Pos0142 distinct expression clusters of interferon-regulated genes associate differently with disease activity in patients with systemic lupus erythematosus.

BackgroundSystemic lupus erythematosus (SLE) is a complex multiorgan autoimmune disease that primarily affects women during child-bearing years. The aetiology of SLE involves inadequate clearance of nuclear material released from apoptotic cells. The persistence of host DNA and RNA triggers the immune system to react as seen in a viral infection, causing persistent activation of antiviral interferon (IFN) signalling pathways. Aberrant production of IFN cytokines, type 1 in particular, results in elevated levels of >1000 IFN-regulated gene (IRG) expression in the blood, termed an IFN signature. The IFN signature is typically measured as a score combining the expression levels of a subset of 3-4 IRGs. Several cross-sectional studies have pointed to an association between the IFN signature and disease activity, however subsequent longitudinal studies and a recent systematic review by our group[1] have failed to reproduce these findings. It was suggested that the lack of association between the IFN signature and disease activity was because the IRGs that are sensitive to disease activity are not typically included in the subset of IRGs used to determine an IFN score[2]. Uncovering the significance of the IFN signature in SLE disease activity is particularly relevant for evaluating the scope of IFN pathway inhibitors and may explain why these fail to have a significance for the primary endpoint in clinical trials[3].Objectives-Determine the mRNA expression of a broad subset of IRGs (>100) in a cross-sectional study of SLE patients with diverse clinical manifestations-Investigate the association between IRG expression and disease activity-Validate the findings from a cross-sectional study in a longitudinal study of SLE patients with fluctuating disease activityMethodsIn a cross-sectional study, peripheral blood samples from 34 SLE patients and 15 healthy controls were collected in PAXgene tubes. Ten SLE patients were followed longitudinally, and peripheral blood samples were collected in PAXgene tubes at time of inclusion and after 12 months. Disease activity was assessed by SJ in all patients and determined by means of SLE Disease Activity Index 2000 (SLEDAI-2K) and European Consensus Lupus Activity Measurement Index (ECLAM). RNA from peripheral blood cells (PBCs) was extracted using the PAXgene Blood RNA kit. The mRNA transcripts of 128 IRGs were measured using the multiplexed NanoString nCounter Gene Expression platform. Bioinformatics and statistical analyses were performed using nSolver and SPSS software.ResultsOut of 128 IRGs, 46 were highly expressed in SLE patients as compared to controls and seemed to co-express in mainly two distinct clusters, Figure 1. Expression scores for cluster K1 did not correlate with SLEDAI or ECLAM in a cross-sectional setting, whereas K2 expression scores did (p<0.01). These findings were confirmed by correlation analysis of changes in K1 and K2 expression scores with scores of disease activity in a longitudinal setting.ConclusionInterferon signatures may express differentially with varying associations with disease activity.References[1]Siddiqi KZ, et al. Transl Res. 2021[2]Chiche L, et al. Arthritis Rheumatol. 2014;66:1583-95[3]Morand EF, et al. N Engl J Med. 2020;382:211-21Figure 1.Disclosure of InterestsNone declared