OBJECTIVE: Rituximab displays therapeutic benefits in the treatment of patients with rheumatoid arthritis (RA) resistant to tumor necrosis factor (TNF) blockade. However, the precise role of B cells in the pathogenesis of RA is still unknown. We undertook this study to investigate the global molecular effects of rituximab in synovial biopsy samples obtained from anti-TNF-resistant RA patients before and after administration of the drug. METHODS: Paired synovial biopsy samples were obtained from the affected knee of anti-TNF-resistant RA patients before (time 0) and 12 weeks after (time 12) initiation of rituximab therapy. Total RNA was extracted, labeled according to standard Affymetrix procedures, and hybridized on GeneChip HGU133 Plus 2.0 slides. Immunohistochemistry and quantitative real-time reverse transcriptase-polymerase chain reaction experiments were performed to confirm the differential expression of selected transcripts. RESULTS: According to Student's paired t-tests, 549 of 54,675 investigated probe sets were differentially expressed between time 0 and time 12. Pathway analysis revealed that genes down-regulated between time 0 and time 12 were significantly enriched in immunoglobulin genes and genes involved in chemotaxis, leukocyte activation, and immune responses (Gene Ontology annotations). In contrast, genes up-regulated between time 0 and time 12 were significantly enriched in transcripts involved in cell development (Gene Ontology annotation) and wound healing (Gene Set Enrichment Analysis). At baseline, higher synovial expression of immunoglobulin genes was associated with response to therapy. CONCLUSION: Rituximab displays unique effects on global gene expression profiles in the synovial tissue of RA patients. These observations open new perspectives in the understanding of the biologic effects of the drug and in the selection of patients likely to benefit from this therapy.
OBJECTIVE:Rituximab displays therapeutic benefits in the treatment of patients with rheumatoid arthritis (RA) resistant to tumor necrosis factor (TNF) blockade. However, the precise role of B cells in the pathogenesis of RA is still unknown. We undertook this study to investigate the global molecular effects of rituximab in synovial biopsy samples obtained from anti-TNF-resistant RApatients before and after administration of the drug. METHODS: Paired synovial biopsy samples were obtained from the affected knee of anti-TNF-resistant RApatients before (time 0) and 12 weeks after (time 12) initiation of rituximab therapy. Total RNA was extracted, labeled according to standard Affymetrix procedures, and hybridized on GeneChip HGU133 Plus 2.0 slides. Immunohistochemistry and quantitative real-time reverse transcriptase-polymerase chain reaction experiments were performed to confirm the differential expression of selected transcripts. RESULTS: According to Student's paired t-tests, 549 of 54,675 investigated probe sets were differentially expressed between time 0 and time 12. Pathway analysis revealed that genes down-regulated between time 0 and time 12 were significantly enriched in immunoglobulin genes and genes involved in chemotaxis, leukocyte activation, and immune responses (Gene Ontology annotations). In contrast, genes up-regulated between time 0 and time 12 were significantly enriched in transcripts involved in cell development (Gene Ontology annotation) and wound healing (Gene Set Enrichment Analysis). At baseline, higher synovial expression of immunoglobulin genes was associated with response to therapy. CONCLUSION:Rituximab displays unique effects on global gene expression profiles in the synovial tissue of RApatients. These observations open new perspectives in the understanding of the biologic effects of the drug and in the selection of patients likely to benefit from this therapy.
Authors: Carl Orr; Elsa Vieira-Sousa; David L Boyle; Maya H Buch; Christopher D Buckley; Juan D Cañete; Anca I Catrina; Ernest H S Choy; Paul Emery; Ursula Fearon; Andrew Filer; Danielle Gerlag; Frances Humby; John D Isaacs; Søren A Just; Bernard R Lauwerys; Benoit Le Goff; Antonio Manzo; Trudy McGarry; Iain B McInnes; Aurélie Najm; Constantino Pitzalis; Arthur Pratt; Malcolm Smith; Paul P Tak; Rogier Thurlings; João E Fonseca; Douglas J Veale; Sander W Tas Journal: Nat Rev Rheumatol Date: 2017-07-13 Impact factor: 20.543
Authors: Bernard R Lauwerys; Daniel Hernández-Lobato; Pierre Gramme; Julie Ducreux; Adrien Dessy; Isabelle Focant; Jérôme Ambroise; Bertrand Bearzatto; Adrien Nzeusseu Toukap; Benoît J Van den Eynde; Dirk Elewaut; Jean-Luc Gala; Patrick Durez; Frédéric A Houssiau; Thibault Helleputte; Pierre Dupont Journal: PLoS One Date: 2015-04-30 Impact factor: 3.240
Authors: Elena V Tchetina; Anastasya N Pivanova; Galina A Markova; Galina V Lukina; Elena N Aleksandrova; Andrey P Aleksankin; Sergey A Makarov; Aleksandr N Kuzin Journal: Arthritis Date: 2016-01-24
Authors: A N Burska; K Roget; M Blits; L Soto Gomez; F van de Loo; L D Hazelwood; C L Verweij; A Rowe; G N Goulielmos; L G M van Baarsen; F Ponchel Journal: Pharmacogenomics J Date: 2014-03-04 Impact factor: 3.550