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P671 Early suppression of the serological macrophage activity biomarker VICM, and not suppression of CRP, predicts the response to infliximab in Crohn's disease patients

Mortensen J.H.*1, van Haaften W.T.2,3, Olesen M.L.1,4, Karsdal M.1, Olinga P.2, Dijkstra G.3, Bay-Jensen A.-C.1

1Nordic Bioscience, Biomarkers & Research, Herlev, Denmark 2University Medical Center Groningen, Department of Pharmaceutical Technology and Biopharmacy, Groningen, Netherlands 3University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, Netherlands 4University of Southern Denmark and Odense University Hospital, Department of Medical Gastroenterology, Odense, Denmark

Background

Anti-tumour necrosis factor-alpha treatments, e.g. infliximab, are an important treatment option for inflammatory bowel disease. However, up to 40% of patients do not respond to infliximab upon evaluation after several infusions. Currently, there are no biomarkers with adequate sensitivity to separate responders from non-responders at an early stage. We hypothesised that macrophage activity may be a measure of early efficacy. We investigated if an early change in serum VICM levels (citrullinated and MMP-degraded vimentin), a biomarker of activated macrophages, would be associated with prediction of a positive clinical benefit defined as responders to infliximab treatment in Crohn's disease (CD) patients.

Methods

Serum VICM levels was measured by ELISA in the induction phase of infliximab treatment (5mg/kg) at baseline, week 2, week 6 and week 14 in 60 CD patients. Disease activity for CD was assessed by applying the Harvey Bradshaw index (HBI,>4=active disease) and the Physician's Global Assessment (PGA,>0: active disease). The median disease duration was 9.3 years. 44 (73%) patients responded, whereas 16 (27%) patients did not respond to infliximab (median follow-up 3.9 years). Clinical response was defined as having >1 decrease in PGA at week 14 or being in remission at last follow-up. Non-response was defined as <2 PGA decrease and failure to induce clinical remission (in PGA and HBI) at last follow-up.

Results

VICM predictive for response to treatment at week 2 (OR=8.5, (CI: 2.059–31.5), p<0.01; AUC=0.65, p<0.05). Responders had significantly decreased VICM levels at week 2 (p<0.001, >30% decrease from baseline), week 6 (p<0.001, >20% decrease from baseline), and week 14 (p<0.001, >20% decrease from baseline) compared to baseline (Fig. 1A). VICM levels in non-responders were not significantly different compared to baseline. VICM serum levels at week 2 were significantly different in responders compared to non-responders (p<0.01) (Fig. 1A). CRP was significantly suppressed in both responders and non-responders at all time points, but showed no significant difference between responders and non-responders (Fig. 1B).

Figure 1. A) VICM and B) CRP in response to infliximab. *Indicates significance, *p<0.05, ***p<0.001. #Indicate significant difference between responders and non-responders (p<0.01). Marker levels are presented as mean and standard error of the mean.

Conclusion

Macrophage activity, quantified by VICM, predicted early response to infliximab in CD patients, with an OR of 8.5. This provides value to patients, by selecting those patients with an early and superior response to infliximab. VICM was time dependently suppressed, suggesting that macrophage activity was significantly attenuated by infliximab treatment.