BACKGROUND: Several studies have employed microarray-based profiling to predict 
response to tumor necrosis factor-alpha inhibitors (TNFi) in rheumatoid 
arthritis (RA); yet efforts to validate these targets have failed to show 
predictive abilities acceptable for clinical practice.
METHODS: The eighty most extreme responders and nonresponders to TNFi therapy 
were selected from the observational BiOCURA cohort. RNA sequencing was 
performed on mRNA from peripheral blood mononuclear cells (PBMCs) collected 
before initiation of treatment. The expression of pathways as well as individual 
gene transcripts between responders and nonresponders was investigated. 
Promising targets were technically replicated and validated in n = 40 new 
patients using qPCR assays.
RESULTS: Before therapy initiation, nonresponders had lower expression of 
pathways related to interferon and cytokine signaling, while also showing higher 
levels of two genes, GPR15 and SEMA6B (p = 0.02). The two targets could be 
validated, however, additional analyses revealed that GPR15 and SEMA6B did not 
independently predict response, but were rather dose-dependent markers of 
smoking (p < 0.0001).
CONCLUSIONS: The study did not identify new transcripts ready to use in clinical 
practice, yet GPR15 and SEMA6B were recognized as candidate explanatory markers 
for the reduced treatment success in RA smokers.