Disease activity (DAS-28CRP) in rheumatoid arthritis correlates with synovial expression of tumor-associated and IL-6-dependent genes

Background/Purpose: The molecular mechanisms that regulate disease activity in rheumatoid arthritis (RA) are unknown. Using high-throughput transcriptomic data sets generated in knee synovial biopsies from patients with RA, we wanted to identify which probe sets display the highest levels of correlation with disease activity (DAS-28CRP values), and whether they cluster in specific molecular pathways. Methods: We retrieved gene expression data obtained after hybridization of 65 synovial biopsy samples using GeneChip HGU133Plus2.0 microarrays. 21 of them originated from untreated RA patients. Paired samples were obtained in 12 of these patients, 3 months after initiation of tocilizumab therapy, and in another 8 patients, 3 months after initiation of methotrexate therapy. The last samples were obtained in methotrexate- and TNF blockade-resistant patients before (n=12) and 3 months (n=12) after administration of rituximab therapy. Correlation coefficients were calculated between normalized expression values of each probe set (n = 51,452) and DAS28-CRP among the samples. Results: When the analyses were performed on all samples, we found that 1,304 probe sets display a >0.50 correlation coefficient with DAS-28CRP values. Strikingly, almost the totality of these probe sets are IL-6 dependent, since they are down-regulated in synovial tissue after administration of tocilizumab. In a previous study, we found that tocilizumab, rituximab and methotrexate therapies preferentially target IL-6-dependent genes in the synovium. Therefore, correlation studies between gene expression and DAS-28CRP values, performed before and after administration of these treatments, presumably result in a bias favorable to these genes. We therefore performed our correlation study on 21 synovial biopsy samples from untreated patients with RA and active disease. In this case, we found that 393 probe sets display a > 0.50 correlation coefficient with DAS-28CRP values. 15% of them are significantly down-regulated by tocilizumab therapy in the synovium, however, the probe sets with the highest correlation coefficients (between 0.65 and 0.75: GADD45B, TACSTD2, PDE4D, …) are associated with chromatin remodeling, regulation of cell cycle and tumor progression in cancer tissues. Conclusion: Our data indicate that two distinct sets of transcripts are associated with disease activity (expressed as DAS-28CRP values) in the RA synovium. Immunohistochemistry experiments are ongoing in order to identify which synovial cells express these IL-6-dependent- versus tumor progression-associated transcripts