Abstract
IntroductionB cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents. However, approximately 40% to 50% of rituximab (RTX) treated RA patients have a poor response. We investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX.MethodsIn 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina® HumanHT beadchip microarrays. Supervised cluster analysis was used to identify genes expressed differentially at baseline between responders and non-responders based on both a difference in 28 joints disease activity score (ΔDAS28 < 1.2) and European League against Rheumatism (EULAR) response criteria after six months RTX. Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n = 26).ResultsGenome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment. Here, we demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with ΔDAS28 and EULAR response outcome (P = 0.0074 and P = 0.0599, respectively). Based on the eight IRGs an IFN-score was calculated that reached an area under the curve (AUC) of 0.82 to separate non-responders from responders in an independent validation cohort of 26 patients using Receiver Operator Characteristics (ROC) curves analysis according to ΔDAS28 < 1.2 criteria. Advanced classifier analysis yielded a three IRG-set that reached an AUC of 87%. Comparable findings applied to EULAR non-response criteria.ConclusionsThis study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.
Highlights
B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents
RA is marked by the presence of rheumatoid factor (RF) and/or anti-citrullinated protein autoantibodies (ACPA), which may precede the appearance of clinical symptoms of arthritis by many years [1,2]
Patient characteristics A total of 40 patients were included, 14 of whom were subjected to genome-wide gene expression profiling and 26 of whom were used for validation
Summary
B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents. We investigated whether baseline gene expression levels can discriminate between clinical nonresponders and responders to RTX. RA is marked by the presence of rheumatoid factor (RF) and/or anti-citrullinated protein autoantibodies (ACPA), which may precede the appearance of clinical symptoms of arthritis by many years [1,2]. Surface expressing RF Bcells may bind immune complexes and thereby serve a role as efficient antigen presenting cells that could lead to a break in T-cell tolerance against autoantigens [3]. Besides producers of auto-antibodies, B cells may contribute to disease pathogenesis through their role in antigen presentation, lymphoneogenesis and cytokine release [6]. It was suggested that B-cells are essential players of the disturbed immune system, which fuelled interest in B-cells as drug target
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
