Background/Purpose RA is known to be a heterogeneous disease, with heterogeneity existing in both clinical symptoms and responses to therapies. Molecular assessment of this heterogeneity would help to describe novel aspects of RA pathogenesis and potentially allow for more accurate predictions of which treatments will be most beneficial to a given patient. We examined the question of whether similar immune-relevant pathways are significantly enriched in different RA populations focusing on whole blood gene expression profiles of 2 large cohorts of clinical trial subjects.

Methods Both cohorts included men and women aged ≥18 yrs with active RA for ≥ 3 months with inadequate response to methotrexate (MTX). Messenger RNA (mRNA) was collected from 487 baseline whole blood samples in Cohort 1 (Clinical study NCT00973479) and 89 baseline whole blood samples in Cohort 2 (Clinical study NCT01597739). Additionally, non-RA serum samples (healthy controls; Cohort 1 n=22, Cohort 2 n=24) were obtained from Bioreclamation (Hicksville,NY).  All samples were profiled using the HT HG-U133+ PM Array (Affymetrix).  Comparisons between the healthy control and diseased experimental groups were performed using iReport (Ingenuity; Redwood, CA) and pathway analyses were performed using IPA (www.ingenuity. com), NextBio (www.nextbio.com), and MetaCore (www.thomsonreuters.com/metacore).  Statistical significance is based on p-value 0.05 and fold change 1.2.

Results The disease profiles (DP) comparing baseline gene expression levels of RA and healthy controls contain 2203 and 1282 differentially expressed genes (DEGs) for Cohorts 1 & 2 respectively. There were 324 DEGs shared between the two cohorts, encompassing 14.7% and 25.5% of Cohort 1 and 2. On a pathway level, IPA identified 119 pathways that were present and significant (Fisher’s Exact Test p-value) in at least one cohort. Of these, 21 (17.6%) were shared and significant in both cohorts and included inflammatory and immune response related pathways. 17 and 81 pathways were uniquely significant to Cohort 1  and Cohort 2 and included complementary pathways such as cell and cytokine signaling pathways.  Analysis via MetaCore identified 406 total pathways; 134 were shared and significant to both cohorts, and 102 and 170 were uniquely significant to Cohorts 1 and 2 respectively. Shared and significant pathways primarily included those related to immune response; pathways unique to only one cohort were enriched for immune response signaling and inflammatory response.

Conclusion  Analysis of disease profiles from 2 independent cohorts via IPA and MetaCore analysis tools showed that the significant pathways common to both cohorts are enriched in inflammatory and immune response pathways. The uniquely significant pathways of Cohort 2 were notably enriched in inflammatory pathways and cell/cytokine signaling. A complimentary approach via MetaCore identified more enriched sets of overlapping and unique pathways relevant to Cohorts 1 and 2, as well as similar trends for unique and common pathways. These results reflect the complexity and diversity of RA across different cohorts and enhance understanding of the interplay of pathways in a given patient.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/assessment-of-ra-heterogeneity-in-two-independent-cohorts-of-patients/