fetching data ... 
Background: Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are the two highly prevalent, debilitating, and sometimes life-threatening systemic inflammatory autoimmune diseases. The etiology and pathogenesis of RA and SLE are interconnected in several ways, yet there is limited knowledge about the underlying molecular mechanisms.
Objectives: To characterize both, the shared and distinct molecular mechanisms underlying the physiopathology of RA and SLE diseases through an integrated transcriptomic analysis.
Methods: Transcriptome was obtained from peripheral blood mononuclear cells (PBMCs) of 27 healthy donors (HD), 86 RA patients and 27 SLE patients (including 11 with SLE plus APS) by RNAseq (Illumina). Gene expression data were projected into gene pathway modules (gene signatures) using a novel functional annotation approach. In parallel, a comprehensive clinical profile, encompassing both clinical and serological landscapes was established, and the relationship between gene expression and disease features was evaluated.
Results: Unsupervised clustering identified 3 clusters displaying differential expression across 13 gene-modules, delineating distinct biological pathways and cell activities such as inflammation, myeloid/monocytes, T-cells, B-cells, cell signaling, mitochondrial dysfunction, cell cycle, and interferon responses.
Cluster 2 exclusively comprised RA patients, whereas clusters 1 and 3 included both RA and SLE patients. Notably, Cluster 3 encompassed half of the SLE+APS patients, whereas Cluster 1 only contained a third of them.
Clinically, Cluster 2 contained RA patients exhibiting the highest disease activity, disease progression, and acute phase reactant (APR) levels compared to those in Clusters 1 and 3.
Among lupus patients, those in Cluster 3 exhibited elevated titers of anti-dsDNA antibodies, a higher incidence of lupus nephritis, proteinuria, arterial hypertension, and pregnancy complications compared to those in Cluster 1.
Furthermore, SLE+APS patients predominantly present in Cluster 3 demonstrated a higher prevalence of arterial and venous thrombosis, recurrent events, altered APR, and cardiovascular risk factors (e.g., atheroma plaques, hypertension, diabetes, and obesity) than their counterparts in Cluster 1.
Modules that characterized each cluster were associated with various clinical features across RA, SLE, and SLE+APS patients. For instance:
Elevated levels of modules related to inflammation and myeloid/monocytes correlated with increased disease activity and disease evolution in RA, positivity for anti-dsDNA antibodies in SLE, and cardiovascular risk factors in SLE+APS.
Deregulated T-cell activation modules were associated with elevated APR in both RA and SLE, nephropathy in SLE, and obstetric complications in SLE+APS.
Alterations in B-cell activity modules were linked to increased levels of ACPAs in RA, elevated APR in SLE, and heightened CV-risk in SLE+APS.
Modules associated with cell signaling, mitochondrial dysfunction, and the cell cycle were simultaneously correlated with elevated APR, positive autoantibodies, thrombotic events, nephropathy, and obstetric complications across all three diseases.
Lastly, alterations in the interferon module corresponded to increased APR in RA, SLE, and SLE+APS patients, as well as nephropathy in SLE and thrombosis in SLE+APS.
Conclusion: Peripheral blood mononuclear cells of RA, SLE and APS+SLE patients exhibit both shared and distinct gene profiles related to specific clinical and serologic characteristics. Integrated transcriptomic analyses would provide the basis for understanding the common and distinctive mechanisms of pathogenesis in these autoimmune disorders, as reported [1].
Ongoing studies will delineate the stability of these identified gene signatures and assess their significance in predicting clinical progression and response to different therapeutic approaches.
REFERENCES: [1] Barturen G, Babaei S, Català-Moll F, et al. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases. Arthritis Rheumatol. 2021;73(6):1073-1085. doi:10.1002/art.41610
Acknowledgements: Supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking 3TR, Projects no. PI21/0591 & CD21/00187 funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. Project no. RD21/0002/0033 funded by ISCIII and funded by the European Union-NextGeneration EU, via Plan de Recuperación, Transformacion y Resiliencia (PRTR) and MINECO (RYC2021-033828-I, and PID2022-141500OA-I00).
Disclosure of Interests: None declared.