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P008 Proteomic markers of response to anti-TNF drugs in patients with Crohn's disease

R. Medina-Medina1, E. Iglesias-Flores1, J. M. Benítez1, S. Marín-Pedrosa1, I. Salgueiro1, G. Ferrín1, C. I. Linares1, S. González-Rubio1, P. Soto1, B. Gros1, C. Moral1, F. Alvarez1, M. Rodríguez-Perálvarez1, E. Chicano-Gálvez1, I. Ortea1, V. García-Sánchez1, P. Aguilar-Melero1

1IMIBIC/Hospital Universitario Reina Sofia/Córdoba University, CÓRDOBA, Spain

Background

Therapy with anti-TNF has improved notably the management of Crohn's disease (CD).1 However, 25–40% of patients treated with these drugs lose response long-term.2 In addition, these treatments are expensive and not without risk of adverse events. Therefore, it is essential to identify reliable markers that will select those patients who can benefit of anti-TNF drugs, thus improving their efficacy and safety

Methods

A consecutive cohort of CD patients, who were naïve to anti-TNF therapy, were enrolled and followed up during 12 months. Demographic, analytical, nutritional and physiopathology were recorded. Patients were stratified according to clinical response as follows: (a) Non-primary response (NPR) at 12 weeks post-treatment; (b) loss of response (LR) within 12 months; (c) sustained clinical response (SCR). In addition, plasma samples were collected previously to anti-TNF treatment and further analysed by SWATH proteomics,3 to identify potential biomarkers of response to anti-TNF. Anova or Kruskal–Wallis tests were used for analysis, according to data distribution. Functional pathways of identified biomarkers was analysed by DAVID Bioinformatics Resources 6.7.4

Results

In total, 54 CD patients were included. Most of them (77.3%) showed an SCR. However, 4.5% of patients had NPR and 18.2% LR. Patients with recent diagnosis of CD (<12 months) were less likely to achieve SCD. Indeed, the interval from diagnosis to anti-TNF therapy was shorter in patients NPR (0 ± 0) as compared with LR (9.9 ± 5.9 years) and SCR (6.32 ± 8.0 years) (p = 0.04). Increased blood leucocytes count before treatment was also associated with NPR (NPR: 13.7 ± 2.1 vs. LR: 8.4 ± 2.3 and SCR: 7.6 ± 2.9) (p = 0.018). In addition, we have identified the overweight as a factor of losing response during the first year of treatment (BMI: NPR: 24.5 ± 7.5, LR: 27.6 ± 4.6 vs. SCR: 23.4 ± 3.6) (p = 0.036). As potential biomarkers of primary response we have identified 18 proteins up-regulated, related to hemostasis and metabolism of carbohydrates, all of them with p ≤ 0.009 and a fold change ≥ 2.4. Seventeen of these proteins are regulated by acetylation. In addition, 4 proteins were potential biomarkers of loss of response (p ≤ 0.05 and fold change from 0.5 to 1.4). Two of them related to lipids metabolism.

Conclusion

Early need for anti-TNF and increased blood leucocytes count, probably related to a more severe disease, are associated with NPR. Overweight is associated with secondary loss of response to anti-TNF. In addition, hemostasis, metabolism of carbohydrates and lipids may be involved in the response to anti-TNF in CD.

References

1. Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol 2011;106:644–59.

2. Van Assche G, Vermeire S, Rutgeerts P. Optimizing treatment of inflammatory bowel diseases with biologic agents. Curr Gastroenterol Rep 2008;10:591–6.

3. Gillet LC, Navarro P, Tate S, et al. Targeted data extraction of the MS/MS spectra generated by data-independent acquisition: a new concept for consistent and accurate proteome analysis. Mol Cell Proteomics 2012;11:O111.016717.

4. Huang DW, (2009), Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009;4:44–57. doi:10.1038/nprot.2008.211.