A personal 'omics' approach to understand the molecular mechanism of response to biologic therapy in rheumatoid arthritis

Background: Anti-tumour necrosis factor (TNF) therapy has revolutionised the treatment of rheumatoid arthritis (RA). Nevertheless, a large number of patients fail to exhibit a complete response to these expensive drugs, which presents a challenge for responsible pharmacological spending and improving long term outcomes. To date, the quest for a biological biomarker or panel of biomarkers to predict and monitor treatment response has not yielded a replicable, clinically applicable test. Methods: Samples were selected from the Biologics in RA Genetics and Genomics Study Syndicate (BRAGGSS) cohort according to European League against Rheumatism (EULAR) criteria (50 good- and 20 non-responders to adalimumab; 37 good- and 18 non-responders to etanercept). Total RNA from baseline (pre-treatment) and 3-month samples were isolated from Tempus-stabilised whole blood and expression measured on the Affymetrix GeneChip Human Transcriptome Array (HTA) platform. Quality control and differential expression/splice analysis were assessed using appropriate Affymetrix and Bioconductor packages. A validation study was performed examining the extreme ends of adalimumab intermediate responders (n =24) using the OpenArray to measure gene expression in top hits from the initial HTA study. Results: In adalimumab good-responders, 198 transcripts were upregulated and 610 were downregulated at 3-months (fold-change > 1.2, false discovery rate (FDR) p-value 1.2, FDR p-value