Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL

ObjectivesOur knowledge about the effect of tocilizumab (TCZ) on the synovium in rheumatoid arthritis (RA) is limited. The aim of this study was to investigate the effect of TCZ on citrullination and on inflammation in the synovial tissue and in the peripheral blood.Methods15 patients with RA underw...

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Veröffentlicht in:Rheumatic & musculoskeletal diseases open 2021-06, Vol.7 (2), p.e001662
Hauptverfasser: Chatzidionysiou, Katerina, Circiumaru, Alexandra, Rethi, Bence, Joshua, Vijay, Engstrom, Marianne, Hensvold, Aase, af Klint, Erik, Catrina, Anca
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container_end_page
container_issue 2
container_start_page e001662
container_title Rheumatic & musculoskeletal diseases open
container_volume 7
creator Chatzidionysiou, Katerina
Circiumaru, Alexandra
Rethi, Bence
Joshua, Vijay
Engstrom, Marianne
Hensvold, Aase
af Klint, Erik
Catrina, Anca
description ObjectivesOur knowledge about the effect of tocilizumab (TCZ) on the synovium in rheumatoid arthritis (RA) is limited. The aim of this study was to investigate the effect of TCZ on citrullination and on inflammation in the synovial tissue and in the peripheral blood.Methods15 patients with RA underwent synovial biopsy before and 8 weeks after TCZ initiation. Clinical evaluation was performed at baseline and at 8 weeks. Using immunohistochemistry, we evaluated the expression of CD68, CD3, CD20, osteoprotegerin (OPG) and receptor activator for nuclear factor-κB ligand (RANKL) before and after treatment with TCZ. We also analysed the expression of protein arginine deiminase (PAD)-2 and PAD-4 enzymes in the synovial tissue and protein citrullination patterns with the help of anticitrullinated protein antibody (ACPA) clones 1325:04C03 and 1325:01B09. Serum levels of interleukin-6 (IL-6), IL-8, RANKL, OPG and C-terminal crosslinked telopeptide type II collagen were measured by ELISA. Paired-wise Wilcoxon signed-rank test was used to compare median values before and after treatment.ResultsDisease activity in patients was reduced from baseline to 8 weeks. Although PAD-2 and PAD-4 expressions remained unchanged after TCZ treatment, the binding of one ACPA clone decreased in the synovial tissue. TCZ did not affect the number of CD68+ macrophages or CD20+ B cells but induced significant decrease in the number of CD3+ T cells. RANKL and OPG expression remained unchanged in the synovial tissue. A significant increase in the levels of IL-6 and RANKL was observed in the serum. This increase was statistically significant in patients who responded to TCZ (achieving Clinical Disease Activity Index low disease activity or remission) but not in non-responders.ConclusionsTCZ reduced synovial T-cell counts but not macrophages. A significant increase of serum IL-6 was observed in responders.
doi_str_mv 10.1136/rmdopen-2021-001662
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The aim of this study was to investigate the effect of TCZ on citrullination and on inflammation in the synovial tissue and in the peripheral blood.Methods15 patients with RA underwent synovial biopsy before and 8 weeks after TCZ initiation. Clinical evaluation was performed at baseline and at 8 weeks. Using immunohistochemistry, we evaluated the expression of CD68, CD3, CD20, osteoprotegerin (OPG) and receptor activator for nuclear factor-κB ligand (RANKL) before and after treatment with TCZ. We also analysed the expression of protein arginine deiminase (PAD)-2 and PAD-4 enzymes in the synovial tissue and protein citrullination patterns with the help of anticitrullinated protein antibody (ACPA) clones 1325:04C03 and 1325:01B09. Serum levels of interleukin-6 (IL-6), IL-8, RANKL, OPG and C-terminal crosslinked telopeptide type II collagen were measured by ELISA. Paired-wise Wilcoxon signed-rank test was used to compare median values before and after treatment.ResultsDisease activity in patients was reduced from baseline to 8 weeks. Although PAD-2 and PAD-4 expressions remained unchanged after TCZ treatment, the binding of one ACPA clone decreased in the synovial tissue. TCZ did not affect the number of CD68+ macrophages or CD20+ B cells but induced significant decrease in the number of CD3+ T cells. RANKL and OPG expression remained unchanged in the synovial tissue. A significant increase in the levels of IL-6 and RANKL was observed in the serum. This increase was statistically significant in patients who responded to TCZ (achieving Clinical Disease Activity Index low disease activity or remission) but not in non-responders.ConclusionsTCZ reduced synovial T-cell counts but not macrophages. A significant increase of serum IL-6 was observed in responders.</description><identifier>ISSN: 2056-5933</identifier><identifier>EISSN: 2056-5933</identifier><identifier>DOI: 10.1136/rmdopen-2021-001662</identifier><identifier>PMID: 34112702</identifier><language>eng</language><publisher>England: EULAR</publisher><subject>Antibodies, Monoclonal, Humanized ; arthritis ; Arthritis, Rheumatoid - drug therapy ; Biopsy ; Cytokines ; Fibroblasts ; Humans ; Immunosuppressive agents ; Inflammation ; Interleukin-6 - blood ; Lymphocytes ; Macrophages ; Monoclonal antibodies ; Patients ; Proteins ; RANK Ligand - blood ; Receptor Activator of Nuclear Factor-kappa B ; rheumatoid ; Rheumatoid Arthritis ; Synovial Membrane ; synovitis ; T-Lymphocytes ; treatment ; Ultrasonic imaging</subject><ispartof>Rheumatic &amp; musculoskeletal diseases open, 2021-06, Vol.7 (2), p.e001662</ispartof><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.</rights><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2022 Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b616t-e0d58ad50bceb95961f220c89649271a3e61221e257db7d46cbca3a706299b93</citedby><cites>FETCH-LOGICAL-b616t-e0d58ad50bceb95961f220c89649271a3e61221e257db7d46cbca3a706299b93</cites><orcidid>0000-0002-2606-8180 ; 0000-0002-1292-1152 ; 0000-0001-8220-5015 ; 0000-0002-2669-1247</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://rmdopen.bmj.com/content/7/2/e001662.full.pdf$$EPDF$$P50$$Gbmj$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://rmdopen.bmj.com/content/7/2/e001662.full$$EHTML$$P50$$Gbmj$$Hfree_for_read</linktohtml><link.rule.ids>230,314,551,724,777,781,861,882,2096,27530,27531,27905,27906,53772,53774,55331,77350,77381,77409,77435</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34112702$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:146861228$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Chatzidionysiou, Katerina</creatorcontrib><creatorcontrib>Circiumaru, Alexandra</creatorcontrib><creatorcontrib>Rethi, Bence</creatorcontrib><creatorcontrib>Joshua, Vijay</creatorcontrib><creatorcontrib>Engstrom, Marianne</creatorcontrib><creatorcontrib>Hensvold, Aase</creatorcontrib><creatorcontrib>af Klint, Erik</creatorcontrib><creatorcontrib>Catrina, Anca</creatorcontrib><title>Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL</title><title>Rheumatic &amp; musculoskeletal diseases open</title><addtitle>RMD Open</addtitle><addtitle>RMD Open</addtitle><description>ObjectivesOur knowledge about the effect of tocilizumab (TCZ) on the synovium in rheumatoid arthritis (RA) is limited. The aim of this study was to investigate the effect of TCZ on citrullination and on inflammation in the synovial tissue and in the peripheral blood.Methods15 patients with RA underwent synovial biopsy before and 8 weeks after TCZ initiation. Clinical evaluation was performed at baseline and at 8 weeks. Using immunohistochemistry, we evaluated the expression of CD68, CD3, CD20, osteoprotegerin (OPG) and receptor activator for nuclear factor-κB ligand (RANKL) before and after treatment with TCZ. We also analysed the expression of protein arginine deiminase (PAD)-2 and PAD-4 enzymes in the synovial tissue and protein citrullination patterns with the help of anticitrullinated protein antibody (ACPA) clones 1325:04C03 and 1325:01B09. Serum levels of interleukin-6 (IL-6), IL-8, RANKL, OPG and C-terminal crosslinked telopeptide type II collagen were measured by ELISA. Paired-wise Wilcoxon signed-rank test was used to compare median values before and after treatment.ResultsDisease activity in patients was reduced from baseline to 8 weeks. Although PAD-2 and PAD-4 expressions remained unchanged after TCZ treatment, the binding of one ACPA clone decreased in the synovial tissue. TCZ did not affect the number of CD68+ macrophages or CD20+ B cells but induced significant decrease in the number of CD3+ T cells. RANKL and OPG expression remained unchanged in the synovial tissue. A significant increase in the levels of IL-6 and RANKL was observed in the serum. This increase was statistically significant in patients who responded to TCZ (achieving Clinical Disease Activity Index low disease activity or remission) but not in non-responders.ConclusionsTCZ reduced synovial T-cell counts but not macrophages. A significant increase of serum IL-6 was observed in responders.</description><subject>Antibodies, Monoclonal, Humanized</subject><subject>arthritis</subject><subject>Arthritis, Rheumatoid - drug therapy</subject><subject>Biopsy</subject><subject>Cytokines</subject><subject>Fibroblasts</subject><subject>Humans</subject><subject>Immunosuppressive agents</subject><subject>Inflammation</subject><subject>Interleukin-6 - blood</subject><subject>Lymphocytes</subject><subject>Macrophages</subject><subject>Monoclonal antibodies</subject><subject>Patients</subject><subject>Proteins</subject><subject>RANK Ligand - blood</subject><subject>Receptor Activator of Nuclear Factor-kappa B</subject><subject>rheumatoid</subject><subject>Rheumatoid Arthritis</subject><subject>Synovial Membrane</subject><subject>synovitis</subject><subject>T-Lymphocytes</subject><subject>treatment</subject><subject>Ultrasonic imaging</subject><issn>2056-5933</issn><issn>2056-5933</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>9YT</sourceid><sourceid>ACMMV</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>D8T</sourceid><sourceid>DOA</sourceid><recordid>eNqNks1u1DAUhSMEolXpEyAhS2zYpPVP7MQbpKoqUDECCc3ecpybiadJPNjOVOWBeE48ZDp0WCBWtnzP-a7te7LsNcEXhDBx6YfGbWDMKaYkx5gIQZ9lpxRzkXPJ2PMn-5PsPIQ1TqKCsZKwl9kJKwihJaan2c-lM7a3P6ZB16gB40EHCGiJDPR9QPUU0egiGrTxbtPpVarZEcUOUHgY3dZOA3It2uhoYYwB3dvYId9BwkVnG6R97LyNNlU62wOyMdkfm-woPWwh9UmMAD7B7BjB9zDd2TEXSI8N-nb15fPiVfai1X2A8_16li0_3CyvP-WLrx9vr68WeS2IiDnghle64bg2UEsuBWkpxaaSopC0JJqBIJQSoLxs6rIphKmNZrrEgkpZS3aW3c7Yxum12ng7aP-gnLbq94HzK5VeZE0PShKK2wJMyykUnHHZCMCFrKBNw-C4Tax8ZoV72Ez1EW1_dJd2oApBGOdJ_37Wp8oAjUn_6XV_ZDuujLZTK7dVFZFpsDvAuz3Au-8ThKgGG3Zj1CO4KSjKC8wJL6sqSd_-JV27yY_pZ5OKyYowIoqkYrMqzT4ED-3hMgSrXQrVPoVql0I1pzC53jx9x8HzmLkkuJgF9bD-T-LlH8Phov9y_AJegvrG</recordid><startdate>202106</startdate><enddate>202106</enddate><creator>Chatzidionysiou, Katerina</creator><creator>Circiumaru, Alexandra</creator><creator>Rethi, Bence</creator><creator>Joshua, Vijay</creator><creator>Engstrom, Marianne</creator><creator>Hensvold, Aase</creator><creator>af Klint, Erik</creator><creator>Catrina, Anca</creator><general>EULAR</general><general>BMJ Publishing Group LTD</general><general>BMJ Publishing Group</general><scope>9YT</scope><scope>ACMMV</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-2606-8180</orcidid><orcidid>https://orcid.org/0000-0002-1292-1152</orcidid><orcidid>https://orcid.org/0000-0001-8220-5015</orcidid><orcidid>https://orcid.org/0000-0002-2669-1247</orcidid></search><sort><creationdate>202106</creationdate><title>Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL</title><author>Chatzidionysiou, Katerina ; Circiumaru, Alexandra ; Rethi, Bence ; Joshua, Vijay ; Engstrom, Marianne ; Hensvold, Aase ; af Klint, Erik ; Catrina, Anca</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b616t-e0d58ad50bceb95961f220c89649271a3e61221e257db7d46cbca3a706299b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antibodies, Monoclonal, Humanized</topic><topic>arthritis</topic><topic>Arthritis, Rheumatoid - drug therapy</topic><topic>Biopsy</topic><topic>Cytokines</topic><topic>Fibroblasts</topic><topic>Humans</topic><topic>Immunosuppressive agents</topic><topic>Inflammation</topic><topic>Interleukin-6 - blood</topic><topic>Lymphocytes</topic><topic>Macrophages</topic><topic>Monoclonal antibodies</topic><topic>Patients</topic><topic>Proteins</topic><topic>RANK Ligand - blood</topic><topic>Receptor Activator of Nuclear Factor-kappa B</topic><topic>rheumatoid</topic><topic>Rheumatoid Arthritis</topic><topic>Synovial Membrane</topic><topic>synovitis</topic><topic>T-Lymphocytes</topic><topic>treatment</topic><topic>Ultrasonic imaging</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chatzidionysiou, Katerina</creatorcontrib><creatorcontrib>Circiumaru, Alexandra</creatorcontrib><creatorcontrib>Rethi, Bence</creatorcontrib><creatorcontrib>Joshua, Vijay</creatorcontrib><creatorcontrib>Engstrom, Marianne</creatorcontrib><creatorcontrib>Hensvold, Aase</creatorcontrib><creatorcontrib>af Klint, Erik</creatorcontrib><creatorcontrib>Catrina, Anca</creatorcontrib><collection>BMJ Open Access Journals</collection><collection>BMJ Journals:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Rheumatic &amp; musculoskeletal diseases open</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chatzidionysiou, Katerina</au><au>Circiumaru, Alexandra</au><au>Rethi, Bence</au><au>Joshua, Vijay</au><au>Engstrom, Marianne</au><au>Hensvold, Aase</au><au>af Klint, Erik</au><au>Catrina, Anca</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL</atitle><jtitle>Rheumatic &amp; musculoskeletal diseases open</jtitle><stitle>RMD Open</stitle><addtitle>RMD Open</addtitle><date>2021-06</date><risdate>2021</risdate><volume>7</volume><issue>2</issue><spage>e001662</spage><pages>e001662-</pages><issn>2056-5933</issn><eissn>2056-5933</eissn><abstract>ObjectivesOur knowledge about the effect of tocilizumab (TCZ) on the synovium in rheumatoid arthritis (RA) is limited. The aim of this study was to investigate the effect of TCZ on citrullination and on inflammation in the synovial tissue and in the peripheral blood.Methods15 patients with RA underwent synovial biopsy before and 8 weeks after TCZ initiation. Clinical evaluation was performed at baseline and at 8 weeks. Using immunohistochemistry, we evaluated the expression of CD68, CD3, CD20, osteoprotegerin (OPG) and receptor activator for nuclear factor-κB ligand (RANKL) before and after treatment with TCZ. We also analysed the expression of protein arginine deiminase (PAD)-2 and PAD-4 enzymes in the synovial tissue and protein citrullination patterns with the help of anticitrullinated protein antibody (ACPA) clones 1325:04C03 and 1325:01B09. Serum levels of interleukin-6 (IL-6), IL-8, RANKL, OPG and C-terminal crosslinked telopeptide type II collagen were measured by ELISA. Paired-wise Wilcoxon signed-rank test was used to compare median values before and after treatment.ResultsDisease activity in patients was reduced from baseline to 8 weeks. Although PAD-2 and PAD-4 expressions remained unchanged after TCZ treatment, the binding of one ACPA clone decreased in the synovial tissue. TCZ did not affect the number of CD68+ macrophages or CD20+ B cells but induced significant decrease in the number of CD3+ T cells. RANKL and OPG expression remained unchanged in the synovial tissue. A significant increase in the levels of IL-6 and RANKL was observed in the serum. This increase was statistically significant in patients who responded to TCZ (achieving Clinical Disease Activity Index low disease activity or remission) but not in non-responders.ConclusionsTCZ reduced synovial T-cell counts but not macrophages. A significant increase of serum IL-6 was observed in responders.</abstract><cop>England</cop><pub>EULAR</pub><pmid>34112702</pmid><doi>10.1136/rmdopen-2021-001662</doi><orcidid>https://orcid.org/0000-0002-2606-8180</orcidid><orcidid>https://orcid.org/0000-0002-1292-1152</orcidid><orcidid>https://orcid.org/0000-0001-8220-5015</orcidid><orcidid>https://orcid.org/0000-0002-2669-1247</orcidid><oa>free_for_read</oa></addata></record>
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subjects Antibodies, Monoclonal, Humanized
arthritis
Arthritis, Rheumatoid - drug therapy
Biopsy
Cytokines
Fibroblasts
Humans
Immunosuppressive agents
Inflammation
Interleukin-6 - blood
Lymphocytes
Macrophages
Monoclonal antibodies
Patients
Proteins
RANK Ligand - blood
Receptor Activator of Nuclear Factor-kappa B
rheumatoid
Rheumatoid Arthritis
Synovial Membrane
synovitis
T-Lymphocytes
treatment
Ultrasonic imaging
title Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL
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