Background The development of tumour necrosis factor alpha (TNFα) inhibitors has led to major advances in the management of rheumatoid arthritis (RA). However, the molecular mechanisms of these agents are poorly understood.
Objective In order to better understand the specifics effects of Adalimumab and Etanercept, we identified and compared the gene expression profiling in peripheral blood mononuclear cells (PBMCs) from responder (R) RA patients treated by methotrexate (MTX)/adalimumab (ADA) or MTX/etanercept (ETA) before and at 3 months after the beginning of the treatment.
Methods Nineteen RA patients were randomised to receive subcutaneously either ADA (40 mg each other week) or ETA (50 mg per week). Thirteen RA patients [average age: 48.6 ± 14.3 years old (yo), MTX: 13.1 ± 6.3 mg/week (w), initial DAS28: 5.5 ± 0.6] received ADA while six RA patients (age: 52.5 ± 16.1 yo, MTX: 18.3 ± 3 mg/w, initial DAS28: 5.7 ± 1.3) were treated by ETA. The drug efficacy was evaluated with the DAS28 after 3 months of treatment according to the EULAR response criteria in order to discriminate R to NR. A blood sample was carried out before the first injection and after 3 months in order to isolate PBMCs and extract total RNA for hybridisation on whole human genome Agilent 4 × 44 k array. A supervised analysis was performed using t-test (GeneSpring GX software) combined with a fold-change 1.5 in order to identify genes whose expression were altered in PBMCs after 3 months from R to each drug. Next, transcripts sets were analysed to identify potential functional pathways (Human Reactome). Gene expression profiles and functional pathways obtained for R to each anti-TNFα were compared.
Results Demographic, clinical and biological characteristics of all the patients were comparable before and after treatment administration. From the R (7/13) patients treated with ADA, a combination of 63 transcripts involved in mTORC1-mediated Signalling was identified. Concerning the R (2/6) treated by ETA, a combination of 16 transcripts involved in TNF Signalling, Death Receptor Signalling was observed. Any overlap was found when we compared these transcripts sets. Moreover, any common biological functions and functional pathways were found between R ADA and R ETA.
Conclusions The absence of overlap of transcripts sets and the absence of common pathways leading us to consider that molecular mechanisms of ADA and ETA are specific.