IL-6 blockade reverses the abnormal STAT activation of peripheral blood leukocytes from rheumatoid arthritis patients

- There is a complex cytokine network operating in chronic inflammatory diseases.
- STAT3, STAT5 and STAT6 are abnormally phosphorylated in peripheral blood leukocytes from RA patients.
- Blocking IL-6 gradually restores the ability of cytokines to activate STATs in leukocytes of RA patients.
- The analysis of STAT status could allow us to identify RA patients who do not respond to tocilizumab.

Considering the interplay of multiple STATs in response to cytokines, we investigated how IL-6 and its blocking affect STAT signaling in rheumatoid arthritis (RA). Leukocytes obtained from RA patients before and after tocilizumab treatment and healthy donors (HDs) were cytokine-stimulated and STAT phosphorylation was analyzed by cytometry. RA patients had significantly fewer pSTAT1 +, pSTAT3 +, and pSTAT6 + monocytes and pSTAT5 + lymphocytes than HDs. After 24 weeks of treatment, percentages of IFNγ-induced pSTAT1 + and IL-10-induced pSTAT3 + monocytes in RA patients increased, reaching levels comparable to HDs. pSTAT1 + and pSTAT3 + cells correlated inversely with RA disease activity index and levels of pSTAT + cells at baseline were higher in patients with good EULAR response to tocilizumab. IFNγ-induced pSTAT1 + cells correlated inversely with memory T cells and anti-CCP levels. IL-10-induced pSTAT3 + cells correlated with Treg/Teff ratio. Our findings suggest that IL-6 blocking reduces the inflammatory mechanisms through the correction of STAT1 and STAT3 activation status.