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Original Articles: Gastroenterology: Inflammatory Bowel Disease

Association Between Infliximab Drug and Antibody Levels and Therapy Outcome in Pediatric Inflammatory Bowel Diseases

Ungar, Bella∗,†; Glidai, Yoav†,‡; Yavzori, Miri∗,†; Picard, Orit∗,†; Fudim, Ella∗,†; Lahad, Avishay; Haberman, Yael†,‡; Shouval, Dror S.†,‡; Weintraub, Ilana; Eliakim, Rami∗,†; Ben-Horin, Shomron∗,†; Weiss, Batia†,‡

Author Information
Journal of Pediatric Gastroenterology and Nutrition: October 2018 - Volume 67 - Issue 4 - p 507-512
doi: 10.1097/MPG.0000000000002051

Abstract

What Is Known

  • Reactive therapeutic drug monitoring of infliximab therapy in adult inflammatory bowel disease patients has been accepted as standard of care.
  • Lower drug levels and positive antibodies’ trough levels have been associated with loss of response in pediatric inflammatory bowel disease, although temporal relationship has not been clearly defined.

What Is New

  • Early infliximab drug and antibody levels are predictive of drug retention by 1 year of therapy.
  • A significant correlation exists between pediatric clinical scores and same time-point drug and antibody levels.
  • Reactive therapeutic drug monitoring can improve patient management in pediatric inflammatory bowel disease patients, similarly to adults.

Anti-TNFα agents, particularly infliximab (IFX), are considered the mainstay of biological therapy for inflammatory bowel diseases (IBD). IFX has been shown to induce clinical, inflammatory and endoscopic remission, to reduce hospitalizations and surgery rates (1–4), and is a leading therapy for moderate-severe pediatric IBD (5,6).

Therapeutic drug monitoring (TDM) is based on measurement of infliximab trough serum levels (TL) and antibodies-to-infliximab (ATI) for assistance in clinical decision-making. When applied upon loss of clinical response (LOR), reactive TDM has been shown to improve outcome. Specifically, IFX-TLs between 3 and 7 μg/mL have been correlated with clinical and endoscopic remission, while positive ATI have been associated with immunogenic LOR to therapy (7–9). Suggested interventions in cases of LOR include dose escalation for low TL, and a switch to another anti-TNF when ATI are detected (10).

TDM is emerging as a valid tool in pediatric IBD as well. Minar et al studied outcomes of clinical interventions, based on reactive TDM (11). They concluded that TDM resulted in improved rates of clinical remission, although this has not been reproduced. Most pediatric studies evaluating the association between IFX-TL, ATI, and clinical or biomarker remission demonstrated an association between drug levels and outcome, however, the number of serum samples or subjects were limited (12–15). Moreover, although infliximab administration is based on body weight, reactive TDM may still be more complex in children due to heterogeneity regarding pharmacokinetic properties (16–18) and body composition (19).

The aim of the present study was to better define the relationship between IFX-TL, ATI, and clinical or biomarker (C-reactive protein, CRP) disease activity in pediatric IBD patients throughout consecutive infliximab therapy. Our secondary aim was to examine the predictive value of early induction infliximab and ATI levels for end of induction and maintenance outcomes.

METHODS

We conducted a retrospective observational cohort study of IBD patients treated with infliximab at the Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Israel, between January 2011 and June 2017. Dosing schedule included induction infusions (weeks 0, 2, 6), followed by maintenance every 8 weeks. Dose intensification was performed at the discretion of the treating physician. Sera for IFX-TL and ATI were prospectively obtained before every infusion and measured at the Gastroenterology Laboratory, Sheba Medical Center. Patients with at least 3 consecutive measurements were included. Clinical, laboratorial, and demographic data were obtained from the patients’ charts. The study was approved by the hospital's ethics committee.

Clinical disease activity was prospectively determined on the infusion day by a pediatric gastroenterologist. Pediatric CD activity index (PCDAI) (20) or Harvey Bradshaw Index (HBI) (21) were applied for CD, and Pediatric UC activity index (PUCAI) (22) for UC patients. Clinical remission was defined by scoring <10 points on PUCAI or PCDAI (20,22), or <5 points on HBI (23). When clinical score was unavailable, we used the documented physician global assessment on infusion day. “Biomarker remission” was defined as CRP normalization. LOR was defined as an elevated clinical score, accompanied by a clinical decision to stop IFX. Immunogenic LOR-positive antibodies and low drug levels at time of LOR. Pharmacokinetic LOR-low drug levels at time of LOR. Pharmacodynamic LOR—LOR at time of normal drug levels and no antibodies. In order to determine whether induction IFX-TLs and ATI could predict clinical or biomarker remission during the first year of treatment, we addressed 3 end-points: week 14 of treatment week 54 of treatment, and infliximab therapy retention during the first year. An additional analysis of drug and antibody levels versus same time-point clinical score/CRP was performed. Infliximab drug and ATI levels were routinely measured at trough by employing the previously described infliximab ELISA assay, developed at Sheba's gastroenterology laboratory. This method allows reliable infliximab measurement in the presence of anti-drug antibodies (24,25).

Statistical Analysis

Continuous variables were analyzed by a 2-tailed Student t test or the Mann-Whitney U test, as appropriate. Correlations were analyzed by the Spearman rank correlation test. Categorical variables were analyzed by Fisher's exact test. Odds ratio (OR) and 95% confidence intervals (CIs) were computed for all variables compared. A receiver-operating characteristic (ROC) analysis was performed for infliximab and ATI trough levels using CRP normalization and clinical remission as classification variables. All statistics were performed using MedCalc software (version 12.2.1.0, Mariakerke, Belgium). A 2-tailed P < 0.05 was considered statistically significant.

RESULTS

Clinical Characteristics and Outcomes

During the study period, 110 patients received infliximab treatment. Forty-seven patients were excluded: 32 were referred for infusions only and had no clinical data, 3 lacked 3 consecutive measurements, and 12 had only 2 IFX-TL measurements. Out of the 63 patients included, 50 had CD and 13 UC. Baseline clinical and demographic characteristics of the study population are shown in Table 1. Median follow-up time was 16 months (IQR 5.5–36.5 months), and 773 sera were analyzed (median 8 per patient, IQR 4–17, range 3–42).

T1
TABLE 1:
Baseline characteristics of study population

Six patients (9.5%) did not complete induction therapy—5 (4 CD, 1 UC) experienced primary non-response and 1 had a severe allergic reaction. Median TL and ATI of the primary non-responders were 0.2 μg/mL (IQR 0.004–8.0 μg/mL) and 6.1 μg/mL-eq (IQR 1.0–8.0 μg/mL-eq), respectively. One patient received a concomitant immunomodulator and all patients had moderate-severe disease. During the first year, 2 additional patients had an allergic response requiring treatment termination. Seven patients (11%) stopped IFX treatment by week 54 due to loss of pharmacokinetic or pharmacodynamic response, and 9 (14%) had not completed 54 weeks of follow-up by the analysis time. Thus, 39 (62%) patients had sustained treatment through week 54, 75% of them were in clinical remission at that point. Dose escalation was necessary in 30 patients: 6-interval shortening, 9-dose escalation, and 15 both.

Cross Sectional Analysis of IFX-TL and ATI Versus Clinical and Biomarker Remission

Out of 773 samples, 682 (88.2%) were acquired during maintenance treatment—224 (32.8%) at time of active disease, and 458 (67.2%) at clinical remission, 327 (66.6%) samples were taken at time of a normal CRP, while 164 (33.4%) at time of elevated CRP. Only maintenance period samples were included in the cross-sectional analysis in order to minimize pharmacokinetic heterogeneity stemming from variability in infusion frequency during induction.

Samples obtained at clinical remission demonstrated significantly higher median IFX-TLs and lower median ATI levels than at time of active disease; IFX-TL 4.0 μg/mL (IQR 2.0–6.4) versus 2.25 μg/mL (IQR 0.5–4.7) (P < 0.0001), respectively (Fig. 1). Median ATI was 1.12 μg/mL-eq (IQR 0.6–2.0) compared to 1.0 μg/mL-eq (IQR 0.6–1.7) (P = 0.03), both below the assay's detection threshold. ATI frequency was not higher among patients with active disease (OR = 1.3, 95% CI 0.9–2 μg/mL-eq, P = 0.2, supp. Tables 1a and 1b https://links.lww.com/MPG/B404). Nevertheless, when stratifying ATI according to levels, high ATI (>9 μg/mL-eq) were more specific for active disease at the same time-point (60% versus 35%, OR = 3.3, P = 0.02).

F1
FIGURE 1:
Infliximab trough levels obtained during maintenance treatment in patients with clinically active disease versus patients in clinical remission.

An analysis of serum IFX-TL against same-point clinical activity scores demonstrated a negative correlation with PCDAI (191 samples, rho = −0.380, P < 0.0001), PUCAI (148 samples, rho = −0.308, P = 0.0001) and HBI (186 samples, rho = −0.33, P < 0.0001, Supplemental digital contents 1–3, https://links.lww.com/MPG/B404, https://links.lww.com/MPG/B405, https://links.lww.com/MPG/B406). IFX-TL ≥ 5.3 μg/mL was 80% sensitive (specificity 33.4%) for clinical remission (area under curve [AUC] = 0.64, P < 0.0001, Youden index = 0.23). IFX-TL of ≥ 6.1 μg/mL yielded 82.3% sensitivity and 30.9% specificity for biomarker remission (AUC = 0.57, P = 0.006)

A subanalysis of 529 CD and 153 UC patient samples was performed for association with clinical scores. In CD, IFX-TLs were significantly higher at clinical remission than during active disease (mean 5.3, 2.6 μg/mL, 95% CI 4.8–5.9, 2–3.15 μg/mL, P < 0.0001). Moreover, ATI levels were higher in active disease, than in clinical remission (mean ATI 2.4, 1.4 μg/mL-eq, 95% CI 1.7–3, 1.3–1.6 μg/mL-eq, P = 0.006). In UC, TLs association with clinical remission was borderline (mean 5.1, 2.5 μg/mL, 95% CI 3.8–6.4, 2.3–4.8 μg/mL, = 0.088) and ATI levels were not different between the subgroups (mean 1.5, 1.7 μg/mL, 95% CI 1.3–1.7, 1–2.4 μg/mL, P = 0.56).

Sera with normal CRP had higher median IFX-TL (3.3 μg/mL, IQR 1.27–6.11) than those with elevated CRP (median 2.7 μg/mL, IQR 0.7–5.1, P = 0.02), but no difference was demonstrated in ATI levels (P = 0.12, tables, Supplemental Digital Content 4 and 5, https://links.lww.com/MPG/B407, https://links.lww.com/MPG/B408). No correlation of IFX-TLs with CRP values (contrary to the categorical analysis) was detected.

Drug and Antibody Levels at Induction and Clinical Outcome

Patients in clinical remission by week 14 had significantly higher week 2 and 6 IFX-TLs than those not achieving remission. Median week 2 IFX-TL was 12.8 μg/mL (IQR 9.7–16.2) in clinical remission compared to 7.6 μg/mL (IQR 2.1–12.9) in clinically active patients (P = 0.02). Moreover, IFX-TL > 9.2 μg/mL at week 2 yielded sensitivity of 71.4% and specificity of 81.2% for clinical remission by week 14 (AUC = 0.73, P = 0.02). Median week 6 IFX-TL was 8.4 μg/mL, (IQR 6.9–17.0) versus 5.5 μg/mL (IQR 0.27–12.3), in patients with week 14 clinical remission versus active disease, respectively (P = 0.04). An IFX-TL > 7.2 μg/mL at week 6 yielded sensitivity of 72% and specificity of 68.5% for clinical remission by week 14 (AUC = 0.69, P = 0.03). ATI were more frequent (OR = 7.3, 95% CI 1.1–48, P = 0.03) at week 2, and their levels were significantly higher, in active disease than in remission (median 2.0 μg/mL (IQR 1.6–3.5), 1.2 μg/mL (IQR 0.45–2.0) respectively, P = 0.04). No association was demonstrated with week 6 ATI levels.

Median week 6 IFX-TLs were lower in patients with elevated CRP than in patients with CRP normalization by week 14 (1.65 μg/mL, IQR 0.1–6.3 versus 9.3 μg/mL, IQR 7.72–17.22, respectively, P = 0.007). Moreover, week 6 ATI levels were higher in patients with elevated CRP (5.0 μg/mL, IQR 0.7–13.35), than those in biomarker remission (1.0 μg/mL, IQR 0.4–1.9, P = 0.05). An analysis of week 2 ATI levels in relation to week 14 biomarker remission was not performed due to a small sample size (n = 23) (Supplemental Digital Content 6, https://links.lww.com/MPG/B409).

No association was detected between week 2, 6, or 14 IFX-TL and ATI levels and week 54 clinical remission (data not shown). Patients who had an elevated CRP at week 54 had significantly lower IFX-TL at week 6 (but not at 2 and 14) than those with biomarker remission (5.59 μg/mL, IQR 4.42–7.07, 10.65 μg/mL, IQR 8.2–12.7, respectively, P = 0.02).

Median week 6 and week 14 IFX-TLs were significantly lower in patients who stopped infliximab due to clinical worsening during the first year of therapy, versus those maintaining therapy (week 6 IFX-TLs: 8.0 μg/mL, IQR 6.57–13.7 versus 0.2 μg/mL, IQR 0.0–1.37, P = 0.0001, week 14 IFX-TLs: 3.8 μg/mL, IQR 1.4–6.07 vs 0.06 μg/mL, IQR 0.003–1.15, P = 0.0062, Fig. 2A). There was no difference in median week 2 IFX-TL between the 2 groups (median 9.2 μg/mL, IQR 7.05–14.4 vs 6.25 μg/mL (IQR 1.45–17.2), P = 0.40).

F2
FIGURE 2:
Early infliximab drug and antibody levels are predictive of drug retention by 1 year of infliximab therapy. A, Week 6 IFX-TLs of patients treated with infliximab beyond 1 year, versus patients who failed infliximab therapy beforehand. B, Week 6 ATI levels of patients treated with infliximab beyond 1 year, versus patients who failed infliximab therapy beforehand. C, Specificity and sensitivity of IFX-TLs at week 6 for sustained response for 1 year of treatment. D, Specificity and sensitivity of IFX-TLs at week 14 for sustained response for 1 year of treatment.

Week 6 and 14 median ATI levels were significantly higher among patients who stopped therapy due to clinical worsening, than among those retaining 1 year therapy (week 6 ATI: 10.3 μg/mL, IQR 3.12–14.87 versus 0.8 μg/mL, IQR 0.15–1.52, P = 0.0009, week 14 ATI: 7.5 μg/mL, IQR 2.14–12.92, versus 0.7 μg/mL, IQR 0.07–1.37 P = 0.0006, Fig. 2B, respectively). Week 2 ATI levels were higher in infliximab failure patients, with borderline significance (2.75 μg/mL, IQR 1.25–10.05. versus 1.1 μg/mL, IQR 0.35–1.85 in those maintaining therapy, respectively, P = 0.06).

IFX-TL > 2.2 μg/mL at week 6 yielded a sensitivity of 88.9% and specificity of 100.0% for treatment retention beyond 1 year (AUC = 0.974, P < 0.0001, Fig. 2C). IFX-TL > 4.2 μg/mL at week 14 yielded sensitivity of 88.9% and specificity of 33.3% for therapy retention by 1 year (AUC = 0.820, P = 0.009, Fig. 2D).

Predictors of Clinical Remission

The only parameters associated with clinical remission at week 14 were week 2 and 6 IFX-TLs and week 2 ATI levels (Supplemental Digital Content 7, https://links.lww.com/MPG/B410). While not associated with clinical outcome, concomitant immunomodulator therapy at induction was associated with higher IFX-TLs (5.6 μg/mL, 95% CI 4.9–6.3, vs 4.5 μg/mL, 95% CI 4–5 in patients with and without combination therapy, respectively, P = 0.01).

DISCUSSION

In the current study, a large cross-sectional analysis (n = 773) of IBD infliximab-treated sera was performed in 63 pediatric patients. To our knowledge, this is the largest reported analysis of association between pharmacokinetics and remission status in the pediatric IBD. A temporal analysis, evaluating the predictive value of early induction IFX-TLs and clinical and biomarker remission by the end of induction and by 1 year of therapy were also performed. Week 2 IFX-TLs over 9.2 μg/mL had 71% sensitivity and 81% specificity for week 14 clinical remission (26); however, week 6 IFX-TLs were associated only with week 54 CRP. This may stem from the limited number of patients at that specific analysis (n = 14), or from the problematic reproducibility of clinical scores. Therefore, the analysis of therapy retention was performed to overcome the potential bias of clinical score assessment.

LOR in our study was 30%, similar to the reported rate in adults (23%–46%) (15,27,28). Median maintenance IFX-TL in the general cohort (3.4 μg/mL, IQR 1.3–5.8), among responders (4.0 μg/mL, IQR 2.0–6.4) and non-responders (2.25 μg/mL, IQR 0.5–4.7) go in line with other pediatric studies (ranged 3.5 to 4.5 μg/mL) (12–14), which strengthens the validity of our findings (14,29). One recent study reported higher median IFX-TLs (4.0 vs. 7.25 μg/mL), possibly due to the stricter definition of remission (clinical index plus CRP normalization) (12).

Most of the pediatric studies reporting the association between IFX-TL and clinical or biomarker remission, demonstrated that drug and antibody levels were associated with clinical outcome, and only a minority of studies detected no association (13,14). In a recent study, a significant difference in IFX-TLs was shown between both CD and UC responders (median 3.99 μg/mL, IQR 0.30–21.96) and non-responders to IFX (median 0.88 μg/mL, IQR 0.0–6.80) (29). A significant association between IFX-TL and disease activity, defined by clinical score and normal CRP, was shown by Rolandsdotter in a 45 pediatric IBD patients (71% CD) with 93 maintenance sera samples (12). In addition, this group found negative correlations between IFX-TL and PCDAI, PUCAI and Erythrocyte Sedimentation Rate and a positive correlation with serum albumin levels. Few studies have focused on infliximab immunogenicity in pediatric IBD patients. In our study, cross-sectional analysis demonstrated that although ATI levels were numerically lower in active disease than in clinical remission (n = 458), their frequency was not different between groups. Nevertheless, in the temporal analysis, which included a smaller group of 31 patients, ATI frequency and levels at week 2 were significantly lower among those in clinical remission by week 14. We believe that the different outcomes of these 2 analyses stem from the fact that, as previously demonstrated in adults (30), immunogenicity is primarily a temporal phenomenon with a lag between antibodies’ appearance and their effect on outcome. Similarly to our study, Vande Casteele showed that low week 14 IFX-TL (<2.2 μg/mL) predict LOR (pharmacokinetic and pharmacodynamic) with 74% specificity and 82% sensitivity (P = 0.0026) in children with CD or UC (31). Another study, of adult CD patients, demonstrated that IFX-TL > 3 μg/mL at week 14–22 had a protective effect from LOR (HR 0.34, AUC = 0.703) (27). In a pediatric study (CD and UC), patients with sustained response at week 54 had a week 14 median IFX-TL of 4.7 versus 2.6 μg/mL in clinically active patients (P = 0.03) (15). That study also showed that week 14 IFX-TL had a moderate predictive value (AUC = 0.68), and a cut-off of > 4 μg/mL was associated with a positive predictive value of 76% (AUC = 0.64) for week 54 remission (15). The current study showed that long-term remission may be predicted earlier than week 14, as early as week 6 of Infliximab treatment. IFX-TL > 4.2 μg/mL at week 14 yielded 88.9% sensitivity and 33.3% specificity for therapy retention by 1 year of treatment (AUC = 0.820, P = 0.009). Previous studies on adult IBD cohorts demonstrated that older age, body mass index, previous surgery, and colonic disease were associated with non-response to infliximab induction therapy (32). In our study, the only parameters associated with week 14 remission were week 2 and 6 IFX-TLs and week 2 ATI levels. Multivariate analysis was not performed due to limited sample size. While IBD type was not associated with clinical remission, TLs and ATI were significantly associated with clinical outcome in CD, but not in UC patients. This may stem from the lower number of serum samples obtained from UC than CD (n = 153 versus n = 529), or from a more limited role of pharmacokinetics and immunogenicity among pediatric UC patients. Previous studies have demonstrated TDM to be as clinically applicable in UC as in CD (9), although additional research is of course pertinent. The lack of association of concomitant immunomodulator therapy with week 14 clinical remission may be perhaps due to the fact that patients who are administered combination therapy a-priori, are often the more severe ones. Nevertheless, significant association was detected between concomitant immunomodulator therapy and week 2 drug levels, implying an indirect effect of immunomodulators on clinical outcome. Our study has several limitations. First, our cohort is limited to 1 tertiary center, and the results may not apply to the general IBD population. Secondly, as this was a retrospective study, and physicians were not blinded to previous drug and ATI levels, the pharmacokinetic data may have affected the clinical assessment during the visit. However, as physicians had sera results available both upon LOR and during remission, this effect minimizes. In addition, various clinical indexes have been applied and there could be possible confounders, which affect clinical outcome. In an effort to overcome this, an analysis of various baseline parameters versus clinical status was performed. Thirdly, endoscopic data and markers of mucosal healing such as fecal calprotectin were not evaluated. Finally, although we had 63 patients with prospective sera monitoring since Infliximab induction, and 773 samples in total, many of the patients have not reached the 54 weeks endpoint, and not all had CRP values at the specified time points, which diminished the statistical power of some of the sub-group analyses.

In conclusion, this is one of the largest pediatric studies on infliximab pharmacokinetics to date, demonstrating that higher IFX-TLs and lower ATI values during induction are predictive of successful completion of induction and clinical response during the first year of therapy. We validated the correlation of drug levels with same-point clinical and biomarker remission in the pediatric IBD population. Week 2 IFX-TLs > 9.2 μg/mL could serve as a prognostic factor for predicting success of induction and remission maintenance, whereas lower levels could prompt the physician for additional interventions.

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Keywords:

antibodies; drug level; outcome

Supplemental Digital Content

Copyright © 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition