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Open Access Highly Accessed Research article

Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics

Glynn Dennis1, Cécile TJ Holweg2, Sarah K Kummerfeld3, David F Choy2, A Francesca Setiadi2, Jason A Hackney3, Peter M Haverty3, Houston Gilbert4, Wei Yu Lin1, Lauri Diehl5, S Fischer6, An Song6, David Musselman7, Micki Klearman7, Cem Gabay8, Arthur Kavanaugh9, Judith Endres10, David A Fox10, Flavius Martin111 and Michael J Townsend2*

  • * Corresponding author: Michael J Townsend townsem1@gene.com

  • † Equal contributors

Author Affiliations

1 Departments of Immunology Discovery, Genentech, South San Francisco, California, USA

2 ITGR Diagnostics Discovery, Genentech, South San Francisco, California, USA

3 Bioinformatics and Computational Biology, Genentech, South San Francisco, California, USA

4 Non-clinical Biostatistics, Genentech, South San Francisco, California, USA

5 Pathology, Genentech, South San Francisco, California, USA

6 Bioanalytical Sciences, Genentech, South San Francisco, California, USA

7 Product Development, Genentech, South San Francisco, California, USA

8 University Hospital of Geneva, Geneva, Switzerland

9 University of California San Diego, San Diego, California, USA

10 Rheumatic Disease Core Center and Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA

11 Current address: Inflammation Therapeutic Area, Amgen, 1201 Amgen Court West, Seattle, Washington, USA

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Arthritis Research & Therapy 2014, 16:R90  doi:10.1186/ar4555

Published: 30 April 2014

Abstract

Introduction

Rheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease. Currently, the relationship between pathogenic molecular drivers of disease in RA and therapeutic response is poorly understood.

Methods

We analyzed synovial tissue samples from two RA cohorts of 49 and 20 patients using a combination of global gene expression, histologic and cellular analyses, and analysis of gene expression data from two further publicly available RA cohorts. To identify candidate serum biomarkers that correspond to differential synovial biology and clinical response to targeted therapies, we performed pre-treatment biomarker analysis compared with therapeutic outcome at week 24 in serum samples from 198 patients from the ADACTA (ADalimumab ACTemrA) phase 4 trial of tocilizumab (anti-IL-6R) monotherapy versus adalimumab (anti-TNFα) monotherapy.

Results

We documented evidence for four major phenotypes of RA synovium – lymphoid, myeloid, low inflammatory, and fibroid - each with distinct underlying gene expression signatures. We observed that baseline synovial myeloid, but not lymphoid, gene signature expression was higher in patients with good compared with poor European league against rheumatism (EULAR) clinical response to anti-TNFα therapy at week 16 (P =0.011). We observed that high baseline serum soluble intercellular adhesion molecule 1 (sICAM1), associated with the myeloid phenotype, and high serum C-X-C motif chemokine 13 (CXCL13), associated with the lymphoid phenotype, had differential relationships with clinical response to anti-TNFα compared with anti-IL6R treatment. sICAM1-high/CXCL13-low patients showed the highest week 24 American College of Rheumatology (ACR) 50 response rate to anti-TNFα treatment as compared with sICAM1-low/CXCL13-high patients (42% versus 13%, respectively, P =0.05) while anti-IL-6R patients showed the opposite relationship with these biomarker subgroups (ACR50 20% versus 69%, P =0.004).

Conclusions

These data demonstrate that underlying molecular and cellular heterogeneity in RA impacts clinical outcome to therapies targeting different biological pathways, with patients with the myeloid phenotype exhibiting the most robust response to anti-TNFα. These data suggest a path to identify and validate serum biomarkers that predict response to targeted therapies in rheumatoid arthritis and possibly other autoimmune diseases.

Trial registration

ClinicalTrials.gov NCT01119859