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P650 Mechanisms of Infliximab failure: the predictive role of MMP3

B. Barberio*1, R. D'Incà2, S. Facchin3, M. Dalla Gasperina1, C. Fohom1, R. Cardin1, E. Savarino2, F. Zingone1

1Dr., Gastroenterology, Padova, Italy, 2University of Padua, Department of Oncological Gastrointestinal Surgery, Padova, Italy, 3University of Padua, Department of Surgery, Oncology and Gastroenterology, Gastroenterology Section, Padova, Italy

Background

Recently, further pathways of degradation of anti-TNF therapies have been hypothesised such as the presence of activated metalloproteinases (MMPs), particularly MMP3, which seem to cleave the IgG1 and neutralise the drug activity. However, no data to have been published evaluating whether levels of MMP3 can be associated to anti-TNF failure in patients with inflammatory bowel disease (IBD) in a longitudinal study.

Methods

Retrospectively, we included 73 IBD patients (37 UC, 36 CD) responder (R 37) and non-responder (NR 36) to infliximab therapy after 52 weeks of treatment and who had started biologic therapy because of moderate-to-severe clinical activity at baseline (T0). Patients underwent MMP3 dosage at baseline, post induction (TPI), and at 12 months (T12). In addition, trough level (TL) and anti-drug antibody (ATI) values were also determined at t12. For comparison, MMP3 levels were determined in 28 healthy subjects as controls. Demographic and clinical features were recorded, including BMI, HBI/Mayo score, endoscopy score, CRP, faecal calprotectin, and albumin. We used medians with inter-quartile for continuous data and percentages for discrete data. Chi-square test and Mann–Whitney U test were used to compare categorical and continuous values, respectively. We also performed Spearman and an ROC analysis. A p-value of <0.05 was considered significant.

Results

Serum levels of MMP3 between R and NR were not statistically significant at T0 (R = 17.92 ng/ml, NR = 21.98 ng/ml, p = 0.80), while they were statistically significant at TPI (R = 8.68, NR = 25.7, p < 0.001) and at T12 (R = 11.63, NR = 29.72, p < 0.001). Instead, calprotectin concentrations were not significant at T0 (R = 967 μg/g, NR = 1362, p = 0.09) and at TPI (R = 415, NR = 743, p = 0.17), and became significant only at T12 (R = 102, NR = 458, p < 0.001) (Figure 1). Serum albumin and patients’ BMI were not significant at T0, TPI, and T12 (p = ns). Finally, among NR patients with low TL, those with high ATI and those without ATI had the same MMP3 levels (32.01 vs. 24.56, p = 0.1). We found a statistically significant negative correlation (Spearman 0.3, p < 0.001) between MMP3 level and TL at T12 in all population (Figure 1). Through an ROC curve analysis, we identified the MMP3 value to discriminate healthy subjects from IBD active patients evaluated at T0 (11.63, Sens. 76.6%, Spec. 85.19%).

Conclusion

High MMP3 levels at post-induction predict loss of response over the next 12 months. Patients NR to Infliximab therapy, both with high ATI and low ATI, have high MMP3 levels; higher MMP3 levels correspond to lower TL.

Spearman correlation