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Tocilizumab is safe and tolerable and reduces C ‐reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients
Author(s) -
Milligan Carol,
Atassi Nazem,
Babu Suma,
Barohn Richard J.,
Caress James B.,
Cudkowicz Merit E.,
Evora Armineuza,
Hawkins Gregory A.,
WosiskiKuhn Marlena,
Macklin Eric A.,
Shefner Jeremy M.,
Simmons Zachary,
Bowser Robert P.,
Ladha Shafeeq S.
Publication year - 2021
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.27339
Subject(s) - tolerability , medicine , tocilizumab , immunology , cerebrospinal fluid , peripheral blood mononuclear cell , placebo , adverse effect , gastroenterology , pathology , biology , rheumatoid arthritis , biochemistry , alternative medicine , in vitro
/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 Asp 358 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 Asp 358 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.