The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients
- Equal contributors
1 Department of Rheumatology, VU University medical center, de Boelelaan 1117, Amsterdam, 1081HV, the Netherlands
2 Department of Pathology, VU University medical center, de Boelelaan 1118, Amsterdam, 1081HV, Amsterdam, the Netherlands
3 Department of Rheumatology, Jan van Breemen Research Institute|Reade, Jan van Breemenstraat 2, Amsterdam, 1056AB, The Netherlands
4 Department of Epidemiology and Biostatistics, VU University medical center, de Boelelaan 1117, Amsterdam, 1081HV, the Netherlands
Arthritis Research & Therapy 2012, 14:R95 doi:10.1186/ar3819Published: 27 April 2012
B 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.
In 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).
Genome-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.
This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.