STAT signaling as a marker of SLE disease severity and implications for clinical therapy

The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is implicated in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). While small-molecule JAK inhibitors (Jakinibs) are currently under investigation for SLE, results of recent studies suggest, that the efficacy of drugs such as methotrexate (MTX) may also be due to their ability to suppress phosphorylation of STAT proteins. A previously identified STAT5 phosphorylation (pSTAT5) and STAT1 protein expression »signature« in circulating CD4+ T cells of patients with SLE was associated with perturbed homeostasis between conventional (Tcon) and activated regulatory (aTreg) subset and with time-adjusted cumulative disease activity during follow-up. Initial observations in SLE patient cohort were validated with additional markers of disease severity and patients were stratified according to medication status. Preliminary results show that lower CD4+ T-cell counts in patients with SLE are associated with higher pSTAT5 levels and Tcon homeostatic proliferation, which was previously found to drive lymphopenia associated autoimmunity. Relapsing disease was better predicted by pSTAT5 levels than CD4 counts. Further, significant correlation was found between mean pSTAT5 levels during follow- up and the markers of disease severity. As patients with SLE, also patients with rheumatoid arthritis (RA) not receiving methotrexate, had significantly higher increase in CD4+ T-cell pSTAT5 levels compared to patients not receiving this specific therapy. However, the difference in pSTAT5 between Tcon and aTreg was independent of treatment with MTX and significantly increased only in patients with SLE. CD4 depletion, driving homeostatic proliferation of Tcon subset, is therefore associated with higher pSTAT5 levels, which confer worse prognosis in patients with SLE. While treatment with MTX may decrease overall pSTAT5 levels in CD4+ T-cells also from patients with RA, increased pSTAT5 levels in Tcon relative to aTreg subset are specific for SLE.