Serological biomarkers of type III and IV collagen remodeling predict and monitor infliximab treatment response in patients with Inflammatory Bowel Disease

BackgroundImmunotherapeutic drugs such as anti-TNFα antibodies have greatly improved the treatment of inflammatory bowel disease (IBD). However, up to 20-40% of patients still fail to respond to therapy as the pattern of disease is variable. Better patient profiling could increase treatment response and improve quality of life. The aim of this study was to assess whether serological biomarkers reflecting tissue formation and different forms of basement membrane (BM) degradation could monitor or predict treatment response to anti-TNFα in patients with Crohn’s disease (CD) and Ulcerative Colitis (UC).MethodsUsing competitive ELISA, serum biomarkers of matrix metalloproteinase (MMP)-mediated type IV collagen degradation (C4M), T-cell related collagen degradation (C4G) and type III and IV collagen formation (PRO-C3, PRO-C4) were measured in 89 patients (CD=63, UC=26) receiving infliximab (IFX) induction therapy. Disease activity was defined by composite assessment of the Harvey-Bradshaw Index (HBI) for CD and Simple Clinical Colitis Activity Index (SCCAI) for UC together with physician’s global assessments (PGA). Clinical remission (HBI <5, SCCAI <2.5) was assessed at week 14. Logistic regression models adjusted for confounding factors (CD: age of diagnosis and ileoceacal surgery, UC: steroid use at week 14) were used to examine prediction value for treatment response.ResultsIn patients with CD, baseline ratios of C4M/C4G (P<0.001, AUC=0.95) and PRO-C4/C4G (P<0.05, AUC=0.92) were significantly lower at baseline in responders (n=57) compared to non-responders (n=6). PRO-C3 levels were increased at week 14 in CD patients responding to therapy compared to those not responding (P<0.01, AUC=0.93). Finally, UC patients responding to treatment (n=19) showed decreased levels of C4M/C4G (P<0.01, AUC=0.96) at week 14 compared to non-responders (n=7).ConclusionIncreased baseline ratios of type IV collagen remodeling (C4M/C4G, PRO-C4/C4G) in serum predict treatment response to IFX in patients with CD, whereas PRO-C3 may serve as a monitoring tool reflecting tissue restoration. The ratio between MMP- and granzyme B-mediated degradation of type IV collagen (C4M/C4G) in serum was elevated in non-responders compared to responders and may serve as non-invasive tool to monitor treatment response in patients with UC. Together, these biomarkers may help reveal different profiles of ECM turnover and inflammation and thus aid in better prediction and monitoring of response to anti-TNFα treatment