Nomogram to predict primary non-response to infliximab in patients with Crohn's disease: a multicenter study

Abstract

Background: Infliximab (IFX) is effective at inducing and maintaining clinical remission and mucosal healing in patients with Crohn's disease (CD); however, 9%-40% of patients do not respond to primary IFX treatment. This study aimed to construct and validate nomograms to predict IFX response in CD patients.

Methods: A total of 343 patients diagnosed with CD who had received IFX induction from four tertiary centers between September 2008 and September 2019 were enrolled in this study and randomly classified into a training cohort (n = 240) and a validation cohort (n = 103). The primary outcome was primary non-response (PNR) and the secondary outcome was mucosal healing (MH). Nomograms were constructed from the training cohort using multivariate logistic regression. Performance of nomograms was evaluated by area under the receiver-operating characteristic curve (AUC) and calibration curve. The clinical usefulness of nomograms was evaluated by decision-curve analysis.

Results: The nomogram for PNR was developed based on four independent predictors: age, C-reactive protein (CRP) at week 2, body mass index, and non-stricturing, non-penetrating behavior (B1). AUC was 0.77 in the training cohort and 0.76 in the validation cohort. The nomogram for MH included four independent factors: baseline Crohn's Disease Endoscopic Index of Severity, CRP at week 2, B1, and disease duration. AUC was 0.79 and 0.72 in the training and validation cohorts, respectively. The two nomograms showed good calibration in both cohorts and were superior to single factors and an existing matrix model. The decision curve indicated the clinical usefulness of the PNR nomogram.

Conclusions: We established and validated nomograms for the prediction of PNR to IFX and MH in CD patients. This graphical tool is easy to use and will assist physicians in therapeutic decision-making.

Keywords: Crohn’s disease; infliximab; mucosal healing; nomogram; primary non-response.

Figure 1.

The display and evaluation of the model for primary non-response (PNR) to infliximab in patients with Crohn’s disease. (A) The nomogram to predict the probability of PNR. Receiver-operating characteristic (ROC) curves for the PNR nomogram in the training cohort (B) and validation cohort (C). Plots (D) and (E) show the calibration curves of the training and validation cohorts, respectively. The distribution of the predicted probabilities of PNR is shown at the bottom of the graphs. The triangles indicate the observed frequencies of PNR by the quintiles of the predicted probability. AUC, area under ROC curve; B1, non-stricturing, non-penetrating behavior; BMI, body mass index; CRP, C-reactive protein.

Figure 2.

Receiver-operating characteristic (ROC) curves in all 343 patients. (A) Comparison of the primary non-response (PNR) nomogram with single factors and the matrix model. (B) Comparison between the mucosal healing (MH) nomogram and single factors. AUC, area under ROC curve; B1, non-stricturing, non-penetrating behavior; BMI, body mass index; CDEIS, Crohn's Disease Endoscopic Index of Severity; CRP₂, C-reactive protein level at week 2; D, duration of disease; Matrix, the matrix model; Nom, nomogram.

Figure 3.

Evaluation of the clinical utility of the nomogram. (A) Decision-curve analysis for the primary non-response (PNR) nomogram. The y-axis represents net benefit and the x-axis shows the threshold probability of response. The ‘All’ line refers to the hypothesis that all patients were treated with infliximab and the ‘None’ line to the assumption that no patient was treated with infliximab. The probability of response is equal to 1 – probability of PNR (PNR%). The PNR nomogram is superior to the curve for ‘treat all’ or ‘treat none’ for thresholds of response between 0.15 and 0.90. Plots (B) and (C) show the risk-classification performance of the nomogram in overall patients and patients with perianal disease, respectively.

Figure 4.

The display and evaluation of the model for mucosal healing (MH) responding to infliximab in patients with Crohn’s disease. (A) The nomogram to predict the probability of MH. Receiver-operating characteristic (ROC) curves for the MH nomogram in the training cohort (B) and validation cohort (C). Plots (D) and (E) show the calibration curves of the training and validation cohorts, respectively. AUC, area under ROC curve; B1 non-stricturing, non-penetrating behavior; CDEIS, Crohn's Disease Endoscopic Index of Severity; CRP, C-reactive protein.