Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement
Identifieur interne : 002253 ( Pmc/Corpus ); précédent : 002252; suivant : 002254Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement
Auteurs : Monika M. Schoels ; Désirée Van Der Heijde ; Ferdinand C. Breedveld ; Gerd R. Burmester ; Maxime Dougados ; Paul Emery ; Gianfranco Ferraccioli ; Cem Gabay ; Allan Gibofsky ; Juan Jesus Gomez-Reino ; Graeme Jones ; Tore K. Kvien ; Miho M. Murikama ; Norihiro Nishimoto ; Josef S. SmolenSource :
- Annals of the Rheumatic Diseases [ 0003-4967 ] ; 2012.
Abstract
Suppression of the immunoinflammatory cascade by targeting interleukin 6 (IL-6) mediated effects constitutes a therapeutic option for chronic inflammatory diseases. Tocilizumab is the only IL-6 inhibitor (IL-6i) licensed for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), but also other agents targeting either IL-6 or its receptor are investigated in various indications.
To review published evidence on safety and efficacy of IL-6i in inflammatory diseases.
We performed systematic literature searches in Medline and Cochrane, screened EULAR and American College of Rheumatology meeting-abstracts, and accessed
Comprehensive evidence supports the efficacy of tocilizumab in RA in DMARD-naïve patients, and after DMARD- and TNFi-failure. Randomised comparisons demonstrate superiority of tocilizumab in JIA, but not ankylosing spondylitis (AS). Other indications are currently investigated. Additional IL-6i show similar efficacy; safety generally appears acceptable.
IL-6i is effective and safe in RA and JIA, but not in AS. Preliminary results in other indications need substantiation.
Url:
DOI: 10.1136/annrheumdis-2012-202470
PubMed: 23144446
PubMed Central: 3595140
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PMC:3595140Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement</title><author><name sortKey="Schoels, Monika M" sort="Schoels, Monika M" uniqKey="Schoels M" first="Monika M" last="Schoels">Monika M. Schoels</name><affiliation><nlm:aff id="af1">2nd Department of Medicine, Center for Rheumatic Disease, Hietzing Hospital, Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Van Der Heijde, Desiree" sort="Van Der Heijde, Desiree" uniqKey="Van Der Heijde D" first="Désirée" last="Van Der Heijde">Désirée Van Der Heijde</name><affiliation><nlm:aff id="af2">Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Breedveld, Ferdinand C" sort="Breedveld, Ferdinand C" uniqKey="Breedveld F" first="Ferdinand C" last="Breedveld">Ferdinand C. Breedveld</name><affiliation><nlm:aff id="af2">Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Burmester, Gerd R" sort="Burmester, Gerd R" uniqKey="Burmester G" first="Gerd R" last="Burmester">Gerd R. Burmester</name><affiliation><nlm:aff id="af3">Department of Rheumatology and Clinical Immunology, Charité, Free University and Humboldt University, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Dougados, Maxime" sort="Dougados, Maxime" uniqKey="Dougados M" first="Maxime" last="Dougados">Maxime Dougados</name><affiliation><nlm:aff id="af4">Department of Rheumatology, Cochin Hospital, René Descartes University, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Emery, Paul" sort="Emery, Paul" uniqKey="Emery P" first="Paul" last="Emery">Paul Emery</name><affiliation><nlm:aff id="af5">Academic Unit of Musculoskeletal Diseases, Leeds University, Leeds, UK</nlm:aff></affiliation></author><author><name sortKey="Ferraccioli, Gianfranco" sort="Ferraccioli, Gianfranco" uniqKey="Ferraccioli G" first="Gianfranco" last="Ferraccioli">Gianfranco Ferraccioli</name><affiliation><nlm:aff id="af6">Division of Rheumatology and Internal Medicine—CIC, Catholic University of the Sacred Heart—School of Medicine, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Gabay, Cem" sort="Gabay, Cem" uniqKey="Gabay C" first="Cem" last="Gabay">Cem Gabay</name><affiliation><nlm:aff id="af7">Division of Rheumatology, University Hospital, University of Geneva, Geneva, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Gibofsky, Allan" sort="Gibofsky, Allan" uniqKey="Gibofsky A" first="Allan" last="Gibofsky">Allan Gibofsky</name><affiliation><nlm:aff id="af8">Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York, USA</nlm:aff></affiliation></author><author><name sortKey="Gomez Reino, Juan Jesus" sort="Gomez Reino, Juan Jesus" uniqKey="Gomez Reino J" first="Juan Jesus" last="Gomez-Reino">Juan Jesus Gomez-Reino</name><affiliation><nlm:aff id="af9">Department of Rheumatology Unit, Hospital Clinico Universitario, Santiago de Compostela, Santiago</nlm:aff></affiliation></author><author><name sortKey="Jones, Graeme" sort="Jones, Graeme" uniqKey="Jones G" first="Graeme" last="Jones">Graeme Jones</name><affiliation><nlm:aff id="af10">Musculoskeletal Unit, Menzies Research Institute, University of Tasmania, Hobart, Australia</nlm:aff></affiliation></author><author><name sortKey="Kvien, Tore K" sort="Kvien, Tore K" uniqKey="Kvien T" first="Tore K" last="Kvien">Tore K. Kvien</name><affiliation><nlm:aff id="af11">Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Murikama, Miho M" sort="Murikama, Miho M" uniqKey="Murikama M" first="Miho M" last="Murikama">Miho M. Murikama</name><affiliation><nlm:aff id="af12">Laboratory of Immune Regulation, Wakayama Medical University, Wakayama, Japan</nlm:aff></affiliation></author><author><name sortKey="Nishimoto, Norihiro" sort="Nishimoto, Norihiro" uniqKey="Nishimoto N" first="Norihiro" last="Nishimoto">Norihiro Nishimoto</name><affiliation><nlm:aff id="af12">Laboratory of Immune Regulation, Wakayama Medical University, Wakayama, Japan</nlm:aff></affiliation></author><author><name sortKey="Smolen, Josef S" sort="Smolen, Josef S" uniqKey="Smolen J" first="Josef S" last="Smolen">Josef S. Smolen</name><affiliation><nlm:aff id="af1">2nd Department of Medicine, Center for Rheumatic Disease, Hietzing Hospital, Vienna, Austria</nlm:aff></affiliation><affiliation><nlm:aff id="af13">Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23144446</idno><idno type="pmc">3595140</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595140</idno><idno type="RBID">PMC:3595140</idno><idno type="doi">10.1136/annrheumdis-2012-202470</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">002253</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002253</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement</title><author><name sortKey="Schoels, Monika M" sort="Schoels, Monika M" uniqKey="Schoels M" first="Monika M" last="Schoels">Monika M. Schoels</name><affiliation><nlm:aff id="af1">2nd Department of Medicine, Center for Rheumatic Disease, Hietzing Hospital, Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Van Der Heijde, Desiree" sort="Van Der Heijde, Desiree" uniqKey="Van Der Heijde D" first="Désirée" last="Van Der Heijde">Désirée Van Der Heijde</name><affiliation><nlm:aff id="af2">Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Breedveld, Ferdinand C" sort="Breedveld, Ferdinand C" uniqKey="Breedveld F" first="Ferdinand C" last="Breedveld">Ferdinand C. Breedveld</name><affiliation><nlm:aff id="af2">Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Burmester, Gerd R" sort="Burmester, Gerd R" uniqKey="Burmester G" first="Gerd R" last="Burmester">Gerd R. Burmester</name><affiliation><nlm:aff id="af3">Department of Rheumatology and Clinical Immunology, Charité, Free University and Humboldt University, Berlin, Germany</nlm:aff></affiliation></author><author><name sortKey="Dougados, Maxime" sort="Dougados, Maxime" uniqKey="Dougados M" first="Maxime" last="Dougados">Maxime Dougados</name><affiliation><nlm:aff id="af4">Department of Rheumatology, Cochin Hospital, René Descartes University, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Emery, Paul" sort="Emery, Paul" uniqKey="Emery P" first="Paul" last="Emery">Paul Emery</name><affiliation><nlm:aff id="af5">Academic Unit of Musculoskeletal Diseases, Leeds University, Leeds, UK</nlm:aff></affiliation></author><author><name sortKey="Ferraccioli, Gianfranco" sort="Ferraccioli, Gianfranco" uniqKey="Ferraccioli G" first="Gianfranco" last="Ferraccioli">Gianfranco Ferraccioli</name><affiliation><nlm:aff id="af6">Division of Rheumatology and Internal Medicine—CIC, Catholic University of the Sacred Heart—School of Medicine, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Gabay, Cem" sort="Gabay, Cem" uniqKey="Gabay C" first="Cem" last="Gabay">Cem Gabay</name><affiliation><nlm:aff id="af7">Division of Rheumatology, University Hospital, University of Geneva, Geneva, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Gibofsky, Allan" sort="Gibofsky, Allan" uniqKey="Gibofsky A" first="Allan" last="Gibofsky">Allan Gibofsky</name><affiliation><nlm:aff id="af8">Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York, USA</nlm:aff></affiliation></author><author><name sortKey="Gomez Reino, Juan Jesus" sort="Gomez Reino, Juan Jesus" uniqKey="Gomez Reino J" first="Juan Jesus" last="Gomez-Reino">Juan Jesus Gomez-Reino</name><affiliation><nlm:aff id="af9">Department of Rheumatology Unit, Hospital Clinico Universitario, Santiago de Compostela, Santiago</nlm:aff></affiliation></author><author><name sortKey="Jones, Graeme" sort="Jones, Graeme" uniqKey="Jones G" first="Graeme" last="Jones">Graeme Jones</name><affiliation><nlm:aff id="af10">Musculoskeletal Unit, Menzies Research Institute, University of Tasmania, Hobart, Australia</nlm:aff></affiliation></author><author><name sortKey="Kvien, Tore K" sort="Kvien, Tore K" uniqKey="Kvien T" first="Tore K" last="Kvien">Tore K. Kvien</name><affiliation><nlm:aff id="af11">Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Murikama, Miho M" sort="Murikama, Miho M" uniqKey="Murikama M" first="Miho M" last="Murikama">Miho M. Murikama</name><affiliation><nlm:aff id="af12">Laboratory of Immune Regulation, Wakayama Medical University, Wakayama, Japan</nlm:aff></affiliation></author><author><name sortKey="Nishimoto, Norihiro" sort="Nishimoto, Norihiro" uniqKey="Nishimoto N" first="Norihiro" last="Nishimoto">Norihiro Nishimoto</name><affiliation><nlm:aff id="af12">Laboratory of Immune Regulation, Wakayama Medical University, Wakayama, Japan</nlm:aff></affiliation></author><author><name sortKey="Smolen, Josef S" sort="Smolen, Josef S" uniqKey="Smolen J" first="Josef S" last="Smolen">Josef S. Smolen</name><affiliation><nlm:aff id="af1">2nd Department of Medicine, Center for Rheumatic Disease, Hietzing Hospital, Vienna, Austria</nlm:aff></affiliation><affiliation><nlm:aff id="af13">Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria</nlm:aff></affiliation></author></analytic><series><title level="j">Annals of the Rheumatic Diseases</title><idno type="ISSN">0003-4967</idno><idno type="eISSN">1468-2060</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Suppression of the immunoinflammatory cascade by targeting interleukin 6 (IL-6) mediated effects constitutes a therapeutic option for chronic inflammatory diseases. Tocilizumab is the only IL-6 inhibitor (IL-6i) licensed for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), but also other agents targeting either IL-6 or its receptor are investigated in various indications.</p></sec><sec><title>Objective</title><p>To review published evidence on safety and efficacy of IL-6i in inflammatory diseases.</p></sec><sec><title>Methods</title><p>We performed systematic literature searches in Medline and Cochrane, screened EULAR and American College of Rheumatology meeting-abstracts, and accessed <ext-link ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">http://www.clinicaltrials.gov</ext-link>.</p></sec><sec><title>Results</title><p>Comprehensive evidence supports the efficacy of tocilizumab in RA in DMARD-naïve patients, and after DMARD- and TNFi-failure. Randomised comparisons demonstrate superiority of tocilizumab in JIA, but not ankylosing spondylitis (AS). Other indications are currently investigated. Additional IL-6i show similar efficacy; safety generally appears acceptable.</p></sec><sec><title>Conclusions</title><p>IL-6i is effective and safe in RA and JIA, but not in AS. 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article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Ann Rheum Dis</journal-id><journal-id journal-id-type="iso-abbrev">Ann. Rheum. Dis</journal-id><journal-id journal-id-type="hwp">annrheumdis</journal-id><journal-id journal-id-type="publisher-id">ard</journal-id><journal-title-group><journal-title>Annals of the Rheumatic Diseases</journal-title></journal-title-group><issn pub-type="ppub">0003-4967</issn><issn pub-type="epub">1468-2060</issn><publisher><publisher-name>BMJ Publishing Group</publisher-name><publisher-loc>BMA House, Tavistock Square, London, WC1H 9JR</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23144446</article-id><article-id pub-id-type="pmc">3595140</article-id><article-id pub-id-type="publisher-id">annrheumdis-2012-202470</article-id><article-id pub-id-type="doi">10.1136/annrheumdis-2012-202470</article-id><article-categories><subj-group subj-group-type="hwp-journal-coll"><subject>1506</subject></subj-group><subj-group subj-group-type="heading"><subject>Clinical and Epidemiological Research</subject></subj-group><series-title>Concise report</series-title></article-categories><title-group><article-title>Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Schoels</surname><given-names>Monika M</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>van der Heijde</surname><given-names>Désirée</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Breedveld</surname><given-names>Ferdinand C</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Burmester</surname><given-names>Gerd R</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Dougados</surname><given-names>Maxime</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Emery</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Ferraccioli</surname><given-names>Gianfranco</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Gabay</surname><given-names>Cem</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Gibofsky</surname><given-names>Allan</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Gomez-Reino</surname><given-names>Juan Jesus</given-names></name><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Jones</surname><given-names>Graeme</given-names></name><xref ref-type="aff" rid="af10">10</xref></contrib><contrib contrib-type="author"><name><surname>Kvien</surname><given-names>Tore K</given-names></name><xref ref-type="aff" rid="af11">11</xref></contrib><contrib contrib-type="author"><name><surname>Murikama</surname><given-names>Miho M</given-names></name><xref ref-type="aff" rid="af12">12</xref></contrib><contrib contrib-type="author"><name><surname>Nishimoto</surname><given-names>Norihiro</given-names></name><xref ref-type="aff" rid="af12">12</xref></contrib><contrib contrib-type="author"><name><surname>Smolen</surname><given-names>Josef S</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af13">13</xref></contrib></contrib-group><aff id="af1"><label>1</label>2nd Department of Medicine, Center for Rheumatic Disease, Hietzing Hospital, Vienna, Austria</aff><aff id="af2"><label>2</label>Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands</aff><aff id="af3"><label>3</label>Department of Rheumatology and Clinical Immunology, Charité, Free University and Humboldt University, Berlin, Germany</aff><aff id="af4"><label>4</label>Department of Rheumatology, Cochin Hospital, René Descartes University, Paris, France</aff><aff id="af5"><label>5</label>Academic Unit of Musculoskeletal Diseases, Leeds University, Leeds, UK</aff><aff id="af6"><label>6</label>Division of Rheumatology and Internal Medicine—CIC, Catholic University of the Sacred Heart—School of Medicine, Rome, Italy</aff><aff id="af7"><label>7</label>Division of Rheumatology, University Hospital, University of Geneva, Geneva, Switzerland</aff><aff id="af8"><label>8</label>Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York, USA</aff><aff id="af9"><label>9</label>Department of Rheumatology Unit, Hospital Clinico Universitario, Santiago de Compostela, Santiago</aff><aff id="af10"><label>10</label>Musculoskeletal Unit, Menzies Research Institute, University of Tasmania, Hobart, Australia</aff><aff id="af11"><label>11</label>Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway</aff><aff id="af12"><label>12</label>Laboratory of Immune Regulation, Wakayama Medical University, Wakayama, Japan</aff><aff id="af13"><label>13</label>Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria</aff><author-notes><fn><p><bold>Handling editor</bold> Tore K Kvien</p></fn><corresp><label>Correspondence to</label> Dr Monika M Schoels, 2nd Department of Internal Medicine, Center for Rheumatic Diseases, Hietzing Hospital, Wolkersbergenstrasse 1, Vienna 1130, Austria; <email>monika.schoels@live.com</email></corresp></author-notes><pub-date pub-type="ppub"><month>4</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>11</day><month>10</month><year>2012</year></pub-date><volume>72</volume><issue>4</issue><fpage>583</fpage><lpage>589</lpage><history><date date-type="accepted"><day>14</day><month>10</month><year>2012</year></date></history><permissions><copyright-statement>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</copyright-statement><copyright-year>2013</copyright-year><license license-type="open-access"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/legalcode">http://creativecommons.org/licenses/by-nc/3.0/legalcode</ext-link></license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="annrheumdis-2012-202470.pdf"></self-uri><abstract><sec><title>Background</title><p>Suppression of the immunoinflammatory cascade by targeting interleukin 6 (IL-6) mediated effects constitutes a therapeutic option for chronic inflammatory diseases. Tocilizumab is the only IL-6 inhibitor (IL-6i) licensed for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), but also other agents targeting either IL-6 or its receptor are investigated in various indications.</p></sec><sec><title>Objective</title><p>To review published evidence on safety and efficacy of IL-6i in inflammatory diseases.</p></sec><sec><title>Methods</title><p>We performed systematic literature searches in Medline and Cochrane, screened EULAR and American College of Rheumatology meeting-abstracts, and accessed <ext-link ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">http://www.clinicaltrials.gov</ext-link>.</p></sec><sec><title>Results</title><p>Comprehensive evidence supports the efficacy of tocilizumab in RA in DMARD-naïve patients, and after DMARD- and TNFi-failure. Randomised comparisons demonstrate superiority of tocilizumab in JIA, but not ankylosing spondylitis (AS). Other indications are currently investigated. Additional IL-6i show similar efficacy; safety generally appears acceptable.</p></sec><sec><title>Conclusions</title><p>IL-6i is effective and safe in RA and JIA, but not in AS. Preliminary results in other indications need substantiation.</p></sec></abstract><kwd-group><kwd>Rheumatoid Arthritis</kwd><kwd>Juvenile Idiopathic Arthritis</kwd><kwd>Treatment</kwd><kwd>DMARDs (biologic)</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>special-feature</meta-name><meta-value>unlocked</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="s1"><title>Introduction</title><p>Therapeutic options for rheumatoid arthritis (RA) and other inflammatory diseases are rapidly increasing. In addition to synthetic disease modifying anti-rheumatic drugs (DMARDs), biological agents that selectively target either cell-bound structures or cytokines are now available. Among those, suppression of the IL-6 mediated pathway has been the most recently introduced treatment principle, confirming the role of IL-6 in the pathophysiology of inflammation.<xref ref-type="bibr" rid="R1">1</xref> The only agent currently approved for IL-6- inhibition is tocilizumab, an antibody to the IL-6-receptor, but other compounds targeting this structure or its ligand IL-6 are currently in development. In this review, we assemble the state of knowledge regarding IL-6 blocking therapy in inflammatory rheumatologic diseases.</p></sec><sec sec-type="methods" id="s2"><title>Methods</title><p>Data Sources and Searches: We performed a systematic literature research of electronic databases. Our initial search included publications of Medline and Cochrane, each from their inception to January 2012. We also searched abstract archives of European League Against Rheumatism (EULAR)<xref ref-type="bibr" rid="R2">2</xref> (2010–2012) and American College of Rheumatology (ACR)<xref ref-type="bibr" rid="R3">3</xref> (2010 and 2011) conferences and accessed the National Institutes of Health database on clinical trials<xref ref-type="bibr" rid="R4">4</xref> for preliminary results from on-going trials.</p><sec id="s2a"><title>Study selection</title><p>By title and abstract screening, we evaluated all retrieved publications according to the inclusion-criteria. Online supplementary table S1 enlists the search terms and describes our approach regarding the population, intervention, control and outcomes.</p></sec><sec id="s2b"><title>Data synthesis</title><p>We performed meta-analyses of comparable randomised controlled trial (RCT) data, using Meta-Analyst software.<xref ref-type="bibr" rid="R5">5</xref> We tested for heterogeneity among the included trials (Cochrane's Q) and present the results of a random effects model (DerSimonian Laird). We provide descriptive comparisons of non-randomised prospective trials and observational data.</p><p>Data Extraction, Quality Assessment: We extracted efficacy data on clinical, functional and radiographic outcomes as well as safety data from all included studies. We evaluated all RCTs according to the Jadad scoring system<xref ref-type="bibr" rid="R6">6</xref> and followed PRISMA reporting guidelines.<xref ref-type="bibr" rid="R7">7</xref> Some of the results are shown in the online supplementary file which is part and parcel of this publication.</p></sec></sec><sec sec-type="results" id="s3"><title>Results</title><p>We initially retrieved 3935 Medline and 39 Cochrane publications for screening, and selected 166 fulltext papers for inclusion in this review. Furthermore, we found 293 eligible abstracts from recent scientific meetings and incorporated results from four ongoing trials (<ext-link ext-link-type="uri" xlink:href="http://www.clincialtrials.gov">http://www.clincialtrials.gov</ext-link>) (<xref ref-type="fig" rid="ANNRHEUMDIS2012202470F1">figure 1</xref>).</p><fig id="ANNRHEUMDIS2012202470F1" position="float"><label>Figure 1</label><caption><p>Search and selection process.AoSD, adult onset Still's disease; ACR, American College of Rheumatology conference, CLE, cutaneous lupus erythematosus; EULAR, European League Against Rheumatism; IBD, inflammatory bowel disease; inhib., inhibitors, JIA, juvenile idiopathic arthritis; N, number; PMR, polymyalgia rheumatica; RA, rheumatoid arthritis, SpA, spondyloarthropathy; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.</p></caption><graphic xlink:href="annrheumdis-2012-202470f01"></graphic></fig><p>Here we focus primarily on RA and tocilizumab, but also address other licensed and off-label indications and other compounds.</p></sec><sec id="s4"><title>Efficacy</title><sec id="s4a"><title>Rheumatoid arthritis (RA)</title><p>Randomised comparisons demonstrated the efficacy of tocilizumab in DMARD-naïve patients,<xref ref-type="bibr" rid="R8">8</xref> in insufficient responders (IR) to DMARDs,<xref ref-type="bibr" rid="R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19">9–19</xref> and in IR to TNF-inhibitors (TNFi).<xref ref-type="bibr" rid="R20 R21 R22">20–22</xref> If not indicated otherwise, results of the 8 mg/kg dose, given intravenously 4-weekly, are reported. Outcomes are summarised in <xref ref-type="table" rid="ANNRHEUMDIS2012202470TB1">table 1</xref>. Quality scoring of RCTs is provided in online supplementary table S2.</p><table-wrap id="ANNRHEUMDIS2012202470TB1" position="float"><label>Table 1</label><caption><p>Tocilizumab: pivotal randomised controlled trials in rheumatoid arthritis</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col></colgroup><thead valign="bottom"><tr><th rowspan="1" colspan="1"></th><th align="left" rowspan="1" colspan="1">Study: Name/Author, PY</th><th align="left" rowspan="1" colspan="1">Previously failed</th><th align="left" rowspan="1" colspan="1">Comparators</th><th align="left" rowspan="1" colspan="1">Combi-nation</th><th align="left" rowspan="1" colspan="1">ACR20</th><th align="left" rowspan="1" colspan="1">ACR50</th><th align="left" rowspan="1" colspan="1">ACR70</th><th align="left" rowspan="1" colspan="1">HAQ (% ≥MCID)</th><th align="left" rowspan="1" colspan="1">x-Ray</th><th align="left" rowspan="1" colspan="1">FU</th></tr></thead><tbody><tr><td rowspan="7" colspan="1">TCZ in combination therapy</td><td rowspan="1" colspan="1">OPTION 2008<xref ref-type="bibr" rid="R11">11</xref></td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">PL/TCZ 4/TCZ 8</td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">26/48/59</td><td rowspan="1" colspan="1">11/31/44</td><td rowspan="1" colspan="1">2/12/22</td><td rowspan="1" colspan="1">47/61/59*</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">24</td></tr><tr><td rowspan="1" colspan="1">TOWARD 2008<xref ref-type="bibr" rid="R10">10</xref></td><td rowspan="1" colspan="1">DMARD</td><td rowspan="1" colspan="1">PL/TCZ 8</td><td rowspan="1" colspan="1">DMARD</td><td rowspan="1" colspan="1">25/61</td><td rowspan="1" colspan="1">9/38</td><td rowspan="1" colspan="1">3/21</td><td rowspan="1" colspan="1">34/60*</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">24</td></tr><tr><td rowspan="1" colspan="1">RADIATE 2008<xref ref-type="bibr" rid="R19">19</xref></td><td rowspan="1" colspan="1">TNFi</td><td rowspan="1" colspan="1">PL/TCZ 4/TCZ 8</td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">10/30/50</td><td rowspan="1" colspan="1">4/17/29</td><td rowspan="1" colspan="1">1/5/12</td><td rowspan="1" colspan="1">Δ−0.4/−0.3/−0.1</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">24</td></tr><tr><td rowspan="1" colspan="1">ROSE 2012<xref ref-type="bibr" rid="R20">20</xref></td><td rowspan="1" colspan="1">DMARD</td><td rowspan="1" colspan="1">PL/TCZ 8</td><td rowspan="1" colspan="1">DMARD</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">11/30</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">LITHE 2011<xref ref-type="bibr" rid="R13">13</xref></td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">PL/TCZ 4/TCZ 8</td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">25/47/56</td><td rowspan="1" colspan="1">10/29/36</td><td rowspan="1" colspan="1">4/16/20</td><td rowspan="1" colspan="1">53/60/63*</td><td rowspan="1" colspan="1">1.1/0.3/0.3†</td><td rowspan="1" colspan="1">52</td></tr><tr><td rowspan="1" colspan="1">NCT00106535<xref ref-type="bibr" rid="R18">18</xref></td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">PL / TCZ 4/TCZ 8</td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">27/51/56</td><td rowspan="1" colspan="1">10/25/32</td><td rowspan="1" colspan="1">2/11/13</td><td rowspan="1" colspan="1">−0.3±0.5/−0.5±0.5/−0.5±0.6†</td><td rowspan="1" colspan="1">n.s. (yet)</td><td rowspan="1" colspan="1">24</td></tr><tr><td rowspan="1" colspan="1">Lim 2012<xref ref-type="bibr" rid="R19">19</xref></td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">PL/TCZ 8</td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">62/17</td><td rowspan="1" colspan="1">30/2</td><td rowspan="1" colspan="1">4/2</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">24</td></tr><tr><td rowspan="3" colspan="1">monotherapy versus Combination</td><td rowspan="1" colspan="1">CHARISMA 2006<xref ref-type="bibr" rid="R15">15</xref></td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">PL/2/4/8 TCZ-m vs. each dose TCZ-c+MTXHere: 4 m/4c//8m/8c</td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">61/63//<break></break>63/74</td><td rowspan="1" colspan="1">28/37//<break></break>41/53</td><td rowspan="1" colspan="1">6/12//<break></break>16/37</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">16</td></tr><tr><td rowspan="1" colspan="1">ACT-RAY 2012<xref ref-type="bibr" rid="R17">17</xref></td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">TCZ 8 m/TCZ 8</td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">71/72</td><td rowspan="1" colspan="1">41/45</td><td rowspan="1" colspan="1">26/25</td><td rowspan="1" colspan="1">33/33§</td><td rowspan="1" colspan="1">0.1(1.9)/0.2(1.1)§</td><td rowspan="1" colspan="1">24</td></tr><tr><td rowspan="1" colspan="1">NCT00891020<xref ref-type="bibr" rid="R22">22</xref></td><td rowspan="1" colspan="1">TNFi</td><td rowspan="1" colspan="1">TCZ 8 m / TCZ 4/TCZ 8</td><td rowspan="1" colspan="1">DMARD</td><td rowspan="1" colspan="1">48/45/50</td><td rowspan="1" colspan="1">25/24/27</td><td rowspan="1" colspan="1">7/9/10</td><td rowspan="1" colspan="1">n.s. (yet)</td><td rowspan="1" colspan="1">n.s. (yet)</td><td rowspan="1" colspan="1">24</td></tr><tr><td rowspan="5" colspan="1">TCZ monotherapy</td><td rowspan="1" colspan="1">Choy 2002<xref ref-type="bibr" rid="R9">9</xref></td><td rowspan="1" colspan="1">DMARD</td><td rowspan="1" colspan="1">PL/single i.v. dose of 0.1/1/5/10 mg MRA</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1"> 2</td></tr><tr><td rowspan="1" colspan="1">Nishimoto 2004<xref ref-type="bibr" rid="R16">16</xref></td><td rowspan="1" colspan="1">DMARD</td><td rowspan="1" colspan="1">PL/TCZ 4/TCZ 8</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">57/78</td><td rowspan="1" colspan="1">26/40</td><td rowspan="1" colspan="1">20/16</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">12</td></tr><tr><td rowspan="1" colspan="1">AMBITION 2010<xref ref-type="bibr" rid="R8">8</xref></td><td rowspan="1" colspan="1">(67% MTX-naïve pts.)</td><td rowspan="1" colspan="1">MTX/TCZ 8</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">52/70 (54/69)</td><td rowspan="1" colspan="1">34/44 (33/45)</td><td rowspan="1" colspan="1">15/28 (14/27)</td><td rowspan="1" colspan="1">Δ−0.5/−0.7</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">24</td></tr><tr><td rowspan="1" colspan="1">SATORI 2009<xref ref-type="bibr" rid="R14">14</xref></td><td rowspan="1" colspan="1">MTX</td><td rowspan="1" colspan="1">MTX/TCZ 8</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">25/80</td><td rowspan="1" colspan="1">11/49</td><td rowspan="1" colspan="1">6/30</td><td rowspan="1" colspan="1">34/67%¶</td><td rowspan="1" colspan="1">n.s.</td><td rowspan="1" colspan="1">24</td></tr><tr><td rowspan="1" colspan="1">SAMURAI 2007<xref ref-type="bibr" rid="R12">12</xref></td><td rowspan="1" colspan="1">DMARD</td><td rowspan="1" colspan="1">DMARDs/TCZ 8</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">34/78</td><td rowspan="1" colspan="1">13/64</td><td rowspan="1" colspan="1">6/44</td><td rowspan="1" colspan="1">40/68%¶</td><td rowspan="1" colspan="1">6.1 (4.2–8.0)/2.3 (1.5–3.2)**</td><td rowspan="1" colspan="1">52</td></tr></tbody></table><table-wrap-foot><fn><p>ACR, American College of Rheumatology; DMARD, disease modifying antirheumatic drug; FU, follow-up (weeks); MCID, minimally clinical important difference; MTX, methotrexate; PL, placebo; PY, year of publication; TCZ, tocilizumab; TCZ-m, tocilizumab-monotherapy; TCZ-c, tocilizumab in combination therapy; TNFi, tumour necrosis factor inhibitor; TNFi, tumour necrosis factor inhibitor *MCID HAQ>0.3.</p></fn><fn><p>†total Genant-modified Sharp Score (GTSS), mean change from BL.</p></fn><fn><p>§GTSS, BL annualised progression rate; mean (SD).</p></fn><fn><p>¶MCID HAQ≥0.22; Δ mean change from BL; GTSS, total Genant modified Sharp Score.</p></fn><fn><p>**vdH-TSS, mean (95%CI) change from baseline TCZ doses are abbreviated with ‘8’=8 mg/kg 4 weekly and ‘4’=4 mg/kg 4 weekly.</p></fn></table-wrap-foot></table-wrap><sec id="s4a1"><title>Clinical outcomes</title><p>ACR20/50/70 responses at 24 weeks were 69/45/27% using tocilizumab monotherapy in DMARD-naïve patients, compared with 54/33/14% on methotrexate (MTX) monotherapy, and 56–80/30–64/4–44% (ACR20/50/70) in DMARD-IR, when compared with placebo-arms (usually continued or de novo MTX therapy, with ACR20/50/70 response rates of 17–34/21–26/2–20%). Finally, in TNFi-IR, tocilizumab achieved 50/27–29/10–12% (ACR20/50/70) at 24 weeks versus 10/4/1% in the MTX plus placebo-arm (<xref ref-type="table" rid="ANNRHEUMDIS2012202470TB1">tables 1</xref> and S2). In a recently published small prospective study of patients receiving tocilizumab after failure of ≥2 DMARDs, one TNFi, and rituximab, 49/20% achieved EULAR good/moderate response.<xref ref-type="bibr" rid="R23">23</xref> Efficacy was sustained during long-term extensions (LTE) of several RCTs.<xref ref-type="bibr" rid="R24 R25 R26 R27">24–27</xref> Drug-free DAS28 remission rates were 35% 24 weeks after withdrawing tocilizumab and 13% 52 weeks thereafter<xref ref-type="bibr" rid="R28">28</xref> and tocilizumab re-treatment upon flares was successful in the Japanese DREAM- and RESTORE studies.<xref ref-type="bibr" rid="R29">29</xref><xref ref-type="bibr" rid="R30">30</xref> Patients can also maintain tocilizumab-free remission rates with continued MTX, as recently reported in sub-analyses of the OPTION-study.<xref ref-type="bibr" rid="R31">31</xref></p><p>In the ACT-RAY-trial,<xref ref-type="bibr" rid="R17">17</xref> MTX-IR were randomised to either tocilizumab monotherapy (withdrawing MTX), or tocilizumab added to MTX. A superior efficacy of the combination treatment could not be demonstrated in any of the clinical, functional or radiographic endpoints. These results have been confirmed in TNFi-IR.<xref ref-type="bibr" rid="R22">22</xref><xref ref-type="fig" rid="ANNRHEUMDIS2012202470F2">Figure 2</xref>A displays the risk ratios (RR) and CIs comparing tocilizumab monotherapy versus combination therapy in RCTs. Several non-randomised, open-label studies support the finding that mono- and combination therapy are similarly effective.<xref ref-type="bibr" rid="R32 R33 R34 R35">32–35</xref></p><fig id="ANNRHEUMDIS2012202470F2" position="float"><label>Figure 2</label><caption><p>ACR20/50/70 response rates. (A) Comparison of tocilizumab monotherapy versus combination of tocilizumab with DMARDs. (B) Comparison of 4 mg/kg versus 8 mg/kg 4-weekly. Risk ratios and 95% CIs are displayed. RR>1 favour combination therapy (in panel A) or the 4 mg/kg TCZ dose (in panel B). ACR, American College of Rheumatology</p></caption><graphic xlink:href="annrheumdis-2012-202470f02"></graphic></fig><p><bold>Physical function</bold> also improved significantly on tocilizumab as monotherapy<xref ref-type="bibr" rid="R8">8</xref><xref ref-type="bibr" rid="R12">12</xref><xref ref-type="bibr" rid="R14">14</xref><xref ref-type="bibr" rid="R17">17</xref> or combined with DMARDs:<xref ref-type="bibr" rid="R11">11</xref><xref ref-type="bibr" rid="R17">17</xref><xref ref-type="bibr" rid="R20">20</xref> 59–60% of patients achieved minimal clinical important difference of Health Assessment Questionnaire (HAQ) (defined ≥0.3 or 0.22) after 24 weeks,<xref ref-type="bibr" rid="R8">8</xref><xref ref-type="bibr" rid="R10">10</xref><xref ref-type="bibr" rid="R11">11</xref><xref ref-type="bibr" rid="R14">14</xref><xref ref-type="bibr" rid="R17">17</xref><xref ref-type="bibr" rid="R20">20</xref> 52% after 52 weeks,<xref ref-type="bibr" rid="R12">12</xref><xref ref-type="bibr" rid="R13">13</xref> compared with 34–53% in the respective placebo groups (<xref ref-type="table" rid="ANNRHEUMDIS2012202470TB1">table 1</xref>).</p><p><bold>Radiographic outcomes</bold> are available from the LITHE-,<xref ref-type="bibr" rid="R13">13</xref> SAMURAI-<xref ref-type="bibr" rid="R12">12</xref> and ACT-RAY-<xref ref-type="bibr" rid="R17">17</xref> trials: tocilizumab in combination with MTX<xref ref-type="bibr" rid="R13">13</xref><xref ref-type="bibr" rid="R17">17</xref> or monotherapy<xref ref-type="bibr" rid="R12">12</xref><xref ref-type="bibr" rid="R17">17</xref> retarded radiographic progression after 24<xref ref-type="bibr" rid="R17">17</xref> or 52 weeks.<xref ref-type="bibr" rid="R12">12</xref><xref ref-type="bibr" rid="R13">13</xref> MRI data showed early and sustained suppression of synovitis and osteitis.<xref ref-type="bibr" rid="R36 R37 R38">36–38</xref> During long-term follow-up, no radiographic progression after 3 years occurred in 67–69%.<xref ref-type="bibr" rid="R39">39</xref> Radiographic benefit was linked to decreased C-reactive protein and cartilage turnover markers.<xref ref-type="bibr" rid="R40">40</xref> Preliminary results indicate that tocilizumab also improves bone mineral density in RA<xref ref-type="bibr" rid="R41">41</xref><xref ref-type="bibr" rid="R42">42</xref> (<xref ref-type="table" rid="ANNRHEUMDIS2012202470TB1">table 1</xref>).</p></sec><sec id="s4a2"><title>Dose</title><p>Superior efficacy of the 8 mg/kg 4-weekly dose was seen with regard to clinical responses in DMARD-IR<xref ref-type="bibr" rid="R11">11</xref><xref ref-type="bibr" rid="R13">13</xref><xref ref-type="bibr" rid="R18">18</xref> and TNFi-IR.<xref ref-type="bibr" rid="R20">20</xref><xref ref-type="bibr" rid="R22">22</xref><xref ref-type="fig" rid="ANNRHEUMDIS2012202470F2">Figure 2</xref>B depicts the risk ratio (RR, and 95% CI) of ACR-responses with 8 mg/kg tocilizumab versus 4 mg/kg; overall, this difference is significant. Nevertheless, radiographic outcome was similar at both doses.<xref ref-type="bibr" rid="R13">13</xref> This could indicate a dissociation between inflammation and damage by tocilizumab.<xref ref-type="bibr" rid="R43">43</xref></p><p>Some meta-analyses of trial data and observational studies suggest superior efficacy of tocilizumab combination with MTX in DMARD-IR when compared with TNFi, abatacept, and rituximab.<xref ref-type="bibr" rid="R44 R45 R46 R47">44–47</xref> However, one network meta-analysis reported higher response rates for etanercept and certolizumab.<xref ref-type="bibr" rid="R48">48</xref> In a meta-analysis of trials including TNFi-IR, outcomes of tocilizumab and abatacept, golimumab, and rituximab were similar.<xref ref-type="bibr" rid="R49">49</xref> Observational data confirmed these analyses showing similar efficacy of biologics combination therapy in TNFi-IR.<xref ref-type="bibr" rid="R50">50</xref> In the first available direct randomised comparison of biologicals as monotherapy,<xref ref-type="bibr" rid="R51">51</xref> tocilizumab was superior to adalimumab in DMARD-IR; however, TNFi monotherapy in general and particularly adalimumab are inferior to combination with MTX.<xref ref-type="bibr" rid="R52">52</xref></p><p>In conclusion, RCTs unanimously confirm efficacy of tocilizumab in RA, and non-randomised prospective studies<xref ref-type="bibr" rid="R35">35</xref><xref ref-type="bibr" rid="R53">53</xref><xref ref-type="bibr" rid="R54">54</xref> observational studies<xref ref-type="bibr" rid="R45">45</xref><xref ref-type="bibr" rid="R55 R56 R57 R58 R59">55–59</xref> and registry data<xref ref-type="bibr" rid="R60">60</xref><xref ref-type="bibr" rid="R61">61</xref> corroborate this. Recently published reviews of tocilizumab in RA also confirm this conclusion.<xref ref-type="bibr" rid="R62">62</xref> Tocilizumab is also effective as subcutaneous formulation.<xref ref-type="bibr" rid="R63">63</xref><xref ref-type="bibr" rid="R64">64</xref></p><p>Another substance directed against the IL-6-receptor, <italic>sarilumab</italic>, is in early phase trials.<xref ref-type="bibr" rid="R65">65</xref><xref ref-type="bibr" rid="R66">66</xref> Agents that directly target IL-6 also show promising preliminary results, among those, <italic>sirukumab,</italic><xref ref-type="bibr" rid="R67 R68 R69">67–69</xref><italic>B-E8</italic>,<xref ref-type="bibr" rid="R70">70</xref> and <italic>BMS-945429</italic>, that demonstrated rapid and sustained ACR-response in MTX-IR.<xref ref-type="bibr" rid="R71 R72 R73">71–73</xref> Lastly, <italic>olokizumab,</italic> a humanised IL-6 antibody, is currently investigated in phase II dose-ranging studies<xref ref-type="bibr" rid="R74">74</xref><xref ref-type="bibr" rid="R75">75</xref> for RA. Data are compiled in online supplementary table S4.</p></sec></sec><sec id="s4b"><title>Juvenile Idiopathic Arthritis (JIA)</title><p>A number of randomised trials show efficacy in systemic JIA. These are summarised in online supplementary table S3. <bold>Clinical response</bold> (ACR30pedi/50/70) to tocilizumab 8 mg/kg q2 weeks was 85/85/71% after 12 weeks;<xref ref-type="bibr" rid="R76">76</xref> sustained efficacy was seen during LTE with 88/89/65% ACR response rates after 1 year<xref ref-type="bibr" rid="R77">77</xref> and 88% (ACR70) and 71% (ACR90) after 2 years.<xref ref-type="bibr" rid="R78">78</xref> Remission rates were 67% over 3.5 years,<xref ref-type="bibr" rid="R79">79</xref> and 38% of patients had drug-free remission at 6 years.<xref ref-type="bibr" rid="R80">80</xref> Several studies also addressed IL-6i in poly- or oligoarticular JIA, and reported clinical success,<xref ref-type="bibr" rid="R81 R82 R83 R84 R85">81–85</xref> however, no randomised comparison in this patient population is available to date.</p></sec><sec id="s4c"><title>Other Indications</title><p>In <italic>ankylosing spondylitis</italic>, no benefit could be shown in randomised comparisons. Results are further elaborated in the online supplement. In this document, also data on case reports or small studies for various indications are expanded. Indications include <italic>adult onset Still's disease, polymyalgia rheumatica, multi-refractory vasculitis, relapsing polychondritis, Castleman's disease, systemic lupus erythematosus</italic> and <italic>systemic sclerosis</italic>. In <italic>Crohn's disease</italic>, tocilizumab was clinically superior to placebo.</p></sec></sec><sec id="s5"><title>Safety</title><p>A Cochrane review of tocilizumab in RA reported 1.2x more frequent adverse events (AE) than for pooled placebo patients (74% vs 65%).<xref ref-type="bibr" rid="R86">86</xref> No significant difference in serious AE (SAE), or withdrawals due to AE was reported.<xref ref-type="bibr" rid="R86">86</xref> Retention rates have been repeatedly confirmed to be high,<xref ref-type="bibr" rid="R55">55</xref><xref ref-type="bibr" rid="R58">58</xref> also suggesting acceptable safety. Cumulative safety data from RA trials, evaluating a total tocilizumab exposure of 8580 patient-years (PY),<xref ref-type="bibr" rid="R87">87</xref> yielded an AE rate of 278/100 PY and SAE rate of 14/100 PY. These results are consistent with LTEs and postmarketing surveillance showing incidence rates of 43–44%<xref ref-type="bibr" rid="R88">88</xref><xref ref-type="bibr" rid="R89">89</xref> or 167 events/100 PY<xref ref-type="bibr" rid="R90">90</xref> (AE), and 9–10%<xref ref-type="bibr" rid="R88">88</xref><xref ref-type="bibr" rid="R89">89</xref> or 27/100 PY<xref ref-type="bibr" rid="R27">27</xref><xref ref-type="bibr" rid="R90">90</xref> (SAE). SAE increased with longer disease duration.<xref ref-type="bibr" rid="R89">89</xref> Comparing the safety profile of tocilizumab to other biologicals, a meta-analysis investigated TNFi, anakinra, abatacept, rituximab, and tocilizumab<xref ref-type="bibr" rid="R91">91</xref> and showed similar rates of SAE, serious infections, lymphoma, and congestive heart failure. An indirect comparison of abatacept, golimumab, and rituximab with tocilizumab in RA following TNFi-IR showed similar safety.<xref ref-type="bibr" rid="R53">53</xref></p><p>AE of tocilizumab and other IL-6i primarily comprise infections, neutropenia, thrombocytopenia, hyperlipidaemia, gastrointestinal AEs and liver enzyme increases; details are presented in the online supplement.</p><sec id="s5a"><title>Myocardial Infarction and Stroke</title><p>Myocardial infarction and stroke rates of pooled RCT treatment groups were 0.25/100 PY and 0.19/100 PY versus 0.49/100 PY and 0.24/100 PY in the pooled control group; without increase over time.<xref ref-type="bibr" rid="R87">87</xref></p></sec></sec><sec id="s6"><title>Pregnancy</title><p>No complications were noticed in registries.<xref ref-type="bibr" rid="R92">92</xref><xref ref-type="bibr" rid="R93">93</xref> Recently, outcomes of all pregnancies occurring in any of the pivotal RA-RCTs or LTEs, covering 10 994 PY, were presented: 33 pregnancies resulted in 7 spontaneous and 13 therapeutic abortions and 11 normal deliveries.<xref ref-type="bibr" rid="R94">94</xref></p></sec><sec sec-type="discussion" id="s7"><title>Discussion</title><p>Tocilizumab is an efficacious biologic agent and is acceptably safe in RA and JIA. The efficacy data relate to clinical and functional aspects of these diseases. In ankylosing spondylitis (AS), randomised comparisons did not show beneficial effects. In other diseases, preliminary data highlight the need for future research: inhibition of the IL-6 pathway seems to become an option for the treatment of several other inflammatory diseases, but conclusive RCT data are still lacking. Antibodies against the ligand IL-6 could soon augment the armamentarium for targeted treatment of RA and JIA and appear to have similar efficacy and safety profiles as IL-6 receptor inhibition.</p></sec><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SD1"><caption><title>Web appendix</title></caption><media xlink:href="annrheumdis-2012-202470-s1.pdf" xlink:type="simple" id="d34e1208" position="anchor" mimetype="application" mime-subtype="pdf"></media></supplementary-material></sec></body><back><ack><p>This study was made possible by a grant from Roche. However, no representative of the company attended the meetings or was involved in the literature search.</p></ack><fn-group><fn><p><bold>Funding:</bold> None.</p></fn><fn><p><bold>Contributors:</bold> All authors contributed and finally approved the current manuscript.</p></fn><fn><p><bold>Competing interests:</bold> DvdH: Consulting and/or speaking activities for and/or research grants from Roche/Chugai, BMS, Sanofi and Aventis; GB has been a consultant and speaker for Roche and BMS and has received grant support from Roche, BMS and Sanofi; MD received grant support from and has participated at advisory board meetings and symposia organised by Roche; PE has provided expert advice for Roche, BMS, Lilly, Sanofi and undertaken clinical trials for Roche and BMS; GFF has received speaking fees and research grants from Roche; CG received consultant/speakers fees from Roche and BMS; AG has been a consultant and speaker for Roche/Genentech and holds shares of BMS; JJGR received grant support from and has participated at advisory board meetings and symposia organised by Roche; GJ has received grant support given talks and served on advisory boards for Roche; TKK received grant support from and/or has participated at advisory board meetings and/or symposia organised by Roche, BMS, UCB; NN has received speaking, consulting fees and/or research grants from Chugai/Roche and BMS; NB's company has received income for services delivered to Roche; JSS received grant support from and has participated at advisory board meetings and symposia organised by Roche/Chugai/Genentech, BMS, Janssen, Sanofi and UCB. MS, FB, and MM declare no conflict.</p></fn><fn><p><bold>Provenance and peer review:</bold> Not commissioned; externally peer reviewed.</p></fn><fn><p><bold>Open Access:</bold> This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) 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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/</p></fn></fn-group><ref-list><title>References</title><ref id="R1"><label>1</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cronstein</surname><given-names>BN</given-names></name></person-group><article-title>Interleukin-6. 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