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