{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T22:24:15Z","timestamp":1787955855855,"version":"build-2784847793"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T00:00:00Z","timestamp":1658188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Dysregulated interleukin (IL)-6 production can be characterised by the levels present, the kinetics of its rise and its inappropriate location. Rapid, excessive IL-6 production can exacerbate tissue damage in vital organs. In this situation, therapy with an anti-IL-6 or anti-IL-6 receptor (IL-6R) monoclonal antibody, if inappropriately dosed, may be insufficient to fully block IL-6 signalling and normalise the immune response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analysed inhibition of C-reactive protein (CRP) \u2013 a biomarker for IL-6 activity \u2013 in patients with COVID-19 or idiopathic multicentric Castleman disease (iMCD) treated with tocilizumab (anti-IL-6R) or siltuximab (anti-IL-6), respectively. We used mathematical modelling to analyse how to optimise anti-IL-6 or anti-IL-6R blockade for the high levels of IL-6 observed in these diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>IL-6 signalling was insufficiently inhibited in patients with COVID-19 or iMCD treated with standard doses of anti-IL-6 therapy. Patients whose disease worsened throughout therapy had only partial inhibition of CRP production. Our model demonstrated that, in a scenario representative of iMCD with persistent high IL-6 production not controlled by a single dose of anti-IL-6 therapy, repeated administration more effectively inhibited IL-6 activity. In a situation with rapid, high, dysregulated IL-6 production, such as severe COVID-19 or a cytokine storm, repeated daily administration of an anti-IL-6\/anti-IL-6R agent, or alternating daily doses of anti-IL-6 and anti-IL-6R therapies, could neutralise IL-6 activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Funding<\/jats:title><jats:p>EUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.919489","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T04:53:28Z","timestamp":1658206408000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling"],"prefix":"10.3389","volume":"13","author":[{"given":"Jean-Fran\u00e7ois","family":"Rossi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Chun","family":"Chiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-Yang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalle","family":"Levon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frits","family":"van Rhee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karan","family":"Kanhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Fajgenbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.595722","article-title":"Dynamic immune\/inflammation precision medicine: the good and the bad inflammation in infection and cancer","volume":"12","author":"Rossi","year":"2021","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxq030","article-title":"IL-6: from its discovery to clinical applications","volume":"22","author":"Kishimoto","year":"2010","journal-title":"Int Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028415","article-title":"Interleukin-6 family cytokines","volume":"10","author":"Rose-John","year":"2018","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-2291","article-title":"Interleukin-6 as a therapeutic target","volume":"21","author":"Rossi","year":"2015","journal-title":"Clin Cancer Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0066-7","article-title":"Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer","volume":"18","author":"Jones","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2026131","article-title":"Cytokine storm","volume":"383","author":"Fajgenbaum","year":"2020","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1988.tb14384.x","article-title":"Plasma clearance, organ distribution and target cells of interleukin-6\/hepatocyte-stimulating factor in the rat","volume":"177","author":"Castell","year":"1988","journal-title":"Eur J Biochem"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70319-5","article-title":"Siltuximab for multicentric castleman\u2019s disease: a randomised, double-blind, placebo-controlled trial","volume":"15","author":"van Rhee","year":"2014","journal-title":"Lancet Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/s1043-4666(05)80007-9","article-title":"Overall interleukin-6 production exceeds 7 mg\/day in multiple myeloma complicated by sepsis","volume":"5","author":"Lu","year":"1993","journal-title":"Cytokine"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.17052","article-title":"Cytokine levels in critically ill patients with COVID-19 and other conditions","volume":"324","author":"Kox","year":"2020","journal-title":"JAMA"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1378\/chest.108.5.1303","article-title":"Inflammatory cytokines in the BAL of patients with ARDS","volume":"108","author":"Meduri","year":"1995","journal-title":"Persistent Elevation Over Time Predicts Poor Outcome Chest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0901-9","article-title":"Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19","volume":"26","author":"Liao","year":"2020","journal-title":"Nat Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V78.5.1198.1198","article-title":"Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia","volume":"78","author":"Klein","year":"1991","journal-title":"Blood"},{"key":"B15","doi-asserted-by":"crossref","DOI":"10.1182\/blood.V86.8.3123.3123","article-title":"Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments","volume":"86","author":"Lu","year":"1995","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1001\/jama.2021.11330","article-title":"WHO rapid evidence appraisal for COVID-19 therapies (REACT) working group. association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis","volume":"326","author":"Shankar-Hari","year":"2021","journal-title":"JAMA"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2021.0395","article-title":"Tocilizumab in treatment for patients with COVID-19","volume":"181","author":"Rossi","year":"2021","journal-title":"JAMA Intern Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.20.7251","article-title":"Interferon beta 2\/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells","volume":"84","author":"Gauldie","year":"1987","journal-title":"Proc Natl Acad Sci USA"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V86.8.3123.3123","article-title":"Testosterone and IL-6 requirements for human c-reactive protein gene expression in transgenic mice","volume":"160","author":"Szalai","year":"1998","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.25801","article-title":"Tocilizumab treatment in COVID-19: a single center experience","volume":"92","author":"Luo","year":"2020","journal-title":"J Med Virol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1208\/s12248-009-9157-5","article-title":"Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease","volume":"12","author":"Tabrizi","year":"2010","journal-title":"AAPS J"},{"key":"B22","doi-asserted-by":"publisher","first-page":"297","DOI":"10.4161\/mabs.23684","article-title":"Antibody biodistribution coefficients: inferring tissue distributions of monoclonal antibodies based on the plasma concentrations in several preclinical species and human","volume":"5","author":"Shah","year":"2013","journal-title":"mAbs"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-2581","article-title":"Pharmacokinetic and pharmacodynamic modeling of an anti-interleukin-6 chimeric monoclonal antibody (siltuximab) in patients with metastatic renal cell carcinoma","volume":"36","author":"Puchalski","year":"2010","journal-title":"Clin Cancer Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1002\/jcph.1703","article-title":"Pharmacokinetics and pharmacodynamics of subcutaneous sarilumab and intravenous tocilizumab following single-dose administration in patients with active rheumatoid arthritis on stable methotrexate","volume":"61","author":"Paccaly","year":"2021","journal-title":"J Clin Pharmacol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602211","article-title":"The relationship between interleukin-6 and c-reactive protein in patients with benign and malignant prostate disease","volume":"91","author":"McArdle","year":"2004","journal-title":"Br J Cancer"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2015.07.004","article-title":"Interleukin-6: biology, signaling and strategies of blockade","volume":"26","author":"Schaper","year":"2015","journal-title":"Cytokine Growth Factor Rev"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.919489\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T04:53:32Z","timestamp":1658206412000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.919489\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,19]]},"references-count":26,"alternative-id":["10.3389\/fimmu.2022.919489"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.919489","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,19]]},"article-number":"919489"}}