Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Glucocorticoids (GC) have been a cornerstone of Rheumatoid arthritis (RA)-therapy for the last decades. However, about a third of RA-patients do not respond adequately. As monocytes and T-cells play an important role in RA-pathogenesis, the differential gene expression of these cells before and 24 hours after start of pulse therapy with methylprednisolone was evaluated in order to find potential predictors of GC-response.
Methods: CD14-positive and CD4-positive cells were isolated by MACS sorting from five GC-Responders meeting the European League against Rheumatism (EULAR) response criteria and five Non-Responders. The clinical response was measured by disease activity score (DAS28) at the end of pulse therapy (3x 1000mg Methylprednisolone) at day 5. Labeled cRNA was hybridized to Agilent 4x44K microarrays and differentially expressed genes were determined by MAANOVA. False discovery rate was used as multiple testing correction and set at 5%. Genes were validated by quantitative real-time PCR (qPCR).
Results: We found eight known genes differentially expressed in CD14-cells and 4 in CD4-T-cells of GC-Responders compared to Non-Responders before start of therapy using microarrays. After 24 hours, 13 known genes were seen differentially expressed in CD14-cells and CD4-T-cells each. Higher expression of ERAP2 in monocytes and CD4-cells (fold change (FC) Responders vs. Non-Responders: 6.6 and 4.9; p<0.007 and p<0.02) and LST1 and FAM26F in CD4-Tcells of GC-Responders (FC: 2.54 and 4.4; p<0.06 and p<0.009) before start of therapy was verified by qPCR and correlated with DAS28 at day 5. In both cell types ERAP2 (CD14-cells: FC: 4.9; p<0.01; CD4-cells: FC: 7.5; p<0.003) and FAM26F (CD14-cells: FC: 4.2; p<0.007; CD4-cells: FC: 8.0; p=0.058) were also significantly higher after 24 hours in GC-Responders measured by qPCR. Additionally, CCNB2 (FC: 0.49; p<0.008) was significantly and TMP4 (FC: 0.62; p=0.058) marginally lower in CD4-Tcells and CEP350 and DICER were marginally higher (FC: 1.8; p=0.054 and FC: 1.55; p=0.063) in CD14-cells of GC-Responders compared to GC-Non-Responders.
Conclusion: We found several differentially expressed genes in GC-Responders versus GC-Non-Responders before and 24 hours after start of pulse therapy. The most striking difference is the significantly higher expression of ERAP2 in T-cells and monocytes of GC-Responders. ERAP2 constitutes a susceptibility locus in autoimmune disease, and functions as proteolytic enzyme implicated in antigen presentation. Its homologue is also known to cleave cell surface receptors (TNFR1, IL1R2, IL6Ra). The increased expression in GC-Responders compared to GC-Non-Responders may thus constitute not only a potential predictor of the clinical response to GC in RA, but also warrants further investigation to elucidate the possible role in the inflammatory process of RA.
Disclosure:
R. Fritsch-Stork,
None;
S. Cardoso,
None;
J. Broen,
None;
M. Groot-Koerkamp,
None;
A. Concepcion,
None;
F. Lafeber,
None;
J. W. J. Bijlsma,
Abbott Immunology Pharmaceuticals,
5,
Roche Pharmaceuticals,
5,
BMS,
5,
UCB,
5,
Pfizer Inc,
5,
Merck Pharmaceuticals,
2,
Pfizer Inc,
2,
UCB,
2,
BMS,
2,
Roche Pharmaceuticals,
2,
Abbott Immunology Pharmaceuticals,
2.
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