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The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients.


ABSTRACT:

Introduction

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.

Methods

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 (?DAS28 < 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).

Results

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 ?DAS28 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 ?DAS28 < 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.

Conclusions

This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.

SUBMITTER: Raterman HG 

PROVIDER: S-EPMC3446469 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients.

Raterman Hennie G HG   Vosslamber Saskia S   de Ridder Sander S   Nurmohamed Michael T MT   Lems Willem F WF   Boers Maarten M   van de Wiel Mark M   Dijkmans Ben A C BA   Verweij Cornelis L CL   Voskuyl Alexandre E AE  

Arthritis research & therapy 20120427 2


<h4>Introduction</h4>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.<h4>Methods</h4>In 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral  ...[more]

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