Pharmacogenomics of infliximab treatment using peripheral blood cells of patients with rheumatoid arthritis.
To provide insight into the pharmacological changes in the peripheral blood (PB) molecular profile induced by tumor necrosis factor (TNF)-blockade in patients with rheumatoid arthritis (RA), blood was obtained in PAXgene tubes from 33 RA patients before and 1 month after TNF-blocking therapy (infliximab). From 15 randomly chosen patients pre- and post-treatment gene expression profiles were determined. The remaining 18 RA patients served as validation cohort. A group-based paired analysis of the gene expression profiles from the post- vs pre-treatment samples revealed a signature of genes significantly regulated by TNF-blockade. Downregulated genes reflected several biological pathways such as inflammation, angiogenesis, B- and T-cell activation. Further analysis revealed that the pharmacological response signature was significantly regulated in all treated patients, irrespective of clinical response, which is indicative for the presence of an active TNF pathway in all RA patients. The data imply that all patients carried features of TNF bioactivity irrespective of clinical response. These results favor a model for the parallel presence of TNF-dependent and TNF-independent pathways in the individual RA patient. Clinical response status to TNF-blockade may be dependent on the relative contribution of TNF-independent effector pathways.
van Baarsen
L G M
LG
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Wijbrandts
C A
CA
Gerlag
D M
DM
Rustenburg
F
F
van der Pouw Kraan
T C T M
TC
Dijkmans
B A C
BA
Tak
P P
PP
Verweij
C L
CL
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D001773:Blood Cells / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab