as having transient ATI when analyzed by HMSA and as ATI negative when analyzed by ELISA. Overall, ATI were detected approximately 1 time point early by HMSA (median 16 wk) in comparison with ELISA (median 25 wk) after start of IFX. This owing to a lower susceptibility to drug when measuring ATI in the HMSA compared with ELISA. Although some patients were classified differently, the ATI results obtained with both assays correlated well (Pearson R = 0.83).26

Furthermore, we evaluated the kinetics of trough levels of IFX and ATI before and after optimization. IFX trough levels only increased among patients who responded to IFX dose intensification. Importantly, none of the 7 patients with ATI levels >200 ng/mL and undetectable IFX trough levels before IFX optimization had a detectable IFX trough level after IFX dose intensification, indicating that these are neutralizing antibodies. In line with our findings, a recent study found that the success of clinical adjustment was correlated with a significant increase in IFX trough levels (P < 0.01), whereas no increase in IFX trough levels was observed in patients with no clinical response.27

Most authors recommend switching IFX treatment to another biological agent in patients with high ATI and low IFX trough levels.17,28 In our study, IFX dose intensification in association with azathioprine treatment initiation in patients not receiving concomitant immunomodulators at study inclusion resulted in a decrease of ATI levels and an increase in IFX trough levels, with half of patients achieving clinical remission at week 8.

In multivariate analysis, 2 factors were independently associated with clinical remission after IFX optimization: IFX <2 μg/mL before drug optimization (LHR, 10.3; 95% CI, 1.24–82.6; P = 0.031) and a delta IFX >0.5 μg/mL (LHR, 2.33; 95% CI, 1.03–5.2; P = 0.044).

Data on MH and therapeutic monitoring of IFX are scarce in IBD. An association between IFX trough levels and MH has been reported in a cohort of 210 patients with CD.25

Recently, a correlation between trough levels of certolizumab (CZP) and MH has been also reported in a post hoc analysis of the MUSIC trial.29 In a cohort of 45 patients, higher Crohn's Disease Endoscopic Index of Severity remission was observed in upper CZP plasma concentration quartiles.29

By using a prospective study, we demonstrated that an increase in IFX trough levels after dose intensification (considered as a positive delta IFX) was strongly associated with MH in patients with IBD (P < 0.0001). Similar results were obtained for CD and UC. Interestingly, there was a parallel increase between IFX trough levels and MH rates by analyzing quartiles of delta IFX. The median delta IFX was higher in patients with IBD who achieved MH than in those who did not achieve MH (2.2 versus 0.2 μg/mL, respectively; P < 0.001). ROC curve analysis identified 0.5 μg/mL as the optimal cutoff for delta IFX to predict MH in IBD. This small delta IFX affects remission and healing results. Indeed, in the article by Van de Casteele et al,26 the delta IFX trough level was significantly greater in patients with a successful IFX dose adjustment (+2.7 μg/mL) compared with patients with an unsuccessful IFX dose adjustment (delta IFX trough level = 0.0 μg/mL; P < 0.00001). In our study, we observed a similar range of delta IFX of 2.2 versus 0.2 for nonresponding patients. Karmiris et al30 reported similar findings with adalimumab. After dose escalation of adalimumab, adalimumab trough serum concentration increased from 4.8 to 9.4 μg/mL and the increase correlated well with the clinical response to escalation (5.9 μg/mL for responders versus 0.0 μg/mL for non responders; P > 0.0001).30

Similar to clinical remission, all 7 patients with IBD with ATI levels >200 ng/mL and IFX trough levels <2 μg/mL did not respond to IFX optimization. Consistently, a threshold of trough levels of IFX <2 μg/mL associated with ATI <200 ng/mL was strongly predictive of MH in both CD and UC. Only 2 of 19 patients with trough levels >2 μg/mL before optimization had an increase of 50% to 100% for delta IFX, with no delta IFX >100%.

In multivariate analysis, only a delta IFX >0.5 μg/mL after drug optimization was independently associated with MH (LHR, 2.02; 95% CI, 1.01–4.06; P = 0.048). Recently, Afif et al17 proposed a treatment algorithm to manage patients based on the results of therapeutic drug monitoring of IFX. This algorithm seems still valid according to our results.

Based on our results, we propose here a modified treatment algorithm for these patients taking into account both ATI and IFX trough levels. Our study clearly lacks power to evaluate the impact of immunomodulators use on clinical outcomes and therapeutic drug monitoring of IFX. In the study by Ben-Horin et al,31 the authors performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed ATI restored response to this drug. In all patients, levels of ATIs gradually decreased and trough levels of IFX increased; clinical responses were restored to all patients (Fig. 4C).31 Because of small sample size, our results need to be confirmed in studies including a higher number of patients.

The main strengths of our study are its prospective study design and the systematic evaluation of clinical disease activity using CDAI for CD and SCCAI for UC. Only fecal calprotectin was used to assess MH in CD, but recent reports indicate that it is a reliable measure of endoscopic activity.16 Even though fecal calprotectin may be an approximation compared with endoscopic evaluation, D'Haens et al16 reported that a fecal calprotectin below 250 μg/g stools for CD predicted mucosal healing defined by a Crohn's Disease Endoscopic Index of Severity ≤3 with 94% sensitivity, 62% specificity, and PPV and NPV to 48% and 96%, respectively. Endoscopy was performed in all patients with UC to assess mucosal lesions as routinely done in our center. Importantly, by using a prospective study, we could identify optimal cutoffs for ATI and IFX trough levels. Furthermore, we evaluated the clinical utility of measuring ATI levels in combination with IFX though levels in patients with IBD on IFX. Finally, even though CD and UC were analyzed together because of the relatively small number of patients, we could demonstrate by subgroup analysis that IBD type did not influence our results.

In conclusion, our data suggest that the measurement of ATI and IFX trough levels may be helpful to predict clinical remission and MH in both CD and UC and that therapeutic drug monitoring of IFX may guide decisions in clinical practice in these patients.

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ACKNOWLEDGMENTS

The whole study was conceived and designed by S.P., and X.R. Statistical analysis was performed by H.M. All authors (S.P., E.D.T., H.M., M.R., A.M., L.C., C.G., J.M.P., and X.R.) were involved in the interpretation of results and discussion. S.P., L.P.B., and X.R. have drafted the manuscript, which was critically revised by all the authors (S.P., E.D.T., H.M., M.R., A.M., L.C., C.G., J.M.P., L.P.B., and X.R.). All authors also approved the final version of the manuscript.

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Keywords:

Crohn's disease; ulcerative colitis; IFX trough levels; ATI; optimization; clinical response; mucosa healing

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