Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients

Muscle Nerve. 2021 Sep;64(3):309-320. doi: 10.1002/mus.27339. Epub 2021 Jun 24.


Introduction/aims: We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients.

Methods: Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 wk in a double-blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp358 Ala polymorphism of the interleukin 6 receptor (IL-6R) gene.

Results: Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P < .001). CSF CRP reduction (-1.8-fold relative change, P = .01) was associated with IL-6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups.

Discussion: Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL-6R Asp358 Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL-6R C allele. These results warrant further study in ALS patients where IL-6R genotype and CRP levels may be useful enrichment biomarkers.

Trial registration: NCT02469896.

Keywords: C-reactive protein; amyotrophic lateral sclerosis; interleukin-6; microglia; tocilizumab.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / blood
  • Amyotrophic Lateral Sclerosis / cerebrospinal fluid
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Anti-Inflammatory Agents / adverse effects*
  • Anti-Inflammatory Agents / therapeutic use
  • Antibodies, Monoclonal, Humanized / adverse effects*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Biomarkers / blood
  • Biomarkers / cerebrospinal fluid
  • C-Reactive Protein / metabolism*
  • Cytokines / blood
  • Cytokines / cerebrospinal fluid
  • Cytokines / metabolism*
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Treatment Outcome
  • Young Adult


  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal, Humanized
  • Biomarkers
  • Cytokines
  • C-Reactive Protein
  • tocilizumab

Associated data