A proteomics study of rheumatoid arthritis patients on etanercept identifies putative biomarkers associated with clinical outcome measures

Abstract

Objectives Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are widely used in patients with rheumatoid arthritis (RA), but response to bDMARDs is heterogeneous. The objective of this work was to identify pre-treatment proteomic biomarkers associated with RA clinical outcome measures in patients starting bDMARDs. Methods Sequential Window Acquisition of all THeoretical fragment ion spectra mass spectrometry (SWATH-MS) was used to generate spectral maps of sera from patients with RA before and after three months of treatment with the bDMARD etanercept. Protein levels were regressed against RA clinical outcome measures, namely, Disease Activity Score of 28 Joints (DAS28) and its sub-components and DAS28 < 2.6 (i.e. remission). The proteins with the strongest evidence for association were analysed in an independent, replication dataset. Finally, sub-network analysis was carried out using the DIAMOnD algorithm and biological plausibility of identified proteins was assessed by enrichment analysis. Results 180 patients with RA were included in the discovery dataset and 58 in the validation dataset from a UK-based prospective multicentre study. Ten individual proteins were found to be significantly associated with RA clinical outcome measures. The association of TCPH with DAS28 remission was replicated in an independent cohort. Sub-network analysis of the ten proteins from the regression analysis identified the ontological theme with the strongest associations being with acute phase and acute inflammatory responses. Conclusion This longitudinal study of 180 patients with RA commencing etanercept has identified several putative protein biomarkers of treatment response to this drug, one of which replicated in an independent cohort.

Towards Personalized Medicine in Rheumatoid Arthritis

“… 125 A more recent, much larger study used sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) in a study of 180 patients on etanercept therapy and identified proteins associated with treatment response. 132 Lower baseline levels of TCPH (Q99832) were associated with future remission and higher baseline levels of EHD1 (Q9H4M9) and TCPH (Q99832) were associated with DAS-28 score. In addition, lower baseline levels of SELENOP (P49908) and higher baseline levels of MAP2K3 (P46734) and CLTC (Q00610) were associated with hsCRP level at 6 months.…”