Background/Purpose: Characterize the molecular landscape of RA patients using a multi-omic approach encompassing transcriptomics and proteomics and assess its association with disease stage and therapeutic outcomes.

Methods: PBMCs from patients with early RA (EA-RA) (diagnosis ≤ 1 year; n=31), stablished RA (ES-RA) (diagnosis ≥ 5 years; n=66), and healthy donors (HDs) (n=27) were profiled by RNAseq on Illumina platforms. A panel of 92 inflammatory mediators was analyzed in the serum using “Proximity extension assay” from the Olink platform. EA-RA cohort included 26 patients starting conventional DMARDs. ES-RA cohort comprised 47 biologics-naïve patients before receiving biologic DMARDs (TNFi) or targeted-synthetic DMARDs (JAKi). Clinical outcomes were assessed after 6 months of treatment following EULAR criteria. Advanced computational analysis evaluated the relationship between the transcriptomic and proteomic profiles with key disease features and therapy response.

Results: Seventy gene modules associated with lymphocyte and myeloid cells activation and inflammation were altered in EA-RA compared to HDs. ES-RA showed even more marked alterations and specific changes in 58 additional gene modules related to other immunoregulatory pathways. At the protein level, ES-RA patients displayed significant inflammatory response changes, with 49 proteins (mainly cytokines and growth factors) differentially expressed compared to HDs, contrasted with 32 deregulated proteins in EA-RA.

Clinically, EA-RA patients showed a negative correlation between disease activity (DAS28, acute phase reactants) and modules associated with T lymphocyte and NK cell activation, and a positive correlation with inflammatory and myeloid gene modules. Protein inflammatory mediators (chemokines, cytokines, growth factors) were also linked with disease severity and positivity for autoantibodies (RF and ACPAS).

These correlations were more pronounced in ES-RA, highlighting the molecular complexity driving disease severity over time. A significant relationship was noted between altered gene modules in PBMCs and circulating inflammatory proteins, indicating a sophisticated molecular network driving disease progression.

Transcriptomic signatures at baseline were associated with clinical response: increased lymphocyte activation-gene modules expression before therapy predicted good response to conventional DMARDs in EA-RA but poor response to JAKi and TNFi in ES-RA.

Conclusion: The study reveals distinct molecular signatures in EA-RA and ES-RA, reflecting disease progression and differences in therapeutic responses. The greater deregulation in ES-RA underscores the complexity of established disease and the need for stage-specific therapeutic strategies. Identified gene modules and proteins could serve as potential biomarkers for disease activity and treatment response, aiding personalized treatment approaches in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/uncovering-common-and-distinctive-molecular-profiles-between-early-and-stablished-rheumatoid-arthritis-through-integrative-multi-omics-analysis-and-its-association-with-disease-status-and-clinical-res/