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No commercial re-use. See rights and permissions. Published by BMJ." /> <meta name="DC.AccessRights" content="restricted" /> <meta name="DC.Description" content="Objective Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N -linked glycans within the variable domains (V-domains). Recently, we showed that N -glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients. Methods ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative). Results V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG. Conclusion Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of N -linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA." /> <meta name="DC.Contributor" content="Theresa Kissel" /> <meta name="DC.Contributor" content="Karin Anna van Schie" /> <meta name="DC.Contributor" content="Lise Hafkenscheid" /> <meta name="DC.Contributor" content="Anders Lundquist" /> <meta name="DC.Contributor" content="Heidi Kokkonen" /> <meta name="DC.Contributor" content="Manfred Wuhrer" /> <meta name="DC.Contributor" content="Tom WJ Huizinga" /> <meta name="DC.Contributor" content="Hans Ulrich Scherer" /> <meta name="DC.Contributor" content="René Toes" /> <meta name="DC.Contributor" content="Solbritt Rantapää-Dahlqvist" /> <meta name="article:published_time" content="2019-12-01" /> <meta name="article:section" content="Rheumatoid arthritis" /> <meta name="citation_title" content="On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis" /> <meta name="citation_abstract" lang="en" content="<h3>Objective</h3> <p>Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of <i>N</i>-linked glycans within the variable domains (V-domains). Recently, we showed that <i>N</i>-glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients.</p><h3>Methods</h3> <p>ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative).</p><h3>Results</h3> <p>V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG.</p><h3>Conclusion</h3> <p>Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of <i>N</i>-linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA.</p>" /> <meta name="citation_journal_title" content="Annals of the Rheumatic Diseases" /> <meta name="citation_publisher" content="BMJ Publishing Group Ltd" /> <meta name="citation_publication_date" content="2019/12/01" /> <meta name="citation_mjid" content="annrheumdis;78/12/1616" /> <meta name="citation_id" content="78/12/1616" /> <meta name="citation_public_url" content="https://ard.bmj.com/content/78/12/1616" /> <meta name="citation_abstract_html_url" content="https://ard.bmj.com/content/78/12/1616.abstract" /> <meta name="citation_full_html_url" content="https://ard.bmj.com/content/78/12/1616.full" /> <meta name="citation_pdf_url" content="https://ard.bmj.com/content/annrheumdis/78/12/1616.full.pdf" /> <meta name="citation_issn" content="0003-4967" /> <meta name="citation_issn" content="1468-2060" /> <meta name="citation_doi" content="10.1136/annrheumdis-2019-215698" /> <meta name="citation_pmid" content="31471298" /> <meta name="citation_volume" content="78" /> <meta name="citation_issue" content="12" /> <meta name="citation_article_type" content="Research Article" /> <meta name="citation_section" content="Rheumatoid arthritis" /> <meta name="citation_firstpage" content="1616" /> <meta name="citation_lastpage" content="1620" /> <meta name="citation_author" content="Theresa Kissel" /> <meta name="citation_author_institution" content="Rheumatology" /> <meta name="citation_author_institution" content="Leiden University Medical Center" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0002-5749-8087" /> <meta name="citation_author" content="Karin Anna van Schie" /> <meta name="citation_author_institution" content="Rheumatology" /> <meta name="citation_author_institution" content="Leiden University Medical Center" /> <meta name="citation_author" content="Lise Hafkenscheid" /> <meta name="citation_author_institution" content="Rheumatology" /> <meta name="citation_author_institution" content="Leiden University Medical Center" /> <meta name="citation_author" content="Anders Lundquist" /> <meta name="citation_author_institution" content="Department of Statistics" /> <meta name="citation_author_institution" content="Umeå University" /> <meta name="citation_author" content="Heidi Kokkonen" /> <meta name="citation_author_institution" content="Department of Public Health and Clinical Medicine/Rheumatology" /> <meta name="citation_author_institution" content="Umeå University" /> <meta name="citation_author" content="Manfred Wuhrer" /> <meta name="citation_author_institution" content="Center for Proteomics and Metabolomics" /> <meta name="citation_author_institution" content="Leiden University Medical Center" /> <meta name="citation_author" content="Tom WJ Huizinga" /> <meta name="citation_author_institution" content="Rheumatology" /> <meta name="citation_author_institution" content="Leiden University Medical Center" /> <meta name="citation_author" content="Hans Ulrich Scherer" /> <meta name="citation_author_institution" content="Rheumatology" /> <meta name="citation_author_institution" content="Leiden University Medical Center" /> <meta name="citation_author" content="René Toes" /> <meta name="citation_author_institution" content="Rheumatology" /> <meta name="citation_author_institution" content="Leiden University Medical Center" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0002-9618-6414" /> <meta name="citation_author" content="Solbritt Rantapää-Dahlqvist" /> <meta name="citation_author_institution" content="Department of Public Health and Clinical Medicine/Rheumatology" /> <meta name="citation_author_institution" content="Umeå University" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0001-8259-3863" /> <meta name="citation_reference" content="citation_journal_title=Journal of Clinical Investigation;citation_journal_abbrev=JCI;citation_author=GA. 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Vidic;citation_title=High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG glycome in three isolated human populations;citation_volume=10;citation_year=2011;citation_pmid=21653738;citation_doi=10.1074/mcp.M111.010090" /> <meta name="twitter:title" content="On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis" /> <meta name="twitter:card" content="summary_large_image" /> <meta name="twitter:image" content="https://ard.bmj.com/sites/default/files/highwire/annrheumdis/78/12.cover-source.jpg" /> <meta name="twitter:description" content="Objective Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N -linked glycans within the variable domains (V-domains). Recently, we showed that N -glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients. Methods ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative). Results V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG. Conclusion Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of N -linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA." /> <meta name="og-title" property="og:title" content="On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis" /> <meta name="og-url" property="og:url" content="https://ard.bmj.com/content/78/12/1616" /> <meta name="og-site-name" property="og:site_name" content="Annals of the Rheumatic Diseases" /> <meta name="og-description" property="og:description" content="Objective Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N -linked glycans within the variable domains (V-domains). Recently, we showed that N -glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients. Methods ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative). Results V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG. Conclusion Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of N -linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. 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panel-region-right"> <div class="inside"><div class="panel-pane pane-bmjj-challenge-modal col-mobile-2 col-narrow-1 pull-right " > <div class="pane-content"> <a href="" class="" data-icon-position="" data-hide-link-title="0"><a href="#" id="chal-modal" class="article-pdf-download"><img alt="Download PDF" src="/sites/default/themes/bmjj/img/icon-pdf.png" /><strong>PDF</strong></a></a> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-entity-field pane-node-field-highwire-article-cat article-category col-narrow-9 col-normal-10" > <div class="pane-content"> <div class="field field-name-field-highwire-article-cat field-type-text field-label-hidden"><div class="field-items"><div class="field-item even">Rheumatoid arthritis</div></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-article-citation col-mobile-10 col-narrow-10 col-normal-11 article-title" > <div class="pane-content"> <div class="highwire-article-citation highwire-citation-type-highwire-article node261629" data-node-nid="261629" id="node-261629--21710510138" data-pisa="annrheumdis;78/12/1616" data-pisa-master="annrheumdis;annrheumdis-2019-215698" data-apath="/annrheumdis/78/12/1616.atom"><cite class="highwire-cite highwire-cite-highwire-article highwire-citation-bmjj-title clearfix"> <div class="highwire-cite-title">On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis</div> <span class="highwire-cite-access"><span class="highwire-citation-access highwire-citation-access-check" data-pisa-id="annrheumdis;annrheumdis-2019-215698" data-atom-uri="/annrheumdis/78/12/1616.atom" data-request-view="full"></span></span> </cite> </div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-panel-tabs-container col-narrow-12 clear" > <div class="pane-content"> <div data-panels-ajax-tab-preloaded="jnl_template_bmjj_tab_art" id="panels-ajax-tab-container-highwire_article_tabs" class="panels-ajax-tab-container"><div class="panels-ajax-tab-loading" style ="display:none"><img class="loading" src="https://ard.bmj.com/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif" alt="Loading" title="Loading" /></div><div class="panels-ajax-tab-wrap-jnl_template_bmjj_tab_art"><div class="panel-display panel-1col clearfix" > <div class="panel-panel panel-col"> <div><div class="panel-pane pane-highwire-markup author-affiliates col-narrow-12 author-affiliates-corresp article" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div xmlns:xhtml="http://www.w3.org/1999/xhtml" class="contributors"><ol class="contributor-list" id="contrib-group-1"><li class="contributor" id="contrib-1"><a href="http://orcid.org/0000-0002-5749-8087" class="bmjj-markup-orcid-logo" target="_blank">http://orcid.org/0000-0002-5749-8087</a><span class="name">Theresa Kissel</span><a id="xref-aff-1-1" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-2"><span class="name">Karin Anna van Schie</span><a id="xref-aff-1-2" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-3"><span class="name">Lise Hafkenscheid</span><a id="xref-aff-1-3" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-4"><span class="name">Anders Lundquist</span><a id="xref-aff-2-1" class="xref-aff" href="#aff-2">2</a>, </li><li class="contributor" id="contrib-5"><span class="name">Heidi Kokkonen</span><a id="xref-aff-3-1" class="xref-aff" href="#aff-3">3</a>, </li><li class="contributor" id="contrib-6"><span class="name">Manfred Wuhrer</span><a id="xref-aff-4-1" class="xref-aff" href="#aff-4">4</a>, </li><li class="contributor" id="contrib-7"><span class="name">Tom WJ Huizinga</span><a id="xref-aff-1-4" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-8"><span class="name">Hans Ulrich Scherer</span><a id="xref-aff-1-5" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-9"><a href="http://orcid.org/0000-0002-9618-6414" class="bmjj-markup-orcid-logo" target="_blank">http://orcid.org/0000-0002-9618-6414</a><span class="name">René Toes</span><a id="xref-aff-1-6" class="xref-aff" href="#aff-1">1</a>, </li><li class="last" id="contrib-10"><a href="http://orcid.org/0000-0001-8259-3863" class="bmjj-markup-orcid-logo" target="_blank">http://orcid.org/0000-0001-8259-3863</a><span class="name">Solbritt Rantapää-Dahlqvist</span><a id="xref-aff-3-2" class="xref-aff" href="#aff-3">3</a></li></ol><ol class="affiliation-list"><li class="aff"><a id="aff-1" name="aff-1"></a><address> <sup>1</sup> <span class="institution">Rheumatology</span>, <span class="institution">Leiden University Medical Center</span>, <span class="addr-line">Leiden</span>, The Netherlands </address></li><li class="aff"><a id="aff-2" name="aff-2"></a><address> <sup>2</sup> <span class="institution">Department of Statistics</span>, <span class="institution">Umeå University</span>, <span class="addr-line">Umeå</span>, Sweden </address></li><li class="aff"><a id="aff-3" name="aff-3"></a><address> <sup>3</sup> <span class="institution">Department of Public Health and Clinical Medicine/Rheumatology</span>, <span class="institution">Umeå University</span>, <span class="addr-line">Umeå</span>, Sweden </address></li><li class="aff"><a id="aff-4" name="aff-4"></a><address> <sup>4</sup> <span class="institution">Center for Proteomics and Metabolomics</span>, <span class="institution">Leiden University Medical Center</span>, <span class="addr-line">Leiden</span>, The Netherlands </address></li></ol><ol class="corresp-list"><li class="corresp" id="corresp-1"><span class="corresp-label">Correspondence to</span> Theresa Kissel, Rheumatology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands; <span class="em-link"><span class="em-addr">T.kissel{at}lumc.nl</span></span> </li></ol></div></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-markup abstract-with-bc" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" id="content-block" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article abstract-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-1"><h2>Abstract</h2><div id="sec-1" class="subsection"><p id="p-1"><strong>Objective</strong> Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of <em>N</em>-linked glycans within the variable domains (V-domains). Recently, we showed that <em>N</em>-glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients.</p></div><div id="sec-2" class="subsection"><p id="p-2"><strong>Methods</strong> ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative).</p></div><div id="sec-3" class="subsection"><p id="p-3"><strong>Results</strong> V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG.</p></div><div id="sec-4" class="subsection"><p id="p-4"><strong>Conclusion</strong> Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of <em>N</em>-linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA.</p></div></div><ul class="kwd-group"><li class="kwd">rheumatoid arthritis (RA)</li><li class="kwd">anti-citrullinated protein antibodies (ACPA)</li><li class="kwd"> <em>N</em>-linked variable domain (V-domain) glycans</li><li class="kwd">‘Sweet’ biomarker</li><li class="kwd">HLA-SE effects</li></ul><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-dfp-pane oas-ads oas-ads-mid pull-right" > <div class="pane-content"> <div id="dfp-ad-mpu-wrapper" class="dfp-tag-wrapper"> <div id="dfp-ad-mpu" class="dfp-tag-wrapper"> <script type="text/javascript"> googletag.cmd.push(function() { googletag.display("dfp-ad-mpu"); }); </script> </div> </div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-custom pane-1" > <div class="pane-content"> <p><a href="https://doi.org/10.1136/annrheumdis-2019-215698" target="_new">https://doi.org/10.1136/annrheumdis-2019-215698</a></p> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-altmetrics" > <h2 class="pane-title">Statistics from Altmetric.com</h2> <div class="pane-content"> <div data-badge-details="right" data-badge-type="medium-donut" data-doi="10.1136/annrheumdis-2019-215698" data-hide-no-mentions="true" class="altmetric-embed"></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-bmjj-jumplinks" > <div class="pane-content"> <div class="highwire-list-wrapper"><div class="highwire-list"><ul></ul></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-custom pane-2 permissions-box" > <h2 class="pane-title">Request Permissions</h2> <div class="pane-content"> <p>If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.</p> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-panels-ajax-pane-content permissions-box pane-highwire-permission-link" id="request-permissions"> <h2 class="pane-title"><span class='panels-ajax-pane-title' data-pid='new-70fd4c70-563e-4b94-ae3b-2a97f3980c13'></span></h2> <div class="pane-content"> <div class='panels-ajax-pane panels-ajax-pane-new-70fd4c70-563e-4b94-ae3b-2a97f3980c13' data-pid='new-70fd4c70-563e-4b94-ae3b-2a97f3980c13'></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-markup" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article abstract-view "><span class="highwire-journal-article-marker-start"></span><ul class="kwd-group"><li class="kwd"><a href="/keyword/rheumatoid-arthritis-ra" class="hw-term hw-article-keyword hw-article-keyword-rheumatoid-arthritis-ra" rel="nofollow">rheumatoid arthritis (RA)</a></li><li class="kwd"><a href="/keyword/anti-citrullinated-protein-antibodies-acpa" class="hw-term hw-article-keyword hw-article-keyword-anti-citrullinated-protein-antibodies-acpa" rel="nofollow">anti-citrullinated protein antibodies (ACPA)</a></li><li class="kwd"><a xmlns:default="http://www.w3.org/1999/xhtml" href="/keyword/n-linked-variable-domain-v-domain-glycans" class="hw-term hw-article-keyword hw-article-keyword-n-linked-variable-domain-v-domain-glycans" rel="nofollow"> <em xmlns:default="http://www.w3.org/1999/xhtml">N</em>-linked variable domain (V-domain) glycans</a></li><li class="kwd"><a href="/keyword/%E2%80%98sweet%E2%80%99-biomarker" class="hw-term hw-article-keyword hw-article-keyword-‘sweet’-biomarker" rel="nofollow">‘Sweet’ biomarker</a></li><li class="kwd"><a href="/keyword/hla-se-effects" class="hw-term hw-article-keyword hw-article-keyword-hla-se-effects" rel="nofollow">HLA-SE effects</a></li></ul><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div><a href="https://ard.bmj.com/content/78/12/1616.full" class="hw-link hw-link-article-full-text" data-icon-position="" data-hide-link-title="0">View Full Text</a></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-markup footnotes" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div xmlns:xhtml="http://www.w3.org/1999/xhtml" class="section fn-group" id="fn-group-1"><h2>Footnotes</h2><ul><li class="fn-other" id="fn-2"><p id="p-29"><span class="fn-label">Handling editor</span> Prof Josef S Smolen</p></li><li class="fn-other" id="fn-3"><p id="p-30"><span class="fn-label">Correction notice</span> This article has been corrected since it published Online First. An error has been corrected in the abstract.</p></li><li class="fn-other" id="fn-4"><p id="p-31"><span class="fn-label">Contributors</span> TK: study concept and design, conducting experiments, aquisition of data, analysis and interpretation of the results, drafting and revising the manuscript, final approval of the manuscript. KAvS: study concept and design, conducting experiments, aquisition of data and interpretation of the results, critical revision and final approval of the manuscript. LH: study concept and design, methodology design, conducting experiments, aquisition of data, critical revision and final approval of the manuscript. AL: statistical analyses, interpretation of the results, critical revision and final approval of the manuscript. HK: statistical analyses, critical revision and final approval of the manuscript. MW: methodology design, critical revision and final approval of the manuscript. TWJH: interpretation of the results, critical revision and final approval of the manuscript. HUS: study concept and design, interpretation of the results, critical revision and final approval of the manuscript. RT: study concept and design, interpretation of the results, drafting and revising the manuscript critically, final approval of the manuscript. SR-D: study concept and design, statistical analyses, interpretation of the results, drafting and revising the manuscript critically, final approval of the manuscript. Department of Biobank Research at Umeå University: providing patient samples and data. Västerbotten Intervention Programme: providing patient samples and data. The Northern Sweden MONICA study: providing patient samples and data. The County Council of Västerbotten: providing patient samples and data. J.W. Drijfhout: providing the CCP2 peptides.</p></li><li class="fn-other" id="fn-5"><p id="p-32"><span class="fn-label">Funding</span> This work has been financially supported by ReumaNederland (17-1-402), the IMI funded project RTCure (777357), ZonMw TOP (91214031), the Swedish Research Council (VR 2017-00650) as well as the King Gustaf V’s 80-Year Fund, the King Gustaf V’s and Queen Victoria’s Fund and the Swedish Rheumatism Association.</p></li><li class="fn-conflict" id="fn-6"><p id="p-33"><span class="fn-label">Competing interests</span> HUS, TWJH and REMT are mentioned inventors on a patent on ACPA-IgG V-domain glycosylation.</p></li><li class="fn-other" id="fn-7"><p id="p-34"><span class="fn-label">Patient consent for publication</span> Not required.</p></li><li class="fn-other" id="fn-8"><p id="p-35"><span class="fn-label">Provenance and peer review</span> Not commissioned; externally peer reviewed.</p></li></ul></div></div></div> </div> </div> <div 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