RESEARCH - Gene expression profiling in the synovium identifies a predictive signature of absence of response to Humira therapy in RA

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Arthritis Research & Therapy 2009, 11:R57doi:10.1186/ar2678

Published: 23 April 2009

Research article

Gene expression profiling in the synovium identifies a predictive

signature of absence of response to adalimumab therapy in rheumatoid

arthritis

Valérie Badot1,2 , Galant3 , Adrien Nzeusseu Toukap1 , Ivan

Theate3 , Anne-Lise Maudoux1 , Benoît J Van den Eynde4 ,

Durez1 , Frédéric A Houssiau1 and Bernard R Lauwerys1

1Rheumatology Department, Cliniques Universitaires Saint-Luc,

Université catholique de Louvain, Avenue Hippocrate 10, B-1200

Brussels, Belgium

2Rheumatology Department, CHU Brugmann, Place Arthur Van Gehuchten 4,

1020 Brussels, Belgium

3Pathology Department, Cliniques Universitaires Saint-Luc, Université

catholique de Louvain, Avenue Hippocrate 10, B-1200 Brussels, Belgium

4Ludwig Institute for Cancer Research, Avenue Hippocrate 74, B-1200

Brussels, Belgium

Abstract

Introduction

To identify markers and mechanisms of resistance to adalimumab

therapy, we studied global gene expression profiles in synovial tissue

specimens obtained from severe rheumatoid arthritis (RA) patients

before and after initiation of treatment.

Methods

Paired synovial biopsies were obtained from the affected knee of 25

DMARD (disease-modifying antirheumatic drug)-resistant RA patients at

baseline (T0) and 12 weeks (T12) after initiation of adalimumab

therapy. DAS28-CRP (disease activity score using 28 joint

counts-C-reactive protein) scores were computed at the same time

points, and patients were categorized as good, moderate, or poor

responders according to European League Against Rheumatism criteria.

Global gene expression profiles were performed in a subset of patients

by means of GeneChip Human Genome U133 Plus 2.0 Arrays, and

confirmatory immunohistochemistry experiments were performed on the

entire cohort.

Results

Gene expression studies performed at baseline identified 439 genes

associated with poor response to therapy. The majority (n = 411) of

these genes were upregulated in poor responders and clustered into two

specific pathways: cell division and regulation of immune responses

(in particular, cytokines, chemokines, and their receptors).

Immunohistochemistry experiments confirmed that high baseline synovial

expression of interleukin-7 receptor α chain (IL-7R), chemokine (C-X-C

motif) ligand 11 (CXCL11), IL-18, IL-18 receptor accessory (IL-18rap),

and MKI67 is associated with poor response to adalimumab therapy. In

vitro experiments indicated that genes overexpressed in poor

responders could be induced in fibroblast-like synoviocytes (FLS)

cultures by the addition of tumor necrosis factor-alpha (TNF-α) alone,

IL-1β alone, the combination of TNF-α and IL-17, and the combination

of TNF-α and IL-1β.

Conclusions

Gene expression studies of the RA synovium may be useful in the

identification of early markers of response to TNF blockade. Genes

significantly overexpressed at baseline in poor responders are induced

by several cytokines in FLSs, thereby suggesting a role for these

cytokines in the resistance to TNF blockade in RA.

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Read the full article here:

http://arthritis-research.com/content/11/2/R57

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