Patients with sporadic
amyotrophic lateral sclerosis (sALS) show
inflammation in the spinal cord and peripheral blood. The
inflammation is driven by stimulation of macrophages by aggregated
superoxide dismutase 1 (SOD1) through caspase1,
interleukin 1 (IL1),
IL6 and
chemokine signaling. Inflammatory gene activation is inhibited in vitro by
tocilizumab, a humanized antibody to
IL6 receptor (IL6R).
Tocilizumab inhibits global
interleukin-6 (
IL6) signaling, a key mechanism in chronic rheumatoid disorders. Here we studied in vivo baseline inflammatory gene transcription in peripheral blood mononuclear cells (PBMCs) of 10 sALS patients, and the effects of
tocilizumab (
Actemra(R)) infusions. At baseline, one half of ALS subjects had strong inflammatory activation (Group 1) (8 genes up regulated >4-fold, P<0.05 vs. controls) and the other half (Group 2) had weak activation. All patients showed greater than four-fold up regulation of MMP1, CCL7, CCL13 and CCL24.
Tocilizumab infusions in the Group 1 patients resulted in down regulation of inflammatory genes (in particular IL1β), whereas in the Group 2 patients in up regulation of inflammatory genes. Post-infusion serum and CSF concentrations of
tocilizumab inhibited caspase1 activation in vitro. Three of 5 patients receiving
tocilizumab infusions showed time-limited attenuation of
clinical progression. In conclusion,
inflammation of sALS patients at baseline is up- or down-regulated in comparison to controls, but is partially normalized by
tocilizumab infusions.