{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:20:29Z","timestamp":1790670029133,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Muscle and Nerve"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction\/Aims<\/jats:title>\n                    <jats:p>We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Twenty\u2010two 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\u00a0mg\/kg intravenous). Participants were followed every 4\u00a0wk in a double\u2010blind fashion for 16\u2009wk 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\n                      <jats:italic>Asp<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>358<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>Ala<\/jats:italic>\n                      polymorphism of the interleukin 6 receptor (\n                      <jats:italic>IL\u20106R)<\/jats:italic>\n                      gene.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\u2010reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (\u22123.0\u2010fold relative change,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u2009.001). CSF CRP reduction (\u22121.8\u2010fold relative change,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a0.01) was associated with\n                      <jats:italic>IL\u20106R C<\/jats:italic>\n                      allele count. No differences in PBMC gene expression or clinical measures were observed between groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>IL\u20106R Asp<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>358<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>Ala<\/jats:italic>\n                      genotype. IL\u20106 trans\u2010signaling may mediate a distinct central nervous system response in individuals inheriting the\n                      <jats:italic>IL\u20106R C<\/jats:italic>\n                      allele. These results warrant further study in ALS patients where\n                      <jats:italic>IL\u20106R<\/jats:italic>\n                      genotype and CRP levels may be useful enrichment biomarkers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mus.27339","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T01:50:36Z","timestamp":1622598636000},"page":"309-320","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Tocilizumab is safe and tolerable and reduces\n                    <scp>C<\/scp>\n                    \u2010reactive protein concentrations in the plasma and cerebrospinal fluid of\n                    <scp>ALS<\/scp>\n                    patients"],"prefix":"10.1002","volume":"64","author":[{"given":"Carol","family":"Milligan","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Anatomy Wake Forest University  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazem","family":"Atassi","sequence":"additional","affiliation":[{"name":"Department of Neurology Sean M. Healey &amp; AMG Center for ALS, Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suma","family":"Babu","sequence":"additional","affiliation":[{"name":"Department of Neurology Sean M. Healey &amp; AMG Center for ALS, Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Barohn","sequence":"additional","affiliation":[{"name":"Department of Neurology Kansas University  Kansas City Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B.","family":"Caress","sequence":"additional","affiliation":[{"name":"Department of Neurology Wake Forest University  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merit E.","family":"Cudkowicz","sequence":"additional","affiliation":[{"name":"Department of Neurology Sean M. Healey &amp; AMG Center for ALS, Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armineuza","family":"Evora","sequence":"additional","affiliation":[{"name":"Department of Neurology Sean M. Healey &amp; AMG Center for ALS, Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A.","family":"Hawkins","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Center for Precision Medicine Wake Forest University  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlena","family":"Wosiski\u2010Kuhn","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Anatomy Wake Forest University  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Macklin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Biostatistics Center Harvard Medical School, Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy M.","family":"Shefner","sequence":"additional","affiliation":[{"name":"Department of Neurology Gregory W. Fulton ALS and Neuromuscular Disease Center Barrow Neurological Institute, St. Joseph\u02bcs Hospital and Medical Center  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8574-5332","authenticated-orcid":false,"given":"Zachary","family":"Simmons","sequence":"additional","affiliation":[{"name":"Department of Neurology Penn State Health Milton S. Hershey Medical Center  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Bowser","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Neurobiology Gregory W. Fulton ALS and Neuromuscular Disease Center Barrow Neurological Institute, St. Joseph\u02bcs Hospital and Medical Center  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shafeeq S.","family":"Ladha","sequence":"additional","affiliation":[{"name":"Department of Neurology Gregory W. Fulton ALS and Neuromuscular Disease Center Barrow Neurological Institute, St. Joseph\u02bcs Hospital and Medical Center  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,24]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4598(200003)23:3<336::AID-MUS4>3.0.CO;2-L"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.09.018"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.26289"},{"issue":"2","key":"e_1_2_11_5_1","first-page":"453","article-title":"Results of treatment of certain diseases of the central nervous system with ACTH and corticosteroids","volume":"13","author":"Baumann J","year":"1965","journal-title":"Acta Neurol Scand Suppl"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1983.04050110070012"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1988.00520280027011"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0404.1990.tb01602.x"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2017.00486"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000188907.97339.76"},{"issue":"3","key":"e_1_2_11_11_1","first-page":"305","article-title":"Tocilizumab attenuates inflammation in ALS patients through inhibition of IL6 receptor signaling","volume":"1","author":"Mizwicki MT","year":"2012","journal-title":"Am J Neurodegener Dis"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000631"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/21678421.2020.1813310"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2830-13.2014"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2016.03.018"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1136(199703)19:3<227::AID-GLIA5>3.0.CO;2-W"},{"issue":"1","key":"e_1_2_11_17_1","first-page":"4","article-title":"The microglial\u2010motoneuron dialogue in ALS","volume":"30","author":"Appel SH","year":"2011","journal-title":"Acta Myol"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-05-155846"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2015.07.004"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.05.018"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10519-014-9656-8"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2012.03.018"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.4137\/CMAMD.S4864"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.26288"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-05-846428"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2018.02.013"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000244"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-04706-5"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2016.6179"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2007.04.031"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(96)01359-5"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2017.09.009"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00362"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2015-310998"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-016-0503-x"}],"container-title":["Muscle &amp; 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