Pharmacological induction of interferon type I activity following treatment with rituximab determines clinical response in XXXX .

@entity1 @entity627 @entity309
OBJECTIVE: Despite the fact that rituximab depletes B cells in all treated @entity1 with @entity309 , not all @entity1 show a favourable clinical response. The goal of this study was to provide insight into pharmacological changes in peripheral blood that are associated with clinical response to rituximab. METHODS: Gene expression profiling was performed on peripheral blood RNA of 13 @entity1 with @entity309 (test group) using Illumina HumanHT beadchip microarrays. An independent group of nine @entity1 was used for validation using TaqMan quantitative PCR. Clinical responder status was determined after 6 months using change in 28-joint Disease Activity Score (/\DAS28) and European League Against @entity627 (EULAR) response criteria. Significance analysis of microarrays and ontology analysis were used for data analysis and interpretation. RESULTS: Pharmacogenomic analyses demonstrated marked interindividual differences in the pharmacological responses at 3 and 6 months after start of treatment with rituximab. Interestingly, only differences in the regulation of type I interferon (IFN)-response genes after 3 months correlated with the /\DAS28 response. Good responders (DAS>1.2; n=7) exhibited a selective increase in the expression of type I IFN-response genes, whereas this activity was unchanged or hardly changed in non-responders (DAS<1.2; n=6) (p=0.0040 at a cut-off of 1.1-fold induction). Similar results were obtained using EULAR response criteria. These results were validated in an independent cohort of nine @entity1 (five non-responders and four responders, p=0.0317). CONCLUSIONS: A good clinical response to rituximab in @entity309 is associated with a selective drug-induced increase in type I IFN-response activity in @entity1 with @entity309 . This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab.
