Molecular discrimination of responders and nonresponders to anti-TNFalpha therapy in rheumatoid arthritis by etanercept

Dirk Koczan¹ , Susanne Drynda² , Michael Hecker³ , Andreas Drynda² , Reinhard Guthke³ , Joern Kekow² and Hans-Juergen Thiesen¹

¹Department of Immunology, University of Rostock, Schillingallee 70, 18055 Rostock, Germany

²Clinic of Rheumatology, University of Magdeburg, Sophie-von-Boetticher-Straße 1, 39245 Vogelsang, Germany

³Leibnitz Institute for Natural Product Research and Infection Biology – Hans-Knoell-Institute e.V., Beutenbergstraße 11a, 07745 Jena, Germany

author email corresponding author email

Arthritis Research & Therapy 2008, 10:R50doi:10.1186/ar2419


Published:	2 May 2008

Abstract

Introduction

About 30% of rheumatoid arthritis patients fail to respond adequately to TNFα-blocking therapy. There is a medical and socioeconomic need to identify molecular markers for an early prediction of responders and nonresponders.

Methods

RNA was extracted from peripheral blood mononuclear cells of 19 rheumatoid arthritis patients before the first application of the TNFα blocker etanercept as well as after 72 hours. Clinical response was assessed over 3 months using the 28-joint-count Disease Activity Score and X-ray scans. Supervised learning methods were applied to Affymetrix Human Genome U133 microarray data analysis to determine highly selective discriminatory gene pairs or triplets with prognostic relevance for the clinical outcome evinced by a decline of the 28-joint-count Disease Activity Score by 1.2.

Results

Early downregulation of expression levels secondary to TNFα neutralization was associated with good clinical responses, as shown by a decline in overall disease activity 3 months after the start of treatment. Informative gene sets include genes (for example, NFKBIA, CCL4, IL8, IL1B, TNFAIP3, PDE4B, PPP1R15A and ADM) involved in different pathways and cellular processes such as TNFα signalling via NFκB, NFκB-independent signalling via cAMP, and the regulation of cellular and oxidative stress response. Pairs and triplets within these genes were found to have a high prognostic value, reflected by prediction accuracies of over 89% for seven selected gene pairs and of 95% for 10 specific gene triplets.

Conclusion

Our data underline that early gene expression profiling is instrumental in identifying candidate biomarkers to predict therapeutic outcomes of anti-TNFα treatment regimes.