Article Text
Abstract
Objective Fatigue is a prevalent and debilitating symptom in SLE and related autoimmune connective tissue diseases (CTDs) which often predates diagnosis or organ manifestations. Its primary immunological mechanisms may be obscured by glucocorticoids, damage, and comorbidity. Anti-nuclear antibody (ANA) positivity is established years in advance of clinical autoimmunity and evolves to overt CTDs in a small subset. We hypothesise that immunological drivers of fatigue in CTDs are established during the prodromal ANA+ subclinical phase and are differentially modulated in established disease states.
Methods Bulk RNASeq on PBMCs from therapy-naive ANA+ individuals (n=35) lacking diagnostic CTD criteria, was analysed with weighted gene co-expression network analysis (WGCNA) and correlated against symptoms and signs of interest. Consensus networks were constructed to identify modular signatures retained in established CTDs.
Results Fatigue burden was high in ANA+ subjects (mean VAS 65/100) but did not correlate with physician global assessment visual analogue score (VAS) (R=0.12, p=0.58). A 122-gene module comprising a dense network of interferon stimulated genes (including OAS1, IRF7, IFI44) showed strongest positive correlation with fatigue VAS (R=0.49, p=0.003) and also correlated with subsequent progression status from ANA+ to SLE at 12 months. Strongest negative modular association (358 genes) with fatigue VAS (R=-0.34, p=0.05) enriched for cellular stress and unfolded protein response (included ATF3, JUNB, HSPA1B). This was significantly related to health assessment questionnaire score (p=0.02) but not pain VAS (p=0.2). Both modules were highly retained in SLE and primary Sjogren’s syndrome WGCNA networks. Pain and tender joint counts displayed distinct modular associations, unrelated to fatigue and progression.
Conclusions Novel modular transcriptomic analyses in sub-clinical ANA+ subjects provide potential insights into the immunological basis for the key symptomatology of early SLE and autoimmune CTDs. We are currently evaluating these signatures established CTDs stratified by symptom burden.
Acknowledgements Lupus UK.
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