Connective tissue remodelling is differently modulated by tocilizumab versus methotrexate monotherapy in patients with early rheumatoid arthritis : the AMBITION study
OBJECTIVE: Associations between rheumatoid arthritis (RA) and effect of treatment at the tissue levels are poorly understood. We investigated the scope of released extracellular matrix (ECM) metabolites as a consequence of tissue remodelling in patients treated with methotrexate (MTX) and tocilizumab (TCZ) compared to placebo.
METHODS: Tissue metabolites from 387 RA patients treated with either TCZ (8 mg/kg) or MTX monotherapy (7.5-20 mg/kg) were measured at baseline and 8 weeks sera by validated ELISA assays. The levels of collagen biomarkers (C1M, C2M, C3M and C4M) together with C-reactive protein (CRP) and CRP metabolite (CRPM) were investigated. Baseline levels of biomarkers have been compared with 72 age- and gender-matched healthy controls. Comparison between treatment and response groups were done by ANCOVA, Spearman's correlation and logistic regression adjusted for age, gender, BMI and disease duration.
RESULTS: C1M and C3M were significantly (P < 0.05) inhibited by TCZ and C3M by MTX (P < 0.01) compared to placebo. C1M and C3M inhibition with TCZ was respectively 23% and 16% greater than that of MTX (P < 0.01 and P < 0.0001). C4M was inhibited by TCZ and MTX, but the effect of TCZ was 22% greater than MTX (P < 0.0001). TCZ and MTX had minimal effect on C2M levels. MTX had no effect on CRP and CRPM, whereas TCZ reduced their levels to 69% and 27% from baseline. Investigated biomarkers revealed a significant (P < 0.05) difference in biomarker profiles of MTX ACR50 treatment responders and non-responders. Change to week 8 in levels of C3M, C4M, CRP and CRPM in MTX patients correlated significantly (rho = 0.41 to 0.18, P < 0.0001 to 0.039) with change in disease activity (DAS28) at weeks 8, 16 and 24, whereas only CRP in TCZ patients (rho = 0.32 to 0.21, P < 0.0001 to 0.01).
CONCLUSION: Patients receiving TCZ treatment for 8 weeks had higher suppression of tissue remodelling and inflammatory biomarkers over patients treated with MTX. Measured biomarkers enabled for a discrimination of biomarker profiles of ACR50 treatment responding patients and identification of those who benefit at the early time point. Week 8 change in levels of C3M, C4M, CRP and CRPM significantly predicted clinical response to treatment and correlated with DAS28 at all time points.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT00109408 . Date of registration: July 2005. Name of the registry: A Study to Assess the Safety and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
Arthritis research & therapy - 23(2021), 1 vom: 07. Jan., Seite 13 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Drobinski, Patryk J [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.06.2021 Date Revised 30.03.2024 published: Electronic ClinicalTrials.gov: NCT00109408 Citation Status MEDLINE |
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| doi: |
10.1186/s13075-020-02378-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM319772527 |
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| 041 | |a eng | ||
| 100 | 1 | |a Drobinski, Patryk J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Connective tissue remodelling is differently modulated by tocilizumab versus methotrexate monotherapy in patients with early rheumatoid arthritis |b the AMBITION study |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 21.06.2021 | ||
| 500 | |a Date Revised 30.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT00109408 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a OBJECTIVE: Associations between rheumatoid arthritis (RA) and effect of treatment at the tissue levels are poorly understood. We investigated the scope of released extracellular matrix (ECM) metabolites as a consequence of tissue remodelling in patients treated with methotrexate (MTX) and tocilizumab (TCZ) compared to placebo | ||
| 520 | |a METHODS: Tissue metabolites from 387 RA patients treated with either TCZ (8 mg/kg) or MTX monotherapy (7.5-20 mg/kg) were measured at baseline and 8 weeks sera by validated ELISA assays. The levels of collagen biomarkers (C1M, C2M, C3M and C4M) together with C-reactive protein (CRP) and CRP metabolite (CRPM) were investigated. Baseline levels of biomarkers have been compared with 72 age- and gender-matched healthy controls. Comparison between treatment and response groups were done by ANCOVA, Spearman's correlation and logistic regression adjusted for age, gender, BMI and disease duration | ||
| 520 | |a RESULTS: C1M and C3M were significantly (P < 0.05) inhibited by TCZ and C3M by MTX (P < 0.01) compared to placebo. C1M and C3M inhibition with TCZ was respectively 23% and 16% greater than that of MTX (P < 0.01 and P < 0.0001). C4M was inhibited by TCZ and MTX, but the effect of TCZ was 22% greater than MTX (P < 0.0001). TCZ and MTX had minimal effect on C2M levels. MTX had no effect on CRP and CRPM, whereas TCZ reduced their levels to 69% and 27% from baseline. Investigated biomarkers revealed a significant (P < 0.05) difference in biomarker profiles of MTX ACR50 treatment responders and non-responders. Change to week 8 in levels of C3M, C4M, CRP and CRPM in MTX patients correlated significantly (rho = 0.41 to 0.18, P < 0.0001 to 0.039) with change in disease activity (DAS28) at weeks 8, 16 and 24, whereas only CRP in TCZ patients (rho = 0.32 to 0.21, P < 0.0001 to 0.01) | ||
| 520 | |a CONCLUSION: Patients receiving TCZ treatment for 8 weeks had higher suppression of tissue remodelling and inflammatory biomarkers over patients treated with MTX. Measured biomarkers enabled for a discrimination of biomarker profiles of ACR50 treatment responding patients and identification of those who benefit at the early time point. Week 8 change in levels of C3M, C4M, CRP and CRPM significantly predicted clinical response to treatment and correlated with DAS28 at all time points | ||
| 520 | |a TRIAL REGISTRATION: ClinicalTrials.gov, NCT00109408 . Date of registration: July 2005. Name of the registry: A Study to Assess the Safety and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Biomarkers | |
| 650 | 4 | |a Extracellular matrix (ECM) | |
| 650 | 4 | |a Methotrexate (MTX) | |
| 650 | 4 | |a Rheumatoid arthritis (RA) | |
| 650 | 4 | |a Tissue remodelling | |
| 650 | 4 | |a Tocilizumab (TCZ) | |
| 650 | 7 | |a Antibodies, Monoclonal, Humanized |2 NLM | |
| 650 | 7 | |a Antirheumatic Agents |2 NLM | |
| 650 | 7 | |a tocilizumab |2 NLM | |
| 650 | 7 | |a I031V2H011 |2 NLM | |
| 650 | 7 | |a Methotrexate |2 NLM | |
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| 700 | 1 | |a Bay-Jensen, Anne C |e verfasserin |4 aut | |
| 700 | 1 | |a Karsdal, Morten A |e verfasserin |4 aut | |
| 700 | 1 | |a Sardar, Samra |e verfasserin |4 aut | |
| 700 | 1 | |a Siebuhr, Anne S |e verfasserin |4 aut | |
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