Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium.
OBJECTIVE
To investigate the global molecular effects of tocilizumab (TCZ) in comparison with methotrexate (MTX) treatment in synovial biopsy tissue obtained from patients with previously untreated rheumatoid arthritis (RA) before therapy (T0) and 12 weeks after the initiation of therapy (T12), and to compare the results with previous gene expression data obtained in synovial biopsy tissue from adalimumab (ADA)- and rituximab (RTX)-treated patients with RA.


METHODS
Paired synovial biopsy samples were obtained at T0 and T12 from the affected knee of TCZ-treated RA patients and MTX-treated RA patients. Gene expression studies were performed using GeneChip Human Genome U133 Plus 2.0 microarrays, and confirmatory quantitative real-time reverse transcription-polymerase chain reaction experiments were performed on selected transcripts. The effects of TCZ and MTX on synovial cell populations and histologic characteristics were assessed by immunohistochemistry.


RESULTS
Gene expression studies showed that blockade of the interleukin-6 receptor (IL-6R) gene (IL6R) using TCZ induced a significant decrease in the expression of numerous chemokine and T cell activation genes in the RA synovium. These effects strongly correlated with the molecular effects of MTX and RTX therapy on RA synovial tissue, but differed from the molecular changes induced by ADA (decreased expression of genes involved in cell proliferation).


CONCLUSIONS
The molecular similarities between the effects of TCZ, RTX, and MTX therapies in the RA synovium indicate that B cell- and IL-6-dependent pathways play synergistic roles in the pathogenesis of the disease, in particular through activation of T cell responses. Moreover, these results open perspectives for the individualization of therapeutic decisions, based on a better knowledge of the synovial molecular effects of each type of RA therapy.
Université Catholique de Louvain, Brussels, Belgium.
Julie
J
Ducreux
Patrick
P
Durez
Christine
C
Galant
Adrien
A
Nzeusseu Toukap
Benoît
B
Van den Eynde
Frédéric A
FA
Houssiau
Bernard R
BR
Lauwerys
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008727:Methotrexate / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes
D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D018925:Chemokines; D016207:Cytokines; C508603:IL6R protein, human; D019947:Receptors, Interleukin-6; C502936:tocilizumab; D008727:Methotrexate