Intest Res.  2018 Apr;16(2):223-232. 10.5217/ir.2018.16.2.223.

Trough level of infliximab is useful for assessing mucosal healing in Crohn's disease: a prospective cohort study

• Koga A
• Matsui T
• Takatsu N
• Takada Y
• Kishi M
• Yano Y
• Beppu T
• Ono Y
• Ninomiya K
• Hirai F
• Nagahama T
• Hisabe T
• Takaki Y
• Yao K
• Imaeda H
• Andoh A

• KMID: 2417674
• DOI: http://doi.org/10.5217/ir.2018.16.2.223

Abstract

BACKGROUND/AIMS
Decreased trough levels of infliximab (TLI) and antibodies to infliximab (ATI) are associated with loss of response (LOR) in Crohn's disease. Two prospective studies were conducted to determine whether TLI or ATI better correlates with LOR (Study 1), and whether TLI could become a predictor of mucosal healing (MH) (Study 2).
METHODS
Study 1 was conducted in 108 patients, including those with LOR and remission to compare ATI and TLI in discriminating the 2 conditions based on receiver operating characteristic (ROC) curve analyses. Study 2 involved 35 patients who were evaluated endoscopically.
RESULTS
In Study 1, there were no differences between the 2 assays in ROC curve analyses; the TLI cutoff value for LOR was 2.6 µg/mL (sensitivity, 70.9%; specificity, 79.2%), and the ATI cutoff value was 4.9 µg/mL (sensitivity, 65.5%; specificity, 67.9%). The AUROC (area under the ROC curve) of TLI was greater than that of ATI. AUROC was useful for discriminating between the 2 conditions. In Study 2, the TLI was significantly higher in the colonic MH group than in the non-MH group (2.7 µg/mL vs. 0.5 µg/mL, P=0.032).
CONCLUSIONS
TLI is better than ATI for clinically diagnosing LOR, and a correlation was observed between TLI and colonic MH.

Keyword

Crohn disease; Infliximab trough level; Mucosal healing; Loss of response; Antibodies to infliximab

MeSH Terms

Antibodies
Cohort Studies*
Colon
Crohn Disease*
Humans
Infliximab*
Prospective Studies*
ROC Curve
Sensitivity and Specificity
Antibodies
Infliximab

Figure

• 

  Fig. 1 Overview of study protocol, subject selection and inclusion criteria in Study. The inclusion criteria in Study 1 and Study 2 were: (1) efficacy of initial infusion of infliximab (IFX) was response, were undergoing maintenance therapy; (2) provided informed consent to blood sampling to measure IFX blood concentrations and to endoscopy; (3) their course could be followed up sufficiently; (4) their CDAI could be measured; and (5) were able to undergo colonoscopy or double-balloon enteroscopy within 2 months before or after the date of IFX blood concentration measurement. Exclusion criteria were: (1) continuous administration of IFX for ≤14 weeks or ≥5 years; (2) a stoma; or (3) not obtaining consent. A total of 72 patients were excluded. In the study design in Study 1, the first assay (assay A and B) was performed with patients divided into loss of response (LOR) group and remission group. Assay A and clinical symptoms in the antibodies to IFX (ATI)-positive patents in the remission group were checked after 1 year. In Study 2, endoscopic examination and assay A were performed after enrollment.

• 

  Fig. 2 Receiver operating characteristic (ROC) curve and cutoff value of infliximab (IFX) trough level and antibodies to IFX (ATI) by assay B (Study 1). (A) ROC curve-cutoff value of the IFX trough level in CD was calculated, as was association between IFX trough level and loss of response, with corresponding sensitivity and specificity for CD. Cutoff value, 2.6 µg/mL; area under the ROC curve (AUROC), 77.8. (B) ROC curve-cutoff value of ATI in CD was calculated, as was association between ATI and loss of response, with corresponding sensitivity and specificity for CD. Cutoff value, 4.9 µg/mL; AUROC, 67.9.

• 

  Fig. 3 Antibodies to infliximab (ATI)-positive rates in loss of response (LOR) group and in remission group. “ATI positive” was defined as ATI positivity in assay A and ATI of ≥4.9 µg/mL in assay B. Assay B was used to measure the percentage of patients with ATI in both the LOR and remission groups. ATI-positive rates with assays A and B, respectively, are 9.1% vs. 65.5% in the LOR group, and 3.8% vs. 32.1% in the remission group. Comparison of ATI-positive rates in the LOR and remission groups shows P=0.4379 with assay A, compared to P=0.0006 with assay B.

• 

  Fig. 4 A) Comparison of infliximab (IFX) trough levels between mucosal healing (MH) group and non-MH (nMH) group with lesions of small intestine (Study 2). MH occurred in 10 patients, and there were 21 patients in the nMH group. TLI (trough levels of infliximab; median values) in the MH and nMH groups were 2.5 µg/mL vs. 1.8 µg/mL, respectively. TLI in the MH and nMH groups showed no significant difference (P=0.380). Number of patients positive for antibodies to IFX (ATI) with assay A: 1 patient (10.0%) in the MH group and 3 patients (14.3%) in the nMH group. (B) Comparison of IFX trough levels between MH group and nMH group with lesions of large intestine (Study 2). There were 13 patients with MH and 8 patients in the nMH group. TLI (median values) in the MH and nMH groups were 2.7 µg/mL vs. 0.5 µg/mL, respectively. Comparison of TLI between the 2 groups showed a significant difference (P=0.032). Number of patients positive for ATI with Assay A: 0 patients (0.0%) in the MH group and 2 patients (25.0%) in the nMH group.

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