Optimisation of anti-interleukin-6 therapy : Precision medicine through mathematical modelling
Copyright © 2022 Rossi, Chiang, Lu, Levon, van Rhee, Kanhai, Fajgenbaum and Klein..
Background: 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.
Methods: We analysed inhibition of C-reactive protein (CRP) - a biomarker for IL-6 activity - 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.
Results: 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.
Conclusion: In clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production.
Funding: EUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Frontiers in immunology - 13(2022) vom: 01., Seite 919489 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rossi, Jean-François [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.08.2022 Date Revised 29.03.2024 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.3389/fimmu.2022.919489 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM344483525 |
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| 100 | 1 | |a Rossi, Jean-François |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Optimisation of anti-interleukin-6 therapy |b Precision medicine through mathematical modelling |
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| 500 | |a Date Revised 29.03.2024 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Rossi, Chiang, Lu, Levon, van Rhee, Kanhai, Fajgenbaum and Klein. | ||
| 520 | |a Background: 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 | ||
| 520 | |a Methods: We analysed inhibition of C-reactive protein (CRP) - a biomarker for IL-6 activity - 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 | ||
| 520 | |a Results: 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 | ||
| 520 | |a Conclusion: In clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production | ||
| 520 | |a Funding: EUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a C-reactive protein | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a cytokine storm | |
| 650 | 4 | |a idiopathic multicentric castleman disease | |
| 650 | 4 | |a interleukin-6 | |
| 650 | 4 | |a mathematic model | |
| 650 | 4 | |a siltuximab | |
| 650 | 4 | |a tocilizumab | |
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| 700 | 1 | |a Chiang, Hao-Chun |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Zhao-Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Levon, Kalle |e verfasserin |4 aut | |
| 700 | 1 | |a van Rhee, Frits |e verfasserin |4 aut | |
| 700 | 1 | |a Kanhai, Karan |e verfasserin |4 aut | |
| 700 | 1 | |a Fajgenbaum, David C |e verfasserin |4 aut | |
| 700 | 1 | |a Klein, Bernard |e verfasserin |4 aut | |
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