Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Gene Expression Signatures in Synovial Tissue Define Distinct Molecular Subtypes of Rheumatoid Arthritis

Dennis Jr.1,  Glynn, Lin1,  Wei Y., Diehl1,  Lauri, Holweg1,  C., Townsend1,  M., Endres2,  Judith, Fox3,  David A.

Genentech, Inc, South San Francisco, CA
Univ of Michigan Med Ctr, Ann Arbor, MI
Univ of Michigan, Ann Arbor, MI

Purpose:

The study aimed to identify molecular subtypes of rheumatoid arthritis (RA) with linkage to pathological features and therapeutic outcome.

Method:

Genome-wide transcriptional profiles for 81 synovial tissue samples obtained by surgery from 50 RA patients were analyzed by bootstrapped hierarchical clustering. Statistical analysis identified differentially expressed genes, over-represented pathways and a gene signature 'proxy' for each molecular subtype. Analysis of tissue histology and immunohistochemistry identified joint pathologies that associated with array-based findings. Gene signatures were tested for association with therapeutic outcome on an independent data set.

Results:

Multi-scale bootstrap resampling of 81 samples (10,000 iterations) inferred four molecular subtypes of RA. The largest subtype grouped 34 samples (87% branch support) that shared extensive lymphoid infiltration and follicle-like lymphoid clusters (each p<0.01). This signature contained abundant transcripts for immunoglobulins and T cell markers. A second subtype (17 samples, 67% branch support) represented a distinct type of inflammation that was characterized by transcripts involved in respiratory burst and chemotaxis pathways. This signature was inversely associated with joint vascularity (p<0.05). Two non-inflammatory subtypes were identified. The first (19 samples, 94% branch support) possessed a signature inversely associated with lymphocyte and CD15+ cell infiltration (each p<0.01) and was enriched for wnt-signaling and tumorigenesis pathway genes. The second non-inflammatory subtype (9 samples, 88% branch support), collectively modulated genes involved in cell adhesion and bone remodeling pathways. This gene signature was associated with a higher degree of synovial lining hyperplasia. Finally, this subtype was found to be associated with a poor response to anti-TNF therapy in an independent dataset.

Conclusion:

Molecular profiling, bootstrap-resampling and over-representation analysis provided statistical support for four molecular subtypes of RA. Each subtype possessed a unique gene signature that mapped differentially to histology indicators of joint pathology and reflected modulation of distinct signaling networks. One of the molecular subtypes represented patients that responded poorly to anti-TNF therapy, suggesting that RA molecular subtyping has prognostic value for patient response to therapy.

To cite this abstract, please use the following information:
Dennis Jr., Glynn, Lin, Wei Y., Diehl, Lauri, Holweg, C., Townsend, M., Endres, Judith, et al; Gene Expression Signatures in Synovial Tissue Define Distinct Molecular Subtypes of Rheumatoid Arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :753
DOI: 10.1002/art.25833

Abstract Supplement

Meeting Menu

2009 ACR/ARHP