Abstract
BackgroundInfliximab is effective in inducing and maintaining remission in patients with Crohn’s disease (CD), but primary non-response (PNR) occurs in 10-30% of cases. We investigated whether serum biomarkers are effective in predicting PNR in patients with CD.MethodsFrom January 2016 to April 2020, a total of 260 patients were recruited to this prospective and retrospective cohort study. Serum samples were collected at baseline and week 2 of infliximab treatment. Serum levels of 35 cytokines were assessed in 18 patients from the discovery cohort and were further evaluated in the 60-patient cohort 1. Then, candidate cytokines and other serological biomarkers were used to construct a predictive model by logistic regression in a 182-patient cohort 2. PNR was defined based on the change of CD activity index or clinical symptoms.ResultsAmong the 35 cytokines, matrix metalloproteinase 3(MMP3) and C-C motif ligand 2 (CCL2) were two effective serum biomarkers associated with PNR in both the discovery cohort and cohort 1. In cohort 2, serum level of MMP3, CCL2 and C-reactive protein (CRP) at 2 weeks after infliximab injection were independent predictors of PNR, with odds ratios (95% confidence interval) of 1.108(1.059-1.159), 0.940(0.920-0.965) and 1.102(1.031-1.117), respectively. A PNR classifier combining these three indicators had a large area under the curve [0.896(95% CI:0.895-0.897)] and negative predictive value [0.918(95%CI:0.917-0.919)] to predict PNR to infliximab.ConclusionsMMP3, CCL2, and CRP are promising biomarkers in prediction of PNR to infliximab, and PNR classifier could accurately predict PNR and may be useful in clinical practice for therapy selection.
Highlights
The introduction of infliximab (IFX), a chimeric monoclonal antibody against tumour necrosis factor (TNF)-a, has significantly improved therapy to induce and maintain remission in Crohn’s disease (CD) [1]
To evaluate the disease activity at week 14 more objectively, we performed a comparison of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and Simple Endoscopic Score for Crohn’s Disease (SESCD) between primary responders and primary nonresponders (Supplement Table 3)
The results showed that primary non-responders had higher CRP, ESR and SESCD levels than primary responders at week 14 in both cohort 1 (CRP: p
Summary
The introduction of infliximab (IFX), a chimeric monoclonal antibody against tumour necrosis factor (TNF)-a, has significantly improved therapy to induce and maintain remission in Crohn’s disease (CD) [1]. 10-30% of patients receiving IFX are non-responsive during induction therapy (primary non-response, PNR) [2]. Genetic polymorphisms [6, 7], microbiome [8] and serum biomarkers [5, 9] have been studied with regard to response to IFX. We believe that the inflammatory state of patients could affect the IFX response, and alterations of inflammatory cytokines in serum might be an appropriate biomarker to predict PNR. Infliximab is effective in inducing and maintaining remission in patients with Crohn’s disease (CD), but primary non-response (PNR) occurs in 10-30% of cases. We investigated whether serum biomarkers are effective in predicting PNR in patients with CD
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