Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy
BackgroundImmune checkpoint inhibitors (ICIs) are associated with rheumatic and musculoskeletal immune-related adverse events (irAEs) in 5%–20% of patients. Currently, patients refractory to corticosteroids and conventional disease-modifying antirheumatic drugs (cDMARD) are treated with biological D...
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| Veröffentlicht in: | Journal for immunotherapy of cancer 2020-06, Vol.8 (1), p.e000281 |
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| description | BackgroundImmune checkpoint inhibitors (ICIs) are associated with rheumatic and musculoskeletal immune-related adverse events (irAEs) in 5%–20% of patients. Currently, patients refractory to corticosteroids and conventional disease-modifying antirheumatic drugs (cDMARD) are treated with biological DMARDs (bDMARDs) targeting tumor necrosis factor α (TNFα) and interleukin-6, although without a clear biological rationale. Synovial tissue (ST) biopsy presents a valuable opportunity to investigate irAE pathogenesis and appropriately stratify bDMARD use in refractory irAE patients.Case presentationWe provide the first report of comparative, parallel ST and synovial fluid (SF) analyses of severe, cDMARD-refractory, seronegative polyarthritis, classified as a grade 3 irAE occurring in response to nivolumab treatment for metastatic squamous cell lung cancer, in comparison with ST and SF from patients with untreated rheumatoid arthritis (RA). We investigated immunohistochemical labeling of ST cytokine expression as a biological rationale for selecting therapy. Flow cytometric analysis of lymphocytes from ST, SF and blood collected before and after synovial biopsy-guided therapy, in comparison with RA, were evaluated for insights into the immunopathogenesis of irAE. Immunolabeling of ST demonstrated an excess of TNFα cytokine expression. Subsequent treatment with infliximab resulted in resolution of inflammatory symptoms and a significant reduction in C reactive protein levels. Flow cytometric analysis of synovial infiltrates indicated absence of programmed cell death protein-1 (PD-1) receptor positivity despite cessation of nivolumab approximately 200 days prior to the analyzes.ConclusionsA deeper understanding of the immunopathogenetic basis of immune activation in irAEs is required in order to select therapy that is likely to be the most effective. This is the first report investigating parallel blood, ST and SF in ICI-induced severe rheumatic irAE. Use of a bDMARD directed by the dominant inflammatory cytokine achieved resolution of synovitis while maintaining cancer remission. |
| doi_str_mv | 10.1136/jitc-2019-000281 |
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Currently, patients refractory to corticosteroids and conventional disease-modifying antirheumatic drugs (cDMARD) are treated with biological DMARDs (bDMARDs) targeting tumor necrosis factor α (TNFα) and interleukin-6, although without a clear biological rationale. Synovial tissue (ST) biopsy presents a valuable opportunity to investigate irAE pathogenesis and appropriately stratify bDMARD use in refractory irAE patients.Case presentationWe provide the first report of comparative, parallel ST and synovial fluid (SF) analyses of severe, cDMARD-refractory, seronegative polyarthritis, classified as a grade 3 irAE occurring in response to nivolumab treatment for metastatic squamous cell lung cancer, in comparison with ST and SF from patients with untreated rheumatoid arthritis (RA). We investigated immunohistochemical labeling of ST cytokine expression as a biological rationale for selecting therapy. Flow cytometric analysis of lymphocytes from ST, SF and blood collected before and after synovial biopsy-guided therapy, in comparison with RA, were evaluated for insights into the immunopathogenesis of irAE. Immunolabeling of ST demonstrated an excess of TNFα cytokine expression. Subsequent treatment with infliximab resulted in resolution of inflammatory symptoms and a significant reduction in C reactive protein levels. Flow cytometric analysis of synovial infiltrates indicated absence of programmed cell death protein-1 (PD-1) receptor positivity despite cessation of nivolumab approximately 200 days prior to the analyzes.ConclusionsA deeper understanding of the immunopathogenetic basis of immune activation in irAEs is required in order to select therapy that is likely to be the most effective. This is the first report investigating parallel blood, ST and SF in ICI-induced severe rheumatic irAE. Use of a bDMARD directed by the dominant inflammatory cytokine achieved resolution of synovitis while maintaining cancer remission.</description><identifier>ISSN: 2051-1426</identifier><identifier>EISSN: 2051-1426</identifier><identifier>DOI: 10.1136/jitc-2019-000281</identifier><identifier>PMID: 32571993</identifier><language>eng</language><publisher>England: BMJ Publishing Group Ltd</publisher><subject>Antibodies ; Antineoplastic Agents, Immunological - adverse effects ; Apoptosis ; Biopsy ; Cancer ; Carcinoma, Squamous Cell ; Case Report ; Cytokines ; Flow cytometry ; Gastrointestinal Agents - therapeutic use ; Histology ; Humans ; Hyperplasia ; Immunotherapy ; Infliximab - therapeutic use ; Labeling ; Ligands ; Lung Neoplasms ; Male ; Middle Aged ; Nivolumab - adverse effects ; Patients ; Prognosis ; Proteins ; Rheumatoid arthritis ; rheumatology ; Synovitis - chemically induced ; Synovitis - drug therapy ; Synovitis - immunology ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; TNF inhibitors ; Tumor necrosis factor-TNF</subject><ispartof>Journal for immunotherapy of cancer, 2020-06, Vol.8 (1), p.e000281</ispartof><rights>Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2020 Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/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)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b563t-e02d6bb0460bc0928b9fc908332cdff74250f84e11b2fa0bc5af8780cd46e17a3</citedby><cites>FETCH-LOGICAL-b563t-e02d6bb0460bc0928b9fc908332cdff74250f84e11b2fa0bc5af8780cd46e17a3</cites><orcidid>0000-0001-6668-9638</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jitc.bmj.com/content/8/1/e000281.full.pdf$$EPDF$$P50$$Gbmj$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://jitc.bmj.com/content/8/1/e000281.full$$EHTML$$P50$$Gbmj$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,27526,27527,27901,27902,53766,53768,55325,77570,77601,77629,77655</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32571993$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Murray-Brown, William</creatorcontrib><creatorcontrib>Wilsdon, Tom D</creatorcontrib><creatorcontrib>Weedon, Helen</creatorcontrib><creatorcontrib>Proudman, Susanna</creatorcontrib><creatorcontrib>Sukumaran, Shawgi</creatorcontrib><creatorcontrib>Klebe, Sonja</creatorcontrib><creatorcontrib>Walker, Jennifer G</creatorcontrib><creatorcontrib>Smith, Malcolm D</creatorcontrib><creatorcontrib>Wechalekar, Mihir D</creatorcontrib><title>Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy</title><title>Journal for immunotherapy of cancer</title><addtitle>J Immunother Cancer</addtitle><addtitle>J Immunother Cancer</addtitle><description>BackgroundImmune checkpoint inhibitors (ICIs) are associated with rheumatic and musculoskeletal immune-related adverse events (irAEs) in 5%–20% of patients. Currently, patients refractory to corticosteroids and conventional disease-modifying antirheumatic drugs (cDMARD) are treated with biological DMARDs (bDMARDs) targeting tumor necrosis factor α (TNFα) and interleukin-6, although without a clear biological rationale. Synovial tissue (ST) biopsy presents a valuable opportunity to investigate irAE pathogenesis and appropriately stratify bDMARD use in refractory irAE patients.Case presentationWe provide the first report of comparative, parallel ST and synovial fluid (SF) analyses of severe, cDMARD-refractory, seronegative polyarthritis, classified as a grade 3 irAE occurring in response to nivolumab treatment for metastatic squamous cell lung cancer, in comparison with ST and SF from patients with untreated rheumatoid arthritis (RA). We investigated immunohistochemical labeling of ST cytokine expression as a biological rationale for selecting therapy. Flow cytometric analysis of lymphocytes from ST, SF and blood collected before and after synovial biopsy-guided therapy, in comparison with RA, were evaluated for insights into the immunopathogenesis of irAE. Immunolabeling of ST demonstrated an excess of TNFα cytokine expression. Subsequent treatment with infliximab resulted in resolution of inflammatory symptoms and a significant reduction in C reactive protein levels. Flow cytometric analysis of synovial infiltrates indicated absence of programmed cell death protein-1 (PD-1) receptor positivity despite cessation of nivolumab approximately 200 days prior to the analyzes.ConclusionsA deeper understanding of the immunopathogenetic basis of immune activation in irAEs is required in order to select therapy that is likely to be the most effective. This is the first report investigating parallel blood, ST and SF in ICI-induced severe rheumatic irAE. Use of a bDMARD directed by the dominant inflammatory cytokine achieved resolution of synovitis while maintaining cancer remission.</description><subject>Antibodies</subject><subject>Antineoplastic Agents, Immunological - adverse effects</subject><subject>Apoptosis</subject><subject>Biopsy</subject><subject>Cancer</subject><subject>Carcinoma, Squamous Cell</subject><subject>Case Report</subject><subject>Cytokines</subject><subject>Flow cytometry</subject><subject>Gastrointestinal Agents - therapeutic use</subject><subject>Histology</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>Immunotherapy</subject><subject>Infliximab - therapeutic use</subject><subject>Labeling</subject><subject>Ligands</subject><subject>Lung Neoplasms</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Nivolumab - adverse effects</subject><subject>Patients</subject><subject>Prognosis</subject><subject>Proteins</subject><subject>Rheumatoid arthritis</subject><subject>rheumatology</subject><subject>Synovitis - chemically induced</subject><subject>Synovitis - drug therapy</subject><subject>Synovitis - immunology</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - immunology</subject><subject>TNF inhibitors</subject><subject>Tumor necrosis factor-TNF</subject><issn>2051-1426</issn><issn>2051-1426</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>9YT</sourceid><sourceid>ACMMV</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkkuLFDEQgBtR3GXduydp8KitVUk_0hdBFh8Li17Wc8hzJk1PZ0zSI-PVP25mexx3D4IQSKj68qWSVFE8R3iDSNu3g0uqIoB9BQCE4aPinECDFdakfXxvfVZcxjhkBoFSxtjT4oySpsO-p-fFry9u58d5I2TlJj0ro8u4n_zOJRfLPNRaBKGSCe5nTsl9aUcfnC5vS2XGsXSTdWMKIjk_lWLSZRDbnA0mZuld8IdL66NSjKV0fhv31Wp2OuvS2mR-_6x4YsUYzeVxvii-ffxwe_W5uvn66frq_U0lm5amygDRrZRQtyAV9ITJ3qoeGKVEaWu7mjRgWW0QJbEiM42wrGOgdN0a7AS9KK4Xr_Zi4NvgNiLsuReO3wV8WHERklOj4dTamoBAhZTW2mppKNIu26ViFgxm17vFtZ3lxmhlpvwK4wPpw8zk1nzld7yjiNB2WfDyKAj--2xi4oOfw5Tvz0nTkJ51pCGZgoVSwccYjD2dgMAPXcAPXcAPXcCXLshbXtyv7LThz59n4NUCyM3wP7rXf-lTif_EfwOPYs1R</recordid><startdate>20200621</startdate><enddate>20200621</enddate><creator>Murray-Brown, William</creator><creator>Wilsdon, Tom D</creator><creator>Weedon, Helen</creator><creator>Proudman, Susanna</creator><creator>Sukumaran, Shawgi</creator><creator>Klebe, Sonja</creator><creator>Walker, Jennifer G</creator><creator>Smith, Malcolm D</creator><creator>Wechalekar, Mihir D</creator><general>BMJ Publishing Group Ltd</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>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-6668-9638</orcidid></search><sort><creationdate>20200621</creationdate><title>Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy</title><author>Murray-Brown, William ; Wilsdon, Tom D ; Weedon, Helen ; Proudman, Susanna ; Sukumaran, Shawgi ; Klebe, Sonja ; Walker, Jennifer G ; Smith, Malcolm D ; Wechalekar, Mihir D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b563t-e02d6bb0460bc0928b9fc908332cdff74250f84e11b2fa0bc5af8780cd46e17a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Antibodies</topic><topic>Antineoplastic Agents, Immunological - adverse effects</topic><topic>Apoptosis</topic><topic>Biopsy</topic><topic>Cancer</topic><topic>Carcinoma, Squamous Cell</topic><topic>Case Report</topic><topic>Cytokines</topic><topic>Flow cytometry</topic><topic>Gastrointestinal Agents - therapeutic use</topic><topic>Histology</topic><topic>Humans</topic><topic>Hyperplasia</topic><topic>Immunotherapy</topic><topic>Infliximab - therapeutic use</topic><topic>Labeling</topic><topic>Ligands</topic><topic>Lung Neoplasms</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Nivolumab - adverse effects</topic><topic>Patients</topic><topic>Prognosis</topic><topic>Proteins</topic><topic>Rheumatoid arthritis</topic><topic>rheumatology</topic><topic>Synovitis - chemically induced</topic><topic>Synovitis - drug therapy</topic><topic>Synovitis - immunology</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - immunology</topic><topic>TNF inhibitors</topic><topic>Tumor necrosis factor-TNF</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Murray-Brown, William</creatorcontrib><creatorcontrib>Wilsdon, Tom D</creatorcontrib><creatorcontrib>Weedon, Helen</creatorcontrib><creatorcontrib>Proudman, Susanna</creatorcontrib><creatorcontrib>Sukumaran, Shawgi</creatorcontrib><creatorcontrib>Klebe, Sonja</creatorcontrib><creatorcontrib>Walker, Jennifer G</creatorcontrib><creatorcontrib>Smith, Malcolm D</creatorcontrib><creatorcontrib>Wechalekar, Mihir D</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 & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</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>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 & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</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>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Journal for immunotherapy of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Murray-Brown, William</au><au>Wilsdon, Tom D</au><au>Weedon, Helen</au><au>Proudman, Susanna</au><au>Sukumaran, Shawgi</au><au>Klebe, Sonja</au><au>Walker, Jennifer G</au><au>Smith, Malcolm D</au><au>Wechalekar, Mihir D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy</atitle><jtitle>Journal for immunotherapy of cancer</jtitle><stitle>J Immunother Cancer</stitle><addtitle>J Immunother Cancer</addtitle><date>2020-06-21</date><risdate>2020</risdate><volume>8</volume><issue>1</issue><spage>e000281</spage><pages>e000281-</pages><issn>2051-1426</issn><eissn>2051-1426</eissn><abstract>BackgroundImmune checkpoint inhibitors (ICIs) are associated with rheumatic and musculoskeletal immune-related adverse events (irAEs) in 5%–20% of patients. Currently, patients refractory to corticosteroids and conventional disease-modifying antirheumatic drugs (cDMARD) are treated with biological DMARDs (bDMARDs) targeting tumor necrosis factor α (TNFα) and interleukin-6, although without a clear biological rationale. Synovial tissue (ST) biopsy presents a valuable opportunity to investigate irAE pathogenesis and appropriately stratify bDMARD use in refractory irAE patients.Case presentationWe provide the first report of comparative, parallel ST and synovial fluid (SF) analyses of severe, cDMARD-refractory, seronegative polyarthritis, classified as a grade 3 irAE occurring in response to nivolumab treatment for metastatic squamous cell lung cancer, in comparison with ST and SF from patients with untreated rheumatoid arthritis (RA). We investigated immunohistochemical labeling of ST cytokine expression as a biological rationale for selecting therapy. Flow cytometric analysis of lymphocytes from ST, SF and blood collected before and after synovial biopsy-guided therapy, in comparison with RA, were evaluated for insights into the immunopathogenesis of irAE. Immunolabeling of ST demonstrated an excess of TNFα cytokine expression. Subsequent treatment with infliximab resulted in resolution of inflammatory symptoms and a significant reduction in C reactive protein levels. Flow cytometric analysis of synovial infiltrates indicated absence of programmed cell death protein-1 (PD-1) receptor positivity despite cessation of nivolumab approximately 200 days prior to the analyzes.ConclusionsA deeper understanding of the immunopathogenetic basis of immune activation in irAEs is required in order to select therapy that is likely to be the most effective. This is the first report investigating parallel blood, ST and SF in ICI-induced severe rheumatic irAE. Use of a bDMARD directed by the dominant inflammatory cytokine achieved resolution of synovitis while maintaining cancer remission.</abstract><cop>England</cop><pub>BMJ Publishing Group Ltd</pub><pmid>32571993</pmid><doi>10.1136/jitc-2019-000281</doi><orcidid>https://orcid.org/0000-0001-6668-9638</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antibodies Antineoplastic Agents, Immunological - adverse effects Apoptosis Biopsy Cancer Carcinoma, Squamous Cell Case Report Cytokines Flow cytometry Gastrointestinal Agents - therapeutic use Histology Humans Hyperplasia Immunotherapy Infliximab - therapeutic use Labeling Ligands Lung Neoplasms Male Middle Aged Nivolumab - adverse effects Patients Prognosis Proteins Rheumatoid arthritis rheumatology Synovitis - chemically induced Synovitis - drug therapy Synovitis - immunology T-Lymphocytes - drug effects T-Lymphocytes - immunology TNF inhibitors Tumor necrosis factor-TNF |
| title | Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy |
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