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 (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).

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 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.

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.

• Authors: Hennie G Raterman, Saskia Vosslamber, Sander de Ridder, Michael T Nurmohamed, Willem F Lems, Maarten Boers, Mark van de Wiel, Ben A C Dijkmans, Cornelis L Verweij, Alexandre E Voskuyl
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 14 Issue 2 Pg. R95 (Apr 27 2012) ISSN: 1478-6362 [Electronic] England
• PMID: 22540992 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Murine-Derived
• Interferon Type I
• Rituximab

Topics

• Aged
• Antibodies, Monoclonal, Murine-Derived (therapeutic use)
• Arthritis, Rheumatoid (drug therapy, genetics)
• Female
• Follow-Up Studies
• Gene Regulatory Networks (drug effects, genetics)
• Genome-Wide Association Study (methods)
• Humans
• Interferon Type I (genetics)
• Male
• Middle Aged
• Predictive Value of Tests
• Rituximab
• Treatment Failure
• Treatment Outcome