Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)
Identifieur interne : 002260 ( Pmc/Corpus ); précédent : 002259; suivant : 002261Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)
Auteurs : Ariane L. Herrick ; Xiaoyan Pan ; Sébastien Peytrignet ; Mark Lunt ; Roger Hesselstrand ; Luc Mouthon ; Alan Silman ; Edith Brown ; Lászl Czirják ; Jörg H W. Distler ; Oliver Distler ; Kim Fligelstone ; William J. Gregory ; Rachel Ochiel ; Madelon Vonk ; Codrina Ancu A ; Voon H. Ong ; Dominique Farge ; Marie Hudson ; Marco Matucci-Cerinic ; Alexandra Balbir-Gurman ; Yvind Midtvedt ; Alison C. Jordan ; Paresh Jobanputra ; Wendy Stevens ; Pia Moinzadeh ; Frances C. Hall ; Christian Agard ; Marina E. Anderson ; Elisabeth Diot ; Rajan Madhok ; Mohammed Akil ; Maya H. Buch ; Lorinda Chung ; Nemanja Damjanov ; Harsha Gunawardena ; Peter Lanyon ; Yasmeen Ahmad ; Kuntal Chakravarty ; S Ren Jacobsen ; Alexander J. Macgregor ; Neil Mchugh ; Ulf Müller-Ladner ; Gabriela Riemekasten ; Michael Becker ; Janet Roddy ; Patricia E. Carreira ; Anne Laure Fauchais ; Eric Hachulla ; Jennifer Hamilton ; Murat Nanç ; John S. Mclaren ; Jacob M. Van Laar ; Sanjay Pathare ; Susannah Proudman ; Anna Rudin ; Joanne Sahhar ; Brigitte Coppere ; Christine Serratrice ; Tom Sheeran ; Douglas J. Veale ; Claire Grange ; Georges-Selim Trad ; Christopher P. DentonSource :
- Annals of the Rheumatic Diseases [ 0003-4967 ] ; 2017.
Abstract
The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.
This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.
Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: −4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months.
These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed.
NCT02339441.
Url:
DOI: 10.1136/annrheumdis-2016-210503
PubMed: 28188239
PubMed Central: 5530354
Links to Exploration step
PMC:5530354Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)</title><author><name sortKey="Herrick, Ariane L" sort="Herrick, Ariane L" uniqKey="Herrick A" first="Ariane L" last="Herrick">Ariane L. Herrick</name><affiliation><nlm:aff id="af1"><institution>Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><addr-line>NIHR Manchester Musculoskeletal Biomedical Research Unit</addr-line>,<institution>Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Pan, Xiaoyan" sort="Pan, Xiaoyan" uniqKey="Pan X" first="Xiaoyan" last="Pan">Xiaoyan Pan</name><affiliation><nlm:aff id="af3"><institution>Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Peytrignet, Sebastien" sort="Peytrignet, Sebastien" uniqKey="Peytrignet S" first="Sébastien" last="Peytrignet">Sébastien Peytrignet</name><affiliation><nlm:aff id="af3"><institution>Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Lunt, Mark" sort="Lunt, Mark" uniqKey="Lunt M" first="Mark" last="Lunt">Mark Lunt</name><affiliation><nlm:aff id="af3"><institution>Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Hesselstrand, Roger" sort="Hesselstrand, Roger" uniqKey="Hesselstrand R" first="Roger" last="Hesselstrand">Roger Hesselstrand</name><affiliation><nlm:aff id="af4"><addr-line>Department of Rheumatology</addr-line>,<institution>Lund University</institution>,<addr-line>Lund</addr-line>,<country>Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Mouthon, Luc" sort="Mouthon, Luc" uniqKey="Mouthon L" first="Luc" last="Mouthon">Luc Mouthon</name><affiliation><nlm:aff id="af5"><addr-line>Service de Médecine Interne</addr-line>,<institution>Hôpital Cochin, Centre de Référence pour les Vascularites Nécrosantes et la Sclérodermie Systémique, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris (AP-HP)</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Silman, Alan" sort="Silman, Alan" uniqKey="Silman A" first="Alan" last="Silman">Alan Silman</name><affiliation><nlm:aff id="af6"><addr-line>Nuffield Department of Orthopaedics</addr-line>,<institution>Rheumatology and Musculoskeletal Sciences,University of Oxford</institution>,<addr-line>Oxford</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Brown, Edith" sort="Brown, Edith" uniqKey="Brown E" first="Edith" last="Brown">Edith Brown</name><affiliation><nlm:aff id="af7"><institution>Member of Steering Committee, contact via Professor Herrick, The University of Manchester</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Czirjak, Laszl" sort="Czirjak, Laszl" uniqKey="Czirjak L" first="Lászl" last="Czirják">Lászl Czirják</name><affiliation><nlm:aff id="af8"><addr-line>Department of Rheumatology and Immunology</addr-line>,<institution>Medical Center, University of Pécs</institution>,<addr-line>Pecs</addr-line>,<country>Hungary</country></nlm:aff></affiliation></author><author><name sortKey="Distler, Jorg H W" sort="Distler, Jorg H W" uniqKey="Distler J" first="Jörg H W" last="Distler">Jörg H W. Distler</name><affiliation><nlm:aff id="af9"><addr-line>Department of Internal Medicine 3</addr-line>,<institution>University of Erlangen-Nuremberg</institution>,<addr-line>Erlangen</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Distler, Oliver" sort="Distler, Oliver" uniqKey="Distler O" first="Oliver" last="Distler">Oliver Distler</name><affiliation><nlm:aff id="af10"><addr-line>Department of Rheumatology</addr-line>,<institution>University of Zurich</institution>,<addr-line>Zurich</addr-line>,<country>Switzerland</country></nlm:aff></affiliation></author><author><name sortKey="Fligelstone, Kim" sort="Fligelstone, Kim" uniqKey="Fligelstone K" first="Kim" last="Fligelstone">Kim Fligelstone</name><affiliation><nlm:aff id="af11"><institution>Royal Free London NHS Foundation Trust</institution>,<addr-line>London</addr-line>,<country>UK</country>.</nlm:aff></affiliation></author><author><name sortKey="Gregory, William J" sort="Gregory, William J" uniqKey="Gregory W" first="William J" last="Gregory">William J. Gregory</name><affiliation><nlm:aff id="af12"><addr-line>Rehabilitation Services</addr-line>,<institution>Salford Royal NHS Foundation Trust</institution>,<addr-line>Salford</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Ochiel, Rachel" sort="Ochiel, Rachel" uniqKey="Ochiel R" first="Rachel" last="Ochiel">Rachel Ochiel</name><affiliation><nlm:aff id="af11"><institution>Royal Free London NHS Foundation Trust</institution>,<addr-line>London</addr-line>,<country>UK</country>.</nlm:aff></affiliation></author><author><name sortKey="Vonk, Madelon" sort="Vonk, Madelon" uniqKey="Vonk M" first="Madelon" last="Vonk">Madelon Vonk</name><affiliation><nlm:aff id="af13"><addr-line>Department of the Rheumatic Diseases</addr-line>,<institution>Radboud University Nijmegen Medical Centre</institution>,<addr-line>Nijmegen</addr-line>,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Ancu A, Codrina" sort="Ancu A, Codrina" uniqKey="Ancu A C" first="Codrina" last="Ancu A">Codrina Ancu A</name><affiliation><nlm:aff id="af14"><addr-line>Rheumatology 2 Department</addr-line>,<institution>“Grigore T. Popa” University of Medicine and Pharmacy, Clinical Rehabilitation Hospital</institution>,<addr-line>Iași</addr-line>,<country>Romania</country></nlm:aff></affiliation></author><author><name sortKey="Ong, Voon H" sort="Ong, Voon H" uniqKey="Ong V" first="Voon H" last="Ong">Voon H. Ong</name><affiliation><nlm:aff id="af15"><addr-line>UCL Division of Medicine</addr-line>,<institution>Centre for Rheumatology and Connective Tissue Diseases</institution>,<addr-line>London</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Farge, Dominique" sort="Farge, Dominique" uniqKey="Farge D" first="Dominique" last="Farge">Dominique Farge</name><affiliation><nlm:aff id="af16"><addr-line>Unité Clinique de Médecine Interne</addr-line>,<institution>Maladies Auto-immunes et Pathologie Vasculaire, UF 04, Hôpital Saint-Louis, AP-HP Assistance Publique des Hôpitaux de Paris, INSERM UMRS 1160, Paris Denis Diderot University,</institution><country>France</country></nlm:aff></affiliation></author><author><name sortKey="Hudson, Marie" sort="Hudson, Marie" uniqKey="Hudson M" first="Marie" last="Hudson">Marie Hudson</name><affiliation><nlm:aff id="af17"><institution>Jewish General Hospital, Lady Davis Institute and McGill University</institution>,<addr-line>Montreal</addr-line>,<country>Canada</country></nlm:aff></affiliation></author><author><name sortKey="Matucci Cerinic, Marco" sort="Matucci Cerinic, Marco" uniqKey="Matucci Cerinic M" first="Marco" last="Matucci-Cerinic">Marco Matucci-Cerinic</name><affiliation><nlm:aff id="af18"><addr-line>Department Experimental and Clinical Medicine, Division of Rheumatology AOUC</addr-line>,<institution>University of Florence</institution>,<addr-line>Florence</addr-line>,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Balbir Gurman, Alexandra" sort="Balbir Gurman, Alexandra" uniqKey="Balbir Gurman A" first="Alexandra" last="Balbir-Gurman">Alexandra Balbir-Gurman</name><affiliation><nlm:aff id="af19"><addr-line>Shine Rheumatology Unit</addr-line>,<institution>Rambam Heath Care Campus; Rappaport Faculty of Medicine</institution>,<addr-line>Haifa</addr-line>,<country>Israel</country></nlm:aff></affiliation></author><author><name sortKey="Midtvedt, Yvind" sort="Midtvedt, Yvind" uniqKey="Midtvedt " first=" Yvind" last="Midtvedt"> Yvind Midtvedt</name><affiliation><nlm:aff id="af20"><addr-line>Rheumatology Unit</addr-line>,<institution>Oslo University Hospital Rikshospitalet</institution>,<addr-line>Oslo</addr-line>,<country>Norway</country></nlm:aff></affiliation></author><author><name sortKey="Jordan, Alison C" sort="Jordan, Alison C" uniqKey="Jordan A" first="Alison C" last="Jordan">Alison C. Jordan</name><affiliation><nlm:aff id="af21"><institution>Queen Elizabeth Hospital Birmingham, UHB Foundation Trust</institution>,<addr-line>Birmingham</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Jobanputra, Paresh" sort="Jobanputra, Paresh" uniqKey="Jobanputra P" first="Paresh" last="Jobanputra">Paresh Jobanputra</name><affiliation><nlm:aff id="af21"><institution>Queen Elizabeth Hospital Birmingham, UHB Foundation Trust</institution>,<addr-line>Birmingham</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Stevens, Wendy" sort="Stevens, Wendy" uniqKey="Stevens W" first="Wendy" last="Stevens">Wendy Stevens</name><affiliation><nlm:aff id="af22"><institution>St Vincent's Hospital</institution>,<addr-line>Melbourne</addr-line>,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Moinzadeh, Pia" sort="Moinzadeh, Pia" uniqKey="Moinzadeh P" first="Pia" last="Moinzadeh">Pia Moinzadeh</name><affiliation><nlm:aff id="af23"><addr-line>Department for Dermatology</addr-line>,<institution>University of Cologne Kerpenerstr. 62</institution>,<addr-line>Köln</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hall, Frances C" sort="Hall, Frances C" uniqKey="Hall F" first="Frances C" last="Hall">Frances C. Hall</name><affiliation><nlm:aff id="af24"><institution>Cambridge University NHS Hospital Foundation Trust</institution>,<addr-line>Cambridge</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Agard, Christian" sort="Agard, Christian" uniqKey="Agard C" first="Christian" last="Agard">Christian Agard</name><affiliation><nlm:aff id="af25"><addr-line>Department of Internal Medicine</addr-line>,<institution>Hôtel-Dieu Hospital</institution>,<institution>University of Nantes</institution>,<addr-line>Nantes</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Anderson, Marina E" sort="Anderson, Marina E" uniqKey="Anderson M" first="Marina E" last="Anderson">Marina E. Anderson</name><affiliation><nlm:aff id="af26"><institution>University of Liverpool, Aintree University Hospital</institution>,<addr-line>Liverpool</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Diot, Elisabeth" sort="Diot, Elisabeth" uniqKey="Diot E" first="Elisabeth" last="Diot">Elisabeth Diot</name><affiliation><nlm:aff id="af27"><addr-line>Service de Médecine Interne</addr-line>,<institution>Hôpital Bretonneau Tours</institution><addr-line>Cedex</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Madhok, Rajan" sort="Madhok, Rajan" uniqKey="Madhok R" first="Rajan" last="Madhok">Rajan Madhok</name><affiliation><nlm:aff id="af28"><institution>Centre for Rheumatic Diseases</institution>,<addr-line>Glasgow Royal Infirmary, Glasgow</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Akil, Mohammed" sort="Akil, Mohammed" uniqKey="Akil M" first="Mohammed" last="Akil">Mohammed Akil</name><affiliation><nlm:aff id="af29"><institution>Sheffield Teaching Hospitals</institution>,<addr-line>Sheffield</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Buch, Maya H" sort="Buch, Maya H" uniqKey="Buch M" first="Maya H" last="Buch">Maya H. Buch</name><affiliation><nlm:aff id="af30"><institution>Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust</institution>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Chung, Lorinda" sort="Chung, Lorinda" uniqKey="Chung L" first="Lorinda" last="Chung">Lorinda Chung</name><affiliation><nlm:aff id="af31"><institution>Stanford University</institution>,<addr-line>Stanford, California</addr-line>,<country>USA</country>.</nlm:aff></affiliation></author><author><name sortKey="Damjanov, Nemanja" sort="Damjanov, Nemanja" uniqKey="Damjanov N" first="Nemanja" last="Damjanov">Nemanja Damjanov</name><affiliation><nlm:aff id="af32"><institution>University of Belgrade School of Medicine, Institute of Rheumatology</institution>,<addr-line>Belgrade</addr-line>,<country>Serbia</country></nlm:aff></affiliation></author><author><name sortKey="Gunawardena, Harsha" sort="Gunawardena, Harsha" uniqKey="Gunawardena H" first="Harsha" last="Gunawardena">Harsha Gunawardena</name><affiliation><nlm:aff id="af33"><institution>Clinical and Academic Rheumatology, North Bristol NHS Trust</institution>,<addr-line>Bristol</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Lanyon, Peter" sort="Lanyon, Peter" uniqKey="Lanyon P" first="Peter" last="Lanyon">Peter Lanyon</name><affiliation><nlm:aff id="af34"><institution>Nottingham University Hospitals NHS Trust, and Nottingham NHS Treatment Centre</institution>,<addr-line>Nottingham</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Ahmad, Yasmeen" sort="Ahmad, Yasmeen" uniqKey="Ahmad Y" first="Yasmeen" last="Ahmad">Yasmeen Ahmad</name><affiliation><nlm:aff id="af35"><institution>Peter Maddison Rheumatology Centre</institution>,<addr-line>Llandudno</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Chakravarty, Kuntal" sort="Chakravarty, Kuntal" uniqKey="Chakravarty K" first="Kuntal" last="Chakravarty">Kuntal Chakravarty</name><affiliation><nlm:aff id="af36"><institution>Queens Hospital</institution>,<addr-line>Romford</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Jacobsen, S Ren" sort="Jacobsen, S Ren" uniqKey="Jacobsen S" first="S Ren" last="Jacobsen">S Ren Jacobsen</name><affiliation><nlm:aff id="af37"><institution>University of Copenhagen, Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Rigshospitalet</institution>,<addr-line>Copenhagen</addr-line>,<country>Denmark</country></nlm:aff></affiliation></author><author><name sortKey="Macgregor, Alexander J" sort="Macgregor, Alexander J" uniqKey="Macgregor A" first="Alexander J" last="Macgregor">Alexander J. Macgregor</name><affiliation><nlm:aff id="af38"><institution>Norwich Medical School, University of East Anglia</institution>,<addr-line>Norwich</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Mchugh, Neil" sort="Mchugh, Neil" uniqKey="Mchugh N" first="Neil" last="Mchugh">Neil Mchugh</name><affiliation><nlm:aff id="af39"><institution>Royal National Hospital for Rheumatic Diseases</institution>,<addr-line>Bath</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Muller Ladner, Ulf" sort="Muller Ladner, Ulf" uniqKey="Muller Ladner U" first="Ulf" last="Müller-Ladner">Ulf Müller-Ladner</name><affiliation><nlm:aff id="af40"><addr-line>Department of Rheumatology and Clinical Immunology</addr-line>,<institution>Justus-Liebig University Giessen</institution>,<addr-line>Bad Nauheim</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Riemekasten, Gabriela" sort="Riemekasten, Gabriela" uniqKey="Riemekasten G" first="Gabriela" last="Riemekasten">Gabriela Riemekasten</name><affiliation><nlm:aff id="af41"><addr-line>Department of Rheumatology</addr-line>,<institution>University of Lübeck</institution>,<addr-line>Lübeck</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Becker, Michael" sort="Becker, Michael" uniqKey="Becker M" first="Michael" last="Becker">Michael Becker</name><affiliation><nlm:aff id="af42"><addr-line>Department of Rheumatology and Clinical Immunology</addr-line>,<institution>University Hospital Charité Berlin</institution>,<addr-line>Berlin</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Roddy, Janet" sort="Roddy, Janet" uniqKey="Roddy J" first="Janet" last="Roddy">Janet Roddy</name><affiliation><nlm:aff id="af43"><addr-line>Department of Rheumatology</addr-line>,<institution>Royal Perth Hospital</institution>,<addr-line>Perth</addr-line>,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Carreira, Patricia E" sort="Carreira, Patricia E" uniqKey="Carreira P" first="Patricia E" last="Carreira">Patricia E. Carreira</name><affiliation><nlm:aff id="af44"><institution>Servicio de Reumatologia. Hospital Universitario 12 de Octubre</institution>,<addr-line>Madrid</addr-line>,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Fauchais, Anne Laure" sort="Fauchais, Anne Laure" uniqKey="Fauchais A" first="Anne Laure" last="Fauchais">Anne Laure Fauchais</name><affiliation><nlm:aff id="af45"><addr-line>Internal Medicine Unit</addr-line>,<institution>Limoges University Hospital</institution>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Hachulla, Eric" sort="Hachulla, Eric" uniqKey="Hachulla E" first="Eric" last="Hachulla">Eric Hachulla</name><affiliation><nlm:aff id="af46"><addr-line>Département de Médecine Interne et Immunologie Clinique</addr-line>,<institution>Centre National de Référence Maladies Systémiques etAuto-immunes Rares, Université de Lille, Inserm, U995, FHU Immune-Mediated Inflammatory Diseases and Targeted Therapies,</institution><addr-line>Lille</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Hamilton, Jennifer" sort="Hamilton, Jennifer" uniqKey="Hamilton J" first="Jennifer" last="Hamilton">Jennifer Hamilton</name><affiliation><nlm:aff id="af47"><institution>Gateshead Hospitals Foundation Trust</institution>,<addr-line>Gateshead</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey=" Nanc, Murat" sort=" Nanc, Murat" uniqKey=" Nanc M" first="Murat" last=" Nanç">Murat Nanç</name><affiliation><nlm:aff id="af48"><addr-line>Department of Internal Medicine, Division of Rheumatology</addr-line>,<institution>Istanbul University</institution>,<addr-line>Istanbul</addr-line>,<country>Turkey</country></nlm:aff></affiliation></author><author><name sortKey="Mclaren, John S" sort="Mclaren, John S" uniqKey="Mclaren J" first="John S" last="Mclaren">John S. Mclaren</name><affiliation><nlm:aff id="af49"><addr-line>Fife Rheumatic Diseases Unit</addr-line>,<institution>Whyteman's Brae Hospital</institution>,<addr-line>Kirkcaldy</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Van Laar, Jacob M" sort="Van Laar, Jacob M" uniqKey="Van Laar J" first="Jacob M" last="Van Laar">Jacob M. Van Laar</name><affiliation><nlm:aff id="af50"><addr-line>Department of Rheumatology and Clinical Immunology</addr-line>,<institution>UMC Utrecht</institution>,<addr-line>Utrecht</addr-line>,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Pathare, Sanjay" sort="Pathare, Sanjay" uniqKey="Pathare S" first="Sanjay" last="Pathare">Sanjay Pathare</name><affiliation><nlm:aff id="af51"><institution>James Cook University Hospital</institution>,<addr-line>Middlesbrough</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Proudman, Susannah" sort="Proudman, Susannah" uniqKey="Proudman S" first="Susannah" last="Proudman">Susannah Proudman</name><affiliation><nlm:aff id="af52"><addr-line>Rheumatology Unit</addr-line>,<institution>Royal Adelaide Hospital, and Discipline of Medicine, University of Adelaide</institution>,<addr-line>Adelaide</addr-line>,<country>South Australia</country></nlm:aff></affiliation></author><author><name sortKey="Rudin, Anna" sort="Rudin, Anna" uniqKey="Rudin A" first="Anna" last="Rudin">Anna Rudin</name><affiliation><nlm:aff id="af53"><addr-line>Department of Rheumatology and Inflammation Research</addr-line>,<institution>The Sahlgrenska Academy at Gothenburg University</institution>,<addr-line>Gothenburg</addr-line>,<country>Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Sahhar, Joanne" sort="Sahhar, Joanne" uniqKey="Sahhar J" first="Joanne" last="Sahhar">Joanne Sahhar</name><affiliation><nlm:aff id="af54"><institution>Monash Centre for Inflammatory Diseases, Monash University</institution>,<addr-line>Clayton, Melbourne</addr-line>,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Coppere, Brigitte" sort="Coppere, Brigitte" uniqKey="Coppere B" first="Brigitte" last="Coppere">Brigitte Coppere</name><affiliation><nlm:aff id="af55"><addr-line>Department of Internal Medicine</addr-line>,<institution>Hôpital Edouard Herriot</institution>,<addr-line>Lyon</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Serratrice, Christine" sort="Serratrice, Christine" uniqKey="Serratrice C" first="Christine" last="Serratrice">Christine Serratrice</name><affiliation><nlm:aff id="af56"><addr-line>Department of Internal Medicine</addr-line>,<institution>Foundation Hospital Saint Joseph</institution>,<addr-line>Marseille</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Sheeran, Tom" sort="Sheeran, Tom" uniqKey="Sheeran T" first="Tom" last="Sheeran">Tom Sheeran</name><affiliation><nlm:aff id="af57"><institution>Cannock Chase Hospital</institution>,<addr-line>Cannock</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Veale, Douglas J" sort="Veale, Douglas J" uniqKey="Veale D" first="Douglas J" last="Veale">Douglas J. Veale</name><affiliation><nlm:aff id="af58"><institution>St Vincent's University Hospital</institution>,<addr-line>Dublin</addr-line>,<country>Ireland</country></nlm:aff></affiliation></author><author><name sortKey="Grange, Claire" sort="Grange, Claire" uniqKey="Grange C" first="Claire" last="Grange">Claire Grange</name><affiliation><nlm:aff id="af59"><addr-line>Department of Internal Medicine</addr-line>,<institution>Centre Hospitalier Lyon Sud</institution>,<addr-line>Pierre Benite</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Trad, Georges Selim" sort="Trad, Georges Selim" uniqKey="Trad G" first="Georges-Selim" last="Trad">Georges-Selim Trad</name><affiliation><nlm:aff id="af60"><addr-line>Internal Medecine</addr-line>,<institution>Ambroise Paré Hospital</institution>,<addr-line>Boulogne Billancourt</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Denton, Christopher P" sort="Denton, Christopher P" uniqKey="Denton C" first="Christopher P" last="Denton">Christopher P. Denton</name><affiliation><nlm:aff id="af15"><addr-line>UCL Division of Medicine</addr-line>,<institution>Centre for Rheumatology and Connective Tissue Diseases</institution>,<addr-line>London</addr-line>,<country>UK</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28188239</idno><idno type="pmc">5530354</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530354</idno><idno type="RBID">PMC:5530354</idno><idno type="doi">10.1136/annrheumdis-2016-210503</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">002260</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002260</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)</title><author><name sortKey="Herrick, Ariane L" sort="Herrick, Ariane L" uniqKey="Herrick A" first="Ariane L" last="Herrick">Ariane L. Herrick</name><affiliation><nlm:aff id="af1"><institution>Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation><affiliation><nlm:aff id="af2"><addr-line>NIHR Manchester Musculoskeletal Biomedical Research Unit</addr-line>,<institution>Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Pan, Xiaoyan" sort="Pan, Xiaoyan" uniqKey="Pan X" first="Xiaoyan" last="Pan">Xiaoyan Pan</name><affiliation><nlm:aff id="af3"><institution>Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Peytrignet, Sebastien" sort="Peytrignet, Sebastien" uniqKey="Peytrignet S" first="Sébastien" last="Peytrignet">Sébastien Peytrignet</name><affiliation><nlm:aff id="af3"><institution>Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Lunt, Mark" sort="Lunt, Mark" uniqKey="Lunt M" first="Mark" last="Lunt">Mark Lunt</name><affiliation><nlm:aff id="af3"><institution>Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Hesselstrand, Roger" sort="Hesselstrand, Roger" uniqKey="Hesselstrand R" first="Roger" last="Hesselstrand">Roger Hesselstrand</name><affiliation><nlm:aff id="af4"><addr-line>Department of Rheumatology</addr-line>,<institution>Lund University</institution>,<addr-line>Lund</addr-line>,<country>Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Mouthon, Luc" sort="Mouthon, Luc" uniqKey="Mouthon L" first="Luc" last="Mouthon">Luc Mouthon</name><affiliation><nlm:aff id="af5"><addr-line>Service de Médecine Interne</addr-line>,<institution>Hôpital Cochin, Centre de Référence pour les Vascularites Nécrosantes et la Sclérodermie Systémique, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris (AP-HP)</institution>,<addr-line>Paris</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Silman, Alan" sort="Silman, Alan" uniqKey="Silman A" first="Alan" last="Silman">Alan Silman</name><affiliation><nlm:aff id="af6"><addr-line>Nuffield Department of Orthopaedics</addr-line>,<institution>Rheumatology and Musculoskeletal Sciences,University of Oxford</institution>,<addr-line>Oxford</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Brown, Edith" sort="Brown, Edith" uniqKey="Brown E" first="Edith" last="Brown">Edith Brown</name><affiliation><nlm:aff id="af7"><institution>Member of Steering Committee, contact via Professor Herrick, The University of Manchester</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Czirjak, Laszl" sort="Czirjak, Laszl" uniqKey="Czirjak L" first="Lászl" last="Czirják">Lászl Czirják</name><affiliation><nlm:aff id="af8"><addr-line>Department of Rheumatology and Immunology</addr-line>,<institution>Medical Center, University of Pécs</institution>,<addr-line>Pecs</addr-line>,<country>Hungary</country></nlm:aff></affiliation></author><author><name sortKey="Distler, Jorg H W" sort="Distler, Jorg H W" uniqKey="Distler J" first="Jörg H W" last="Distler">Jörg H W. Distler</name><affiliation><nlm:aff id="af9"><addr-line>Department of Internal Medicine 3</addr-line>,<institution>University of Erlangen-Nuremberg</institution>,<addr-line>Erlangen</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Distler, Oliver" sort="Distler, Oliver" uniqKey="Distler O" first="Oliver" last="Distler">Oliver Distler</name><affiliation><nlm:aff id="af10"><addr-line>Department of Rheumatology</addr-line>,<institution>University of Zurich</institution>,<addr-line>Zurich</addr-line>,<country>Switzerland</country></nlm:aff></affiliation></author><author><name sortKey="Fligelstone, Kim" sort="Fligelstone, Kim" uniqKey="Fligelstone K" first="Kim" last="Fligelstone">Kim Fligelstone</name><affiliation><nlm:aff id="af11"><institution>Royal Free London NHS Foundation Trust</institution>,<addr-line>London</addr-line>,<country>UK</country>.</nlm:aff></affiliation></author><author><name sortKey="Gregory, William J" sort="Gregory, William J" uniqKey="Gregory W" first="William J" last="Gregory">William J. Gregory</name><affiliation><nlm:aff id="af12"><addr-line>Rehabilitation Services</addr-line>,<institution>Salford Royal NHS Foundation Trust</institution>,<addr-line>Salford</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Ochiel, Rachel" sort="Ochiel, Rachel" uniqKey="Ochiel R" first="Rachel" last="Ochiel">Rachel Ochiel</name><affiliation><nlm:aff id="af11"><institution>Royal Free London NHS Foundation Trust</institution>,<addr-line>London</addr-line>,<country>UK</country>.</nlm:aff></affiliation></author><author><name sortKey="Vonk, Madelon" sort="Vonk, Madelon" uniqKey="Vonk M" first="Madelon" last="Vonk">Madelon Vonk</name><affiliation><nlm:aff id="af13"><addr-line>Department of the Rheumatic Diseases</addr-line>,<institution>Radboud University Nijmegen Medical Centre</institution>,<addr-line>Nijmegen</addr-line>,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Ancu A, Codrina" sort="Ancu A, Codrina" uniqKey="Ancu A C" first="Codrina" last="Ancu A">Codrina Ancu A</name><affiliation><nlm:aff id="af14"><addr-line>Rheumatology 2 Department</addr-line>,<institution>“Grigore T. Popa” University of Medicine and Pharmacy, Clinical Rehabilitation Hospital</institution>,<addr-line>Iași</addr-line>,<country>Romania</country></nlm:aff></affiliation></author><author><name sortKey="Ong, Voon H" sort="Ong, Voon H" uniqKey="Ong V" first="Voon H" last="Ong">Voon H. Ong</name><affiliation><nlm:aff id="af15"><addr-line>UCL Division of Medicine</addr-line>,<institution>Centre for Rheumatology and Connective Tissue Diseases</institution>,<addr-line>London</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Farge, Dominique" sort="Farge, Dominique" uniqKey="Farge D" first="Dominique" last="Farge">Dominique Farge</name><affiliation><nlm:aff id="af16"><addr-line>Unité Clinique de Médecine Interne</addr-line>,<institution>Maladies Auto-immunes et Pathologie Vasculaire, UF 04, Hôpital Saint-Louis, AP-HP Assistance Publique des Hôpitaux de Paris, INSERM UMRS 1160, Paris Denis Diderot University,</institution><country>France</country></nlm:aff></affiliation></author><author><name sortKey="Hudson, Marie" sort="Hudson, Marie" uniqKey="Hudson M" first="Marie" last="Hudson">Marie Hudson</name><affiliation><nlm:aff id="af17"><institution>Jewish General Hospital, Lady Davis Institute and McGill University</institution>,<addr-line>Montreal</addr-line>,<country>Canada</country></nlm:aff></affiliation></author><author><name sortKey="Matucci Cerinic, Marco" sort="Matucci Cerinic, Marco" uniqKey="Matucci Cerinic M" first="Marco" last="Matucci-Cerinic">Marco Matucci-Cerinic</name><affiliation><nlm:aff id="af18"><addr-line>Department Experimental and Clinical Medicine, Division of Rheumatology AOUC</addr-line>,<institution>University of Florence</institution>,<addr-line>Florence</addr-line>,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="Balbir Gurman, Alexandra" sort="Balbir Gurman, Alexandra" uniqKey="Balbir Gurman A" first="Alexandra" last="Balbir-Gurman">Alexandra Balbir-Gurman</name><affiliation><nlm:aff id="af19"><addr-line>Shine Rheumatology Unit</addr-line>,<institution>Rambam Heath Care Campus; Rappaport Faculty of Medicine</institution>,<addr-line>Haifa</addr-line>,<country>Israel</country></nlm:aff></affiliation></author><author><name sortKey="Midtvedt, Yvind" sort="Midtvedt, Yvind" uniqKey="Midtvedt " first=" Yvind" last="Midtvedt"> Yvind Midtvedt</name><affiliation><nlm:aff id="af20"><addr-line>Rheumatology Unit</addr-line>,<institution>Oslo University Hospital Rikshospitalet</institution>,<addr-line>Oslo</addr-line>,<country>Norway</country></nlm:aff></affiliation></author><author><name sortKey="Jordan, Alison C" sort="Jordan, Alison C" uniqKey="Jordan A" first="Alison C" last="Jordan">Alison C. Jordan</name><affiliation><nlm:aff id="af21"><institution>Queen Elizabeth Hospital Birmingham, UHB Foundation Trust</institution>,<addr-line>Birmingham</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Jobanputra, Paresh" sort="Jobanputra, Paresh" uniqKey="Jobanputra P" first="Paresh" last="Jobanputra">Paresh Jobanputra</name><affiliation><nlm:aff id="af21"><institution>Queen Elizabeth Hospital Birmingham, UHB Foundation Trust</institution>,<addr-line>Birmingham</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Stevens, Wendy" sort="Stevens, Wendy" uniqKey="Stevens W" first="Wendy" last="Stevens">Wendy Stevens</name><affiliation><nlm:aff id="af22"><institution>St Vincent's Hospital</institution>,<addr-line>Melbourne</addr-line>,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Moinzadeh, Pia" sort="Moinzadeh, Pia" uniqKey="Moinzadeh P" first="Pia" last="Moinzadeh">Pia Moinzadeh</name><affiliation><nlm:aff id="af23"><addr-line>Department for Dermatology</addr-line>,<institution>University of Cologne Kerpenerstr. 62</institution>,<addr-line>Köln</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Hall, Frances C" sort="Hall, Frances C" uniqKey="Hall F" first="Frances C" last="Hall">Frances C. Hall</name><affiliation><nlm:aff id="af24"><institution>Cambridge University NHS Hospital Foundation Trust</institution>,<addr-line>Cambridge</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Agard, Christian" sort="Agard, Christian" uniqKey="Agard C" first="Christian" last="Agard">Christian Agard</name><affiliation><nlm:aff id="af25"><addr-line>Department of Internal Medicine</addr-line>,<institution>Hôtel-Dieu Hospital</institution>,<institution>University of Nantes</institution>,<addr-line>Nantes</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Anderson, Marina E" sort="Anderson, Marina E" uniqKey="Anderson M" first="Marina E" last="Anderson">Marina E. Anderson</name><affiliation><nlm:aff id="af26"><institution>University of Liverpool, Aintree University Hospital</institution>,<addr-line>Liverpool</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Diot, Elisabeth" sort="Diot, Elisabeth" uniqKey="Diot E" first="Elisabeth" last="Diot">Elisabeth Diot</name><affiliation><nlm:aff id="af27"><addr-line>Service de Médecine Interne</addr-line>,<institution>Hôpital Bretonneau Tours</institution><addr-line>Cedex</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Madhok, Rajan" sort="Madhok, Rajan" uniqKey="Madhok R" first="Rajan" last="Madhok">Rajan Madhok</name><affiliation><nlm:aff id="af28"><institution>Centre for Rheumatic Diseases</institution>,<addr-line>Glasgow Royal Infirmary, Glasgow</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Akil, Mohammed" sort="Akil, Mohammed" uniqKey="Akil M" first="Mohammed" last="Akil">Mohammed Akil</name><affiliation><nlm:aff id="af29"><institution>Sheffield Teaching Hospitals</institution>,<addr-line>Sheffield</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Buch, Maya H" sort="Buch, Maya H" uniqKey="Buch M" first="Maya H" last="Buch">Maya H. Buch</name><affiliation><nlm:aff id="af30"><institution>Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust</institution>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Chung, Lorinda" sort="Chung, Lorinda" uniqKey="Chung L" first="Lorinda" last="Chung">Lorinda Chung</name><affiliation><nlm:aff id="af31"><institution>Stanford University</institution>,<addr-line>Stanford, California</addr-line>,<country>USA</country>.</nlm:aff></affiliation></author><author><name sortKey="Damjanov, Nemanja" sort="Damjanov, Nemanja" uniqKey="Damjanov N" first="Nemanja" last="Damjanov">Nemanja Damjanov</name><affiliation><nlm:aff id="af32"><institution>University of Belgrade School of Medicine, Institute of Rheumatology</institution>,<addr-line>Belgrade</addr-line>,<country>Serbia</country></nlm:aff></affiliation></author><author><name sortKey="Gunawardena, Harsha" sort="Gunawardena, Harsha" uniqKey="Gunawardena H" first="Harsha" last="Gunawardena">Harsha Gunawardena</name><affiliation><nlm:aff id="af33"><institution>Clinical and Academic Rheumatology, North Bristol NHS Trust</institution>,<addr-line>Bristol</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Lanyon, Peter" sort="Lanyon, Peter" uniqKey="Lanyon P" first="Peter" last="Lanyon">Peter Lanyon</name><affiliation><nlm:aff id="af34"><institution>Nottingham University Hospitals NHS Trust, and Nottingham NHS Treatment Centre</institution>,<addr-line>Nottingham</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Ahmad, Yasmeen" sort="Ahmad, Yasmeen" uniqKey="Ahmad Y" first="Yasmeen" last="Ahmad">Yasmeen Ahmad</name><affiliation><nlm:aff id="af35"><institution>Peter Maddison Rheumatology Centre</institution>,<addr-line>Llandudno</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Chakravarty, Kuntal" sort="Chakravarty, Kuntal" uniqKey="Chakravarty K" first="Kuntal" last="Chakravarty">Kuntal Chakravarty</name><affiliation><nlm:aff id="af36"><institution>Queens Hospital</institution>,<addr-line>Romford</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Jacobsen, S Ren" sort="Jacobsen, S Ren" uniqKey="Jacobsen S" first="S Ren" last="Jacobsen">S Ren Jacobsen</name><affiliation><nlm:aff id="af37"><institution>University of Copenhagen, Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Rigshospitalet</institution>,<addr-line>Copenhagen</addr-line>,<country>Denmark</country></nlm:aff></affiliation></author><author><name sortKey="Macgregor, Alexander J" sort="Macgregor, Alexander J" uniqKey="Macgregor A" first="Alexander J" last="Macgregor">Alexander J. Macgregor</name><affiliation><nlm:aff id="af38"><institution>Norwich Medical School, University of East Anglia</institution>,<addr-line>Norwich</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Mchugh, Neil" sort="Mchugh, Neil" uniqKey="Mchugh N" first="Neil" last="Mchugh">Neil Mchugh</name><affiliation><nlm:aff id="af39"><institution>Royal National Hospital for Rheumatic Diseases</institution>,<addr-line>Bath</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Muller Ladner, Ulf" sort="Muller Ladner, Ulf" uniqKey="Muller Ladner U" first="Ulf" last="Müller-Ladner">Ulf Müller-Ladner</name><affiliation><nlm:aff id="af40"><addr-line>Department of Rheumatology and Clinical Immunology</addr-line>,<institution>Justus-Liebig University Giessen</institution>,<addr-line>Bad Nauheim</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Riemekasten, Gabriela" sort="Riemekasten, Gabriela" uniqKey="Riemekasten G" first="Gabriela" last="Riemekasten">Gabriela Riemekasten</name><affiliation><nlm:aff id="af41"><addr-line>Department of Rheumatology</addr-line>,<institution>University of Lübeck</institution>,<addr-line>Lübeck</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Becker, Michael" sort="Becker, Michael" uniqKey="Becker M" first="Michael" last="Becker">Michael Becker</name><affiliation><nlm:aff id="af42"><addr-line>Department of Rheumatology and Clinical Immunology</addr-line>,<institution>University Hospital Charité Berlin</institution>,<addr-line>Berlin</addr-line>,<country>Germany</country></nlm:aff></affiliation></author><author><name sortKey="Roddy, Janet" sort="Roddy, Janet" uniqKey="Roddy J" first="Janet" last="Roddy">Janet Roddy</name><affiliation><nlm:aff id="af43"><addr-line>Department of Rheumatology</addr-line>,<institution>Royal Perth Hospital</institution>,<addr-line>Perth</addr-line>,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Carreira, Patricia E" sort="Carreira, Patricia E" uniqKey="Carreira P" first="Patricia E" last="Carreira">Patricia E. Carreira</name><affiliation><nlm:aff id="af44"><institution>Servicio de Reumatologia. Hospital Universitario 12 de Octubre</institution>,<addr-line>Madrid</addr-line>,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Fauchais, Anne Laure" sort="Fauchais, Anne Laure" uniqKey="Fauchais A" first="Anne Laure" last="Fauchais">Anne Laure Fauchais</name><affiliation><nlm:aff id="af45"><addr-line>Internal Medicine Unit</addr-line>,<institution>Limoges University Hospital</institution>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Hachulla, Eric" sort="Hachulla, Eric" uniqKey="Hachulla E" first="Eric" last="Hachulla">Eric Hachulla</name><affiliation><nlm:aff id="af46"><addr-line>Département de Médecine Interne et Immunologie Clinique</addr-line>,<institution>Centre National de Référence Maladies Systémiques etAuto-immunes Rares, Université de Lille, Inserm, U995, FHU Immune-Mediated Inflammatory Diseases and Targeted Therapies,</institution><addr-line>Lille</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Hamilton, Jennifer" sort="Hamilton, Jennifer" uniqKey="Hamilton J" first="Jennifer" last="Hamilton">Jennifer Hamilton</name><affiliation><nlm:aff id="af47"><institution>Gateshead Hospitals Foundation Trust</institution>,<addr-line>Gateshead</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey=" Nanc, Murat" sort=" Nanc, Murat" uniqKey=" Nanc M" first="Murat" last=" Nanç">Murat Nanç</name><affiliation><nlm:aff id="af48"><addr-line>Department of Internal Medicine, Division of Rheumatology</addr-line>,<institution>Istanbul University</institution>,<addr-line>Istanbul</addr-line>,<country>Turkey</country></nlm:aff></affiliation></author><author><name sortKey="Mclaren, John S" sort="Mclaren, John S" uniqKey="Mclaren J" first="John S" last="Mclaren">John S. Mclaren</name><affiliation><nlm:aff id="af49"><addr-line>Fife Rheumatic Diseases Unit</addr-line>,<institution>Whyteman's Brae Hospital</institution>,<addr-line>Kirkcaldy</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Van Laar, Jacob M" sort="Van Laar, Jacob M" uniqKey="Van Laar J" first="Jacob M" last="Van Laar">Jacob M. Van Laar</name><affiliation><nlm:aff id="af50"><addr-line>Department of Rheumatology and Clinical Immunology</addr-line>,<institution>UMC Utrecht</institution>,<addr-line>Utrecht</addr-line>,<country>The Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Pathare, Sanjay" sort="Pathare, Sanjay" uniqKey="Pathare S" first="Sanjay" last="Pathare">Sanjay Pathare</name><affiliation><nlm:aff id="af51"><institution>James Cook University Hospital</institution>,<addr-line>Middlesbrough</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Proudman, Susannah" sort="Proudman, Susannah" uniqKey="Proudman S" first="Susannah" last="Proudman">Susannah Proudman</name><affiliation><nlm:aff id="af52"><addr-line>Rheumatology Unit</addr-line>,<institution>Royal Adelaide Hospital, and Discipline of Medicine, University of Adelaide</institution>,<addr-line>Adelaide</addr-line>,<country>South Australia</country></nlm:aff></affiliation></author><author><name sortKey="Rudin, Anna" sort="Rudin, Anna" uniqKey="Rudin A" first="Anna" last="Rudin">Anna Rudin</name><affiliation><nlm:aff id="af53"><addr-line>Department of Rheumatology and Inflammation Research</addr-line>,<institution>The Sahlgrenska Academy at Gothenburg University</institution>,<addr-line>Gothenburg</addr-line>,<country>Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Sahhar, Joanne" sort="Sahhar, Joanne" uniqKey="Sahhar J" first="Joanne" last="Sahhar">Joanne Sahhar</name><affiliation><nlm:aff id="af54"><institution>Monash Centre for Inflammatory Diseases, Monash University</institution>,<addr-line>Clayton, Melbourne</addr-line>,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Coppere, Brigitte" sort="Coppere, Brigitte" uniqKey="Coppere B" first="Brigitte" last="Coppere">Brigitte Coppere</name><affiliation><nlm:aff id="af55"><addr-line>Department of Internal Medicine</addr-line>,<institution>Hôpital Edouard Herriot</institution>,<addr-line>Lyon</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Serratrice, Christine" sort="Serratrice, Christine" uniqKey="Serratrice C" first="Christine" last="Serratrice">Christine Serratrice</name><affiliation><nlm:aff id="af56"><addr-line>Department of Internal Medicine</addr-line>,<institution>Foundation Hospital Saint Joseph</institution>,<addr-line>Marseille</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Sheeran, Tom" sort="Sheeran, Tom" uniqKey="Sheeran T" first="Tom" last="Sheeran">Tom Sheeran</name><affiliation><nlm:aff id="af57"><institution>Cannock Chase Hospital</institution>,<addr-line>Cannock</addr-line>,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Veale, Douglas J" sort="Veale, Douglas J" uniqKey="Veale D" first="Douglas J" last="Veale">Douglas J. Veale</name><affiliation><nlm:aff id="af58"><institution>St Vincent's University Hospital</institution>,<addr-line>Dublin</addr-line>,<country>Ireland</country></nlm:aff></affiliation></author><author><name sortKey="Grange, Claire" sort="Grange, Claire" uniqKey="Grange C" first="Claire" last="Grange">Claire Grange</name><affiliation><nlm:aff id="af59"><addr-line>Department of Internal Medicine</addr-line>,<institution>Centre Hospitalier Lyon Sud</institution>,<addr-line>Pierre Benite</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Trad, Georges Selim" sort="Trad, Georges Selim" uniqKey="Trad G" first="Georges-Selim" last="Trad">Georges-Selim Trad</name><affiliation><nlm:aff id="af60"><addr-line>Internal Medecine</addr-line>,<institution>Ambroise Paré Hospital</institution>,<addr-line>Boulogne Billancourt</addr-line>,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="Denton, Christopher P" sort="Denton, Christopher P" uniqKey="Denton C" first="Christopher P" last="Denton">Christopher P. Denton</name><affiliation><nlm:aff id="af15"><addr-line>UCL Division of Medicine</addr-line>,<institution>Centre for Rheumatology and Connective Tissue Diseases</institution>,<addr-line>London</addr-line>,<country>UK</country></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="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Objectives</title><p>The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.</p></sec><sec><title>Methods</title><p>This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.</p></sec><sec><title>Results</title><p>Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: −4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months.</p></sec><sec><title>Conclusions</title><p>These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed.</p></sec><sec><title>Trial registration number</title><p>NCT02339441.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Nikpour, M" uniqKey="Nikpour M">M Nikpour</name></author><author><name sortKey="Stevens, Wm" uniqKey="Stevens W">WM Stevens</name></author><author><name sortKey="Herrick, Al" uniqKey="Herrick A">AL Herrick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rubio Rivas, M" uniqKey="Rubio Rivas M">M Rubio-Rivas</name></author><author><name sortKey="Royo, C" uniqKey="Royo C">C Royo</name></author><author><name sortKey="Simeon, Cp" uniqKey="Simeon C">CP Simeon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nihtyanova, Si" uniqKey="Nihtyanova S">SI Nihtyanova</name></author><author><name sortKey="Schreiber, Be" uniqKey="Schreiber B">BE Schreiber</name></author><author><name sortKey="Ong, Vh" uniqKey="Ong V">VH Ong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Merkel, Pa" uniqKey="Merkel P">PA Merkel</name></author><author><name sortKey="Silliman, Np" uniqKey="Silliman N">NP Silliman</name></author><author><name sortKey="Clements, Pj" uniqKey="Clements P">PJ Clements</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Silverman, Sl" uniqKey="Silverman S">SL Silverman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Halpern, Sd" uniqKey="Halpern S">SD Halpern</name></author><author><name sortKey="Karlawish, Jt" uniqKey="Karlawish J">JT Karlawish</name></author><author><name sortKey="Berlin, Ja" uniqKey="Berlin J">JA Berlin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pope, Je" uniqKey="Pope J">JE Pope</name></author><author><name sortKey="Bellamy, N" uniqKey="Bellamy N">N Bellamy</name></author><author><name sortKey="Seibold, Jr" uniqKey="Seibold J">JR Seibold</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Denton, Cp" uniqKey="Denton C">CP Denton</name></author><author><name sortKey="Merkel, Pa" uniqKey="Merkel P">PA Merkel</name></author><author><name sortKey="Furst, De" uniqKey="Furst D">DE Furst</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kowal Bielecka, O" uniqKey="Kowal Bielecka O">O Kowal-Bielecka</name></author><author><name sortKey="Landewe, R" uniqKey="Landewe R">R Landewé</name></author><author><name sortKey="Avouac, J" uniqKey="Avouac J">J Avouac</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rawlins, Md" uniqKey="Rawlins M">MD Rawlins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gagne, J" uniqKey="Gagne J">J Gagne</name></author><author><name sortKey="Thompson, L" uniqKey="Thompson L">L Thompson</name></author><author><name sortKey="O Keefe, K" uniqKey="O Keefe K">K O'Keefe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leroy, Ec" uniqKey="Leroy E">EC LeRoy</name></author><author><name sortKey="Black, C" uniqKey="Black C">C Black</name></author><author><name sortKey="Fleischmajer, R" uniqKey="Fleischmajer R">R Fleischmajer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Clements, P" uniqKey="Clements P">P Clements</name></author><author><name sortKey="Lachenbruch, P" uniqKey="Lachenbruch P">P Lachenbruch</name></author><author><name sortKey="Siebold, J" uniqKey="Siebold J">J Siebold</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Clements, Pj" uniqKey="Clements P">PJ Clements</name></author><author><name sortKey="Hurwitz, El" uniqKey="Hurwitz E">EL Hurwitz</name></author><author><name sortKey="Wong, Wk" uniqKey="Wong W">WK Wong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Steen, Vd" uniqKey="Steen V">VD Steen</name></author><author><name sortKey="Medsger, Ta" uniqKey="Medsger T">TA Medsger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Webster, K" uniqKey="Webster K">K Webster</name></author><author><name sortKey="Cella, D" uniqKey="Cella D">D Cella</name></author><author><name sortKey="Yost, K" uniqKey="Yost K">K Yost</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Harel, D" uniqKey="Harel D">D Harel</name></author><author><name sortKey="Thombs, Bd" uniqKey="Thombs B">BD Thombs</name></author><author><name sortKey="Hudson, M" uniqKey="Hudson M">M Hudson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rannou, F" uniqKey="Rannou F">F Rannou</name></author><author><name sortKey="Poiraudeau, S" uniqKey="Poiraudeau S">S Poiraudeau</name></author><author><name sortKey="Berezne, A" uniqKey="Berezne A">A Berezne</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brookhart, Ma" uniqKey="Brookhart M">MA Brookhart</name></author><author><name sortKey="Schneeweiss, S" uniqKey="Schneeweiss S">S Schneeweiss</name></author><author><name sortKey="Rothman, Kj" uniqKey="Rothman K">KJ Rothman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Austin, Pc" uniqKey="Austin P">PC Austin</name></author><author><name sortKey="Grootendorst, P" uniqKey="Grootendorst P">P Grootendorst</name></author><author><name sortKey="Normand, S Lt" uniqKey="Normand S">S-LT Normand</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sato, T" uniqKey="Sato T">T Sato</name></author><author><name sortKey="Matsuyama, Y" uniqKey="Matsuyama Y">Y Matsuyama</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Imbens, G" uniqKey="Imbens G">G Imbens</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fewell, Z" uniqKey="Fewell Z">Z Fewell</name></author><author><name sortKey="Hernan, Ma" uniqKey="Hernan M">MA Hernan</name></author><author><name sortKey="Wolfe, F" uniqKey="Wolfe F">F Wolfe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cole, Sr" uniqKey="Cole S">SR Cole</name></author><author><name sortKey="Hernan, Ma" uniqKey="Hernan M">MA Hernán</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tashkin, Dp" uniqKey="Tashkin D">DP Tashkin</name></author><author><name sortKey="Elashoff, R" uniqKey="Elashoff R">R Elashoff</name></author><author><name sortKey="Clements, Pj" uniqKey="Clements P">PJ Clements</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tashkin, Dp" uniqKey="Tashkin D">DP Tashkin</name></author><author><name sortKey="Roth, Md" uniqKey="Roth M">MD Roth</name></author><author><name sortKey="Clements, Pj" uniqKey="Clements P">PJ Clements</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Laar, Jm" uniqKey="Van Laar J">JM Van Laar</name></author><author><name sortKey="Farge, D" uniqKey="Farge D">D Farge</name></author><author><name sortKey="Sont, Jk" uniqKey="Sont J">JK Sont</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Herrick, A" uniqKey="Herrick A">A Herrick</name></author><author><name sortKey="Lunt, M" uniqKey="Lunt M">M Lunt</name></author><author><name sortKey="Whidby, N" uniqKey="Whidby N">N Whidby</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Khanna, D" uniqKey="Khanna D">D Khanna</name></author><author><name sortKey="Denton, Cp" uniqKey="Denton C">CP Denton</name></author><author><name sortKey="Jahreis, A" uniqKey="Jahreis A">A Jahreis</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc 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">28188239</article-id><article-id pub-id-type="pmc">5530354</article-id><article-id pub-id-type="publisher-id">annrheumdis-2016-210503</article-id><article-id pub-id-type="doi">10.1136/annrheumdis-2016-210503</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>Extended report</series-title></article-categories><title-group><article-title>Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Herrick</surname><given-names>Ariane L</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Pan</surname><given-names>Xiaoyan</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Peytrignet</surname><given-names>Sébastien</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Lunt</surname><given-names>Mark</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hesselstrand</surname><given-names>Roger</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Mouthon</surname><given-names>Luc</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Silman</surname><given-names>Alan</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Brown</surname><given-names>Edith</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Czirják</surname><given-names>László</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Distler</surname><given-names>Jörg H W</given-names></name><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Distler</surname><given-names>Oliver</given-names></name><xref ref-type="aff" rid="af10">10</xref></contrib><contrib contrib-type="author"><name><surname>Fligelstone</surname><given-names>Kim</given-names></name><xref ref-type="aff" rid="af11">11</xref></contrib><contrib contrib-type="author"><name><surname>Gregory</surname><given-names>William J</given-names></name><xref ref-type="aff" rid="af12">12</xref></contrib><contrib contrib-type="author"><name><surname>Ochiel</surname><given-names>Rachel</given-names></name><xref ref-type="aff" rid="af11">11</xref></contrib><contrib contrib-type="author"><name><surname>Vonk</surname><given-names>Madelon</given-names></name><xref ref-type="aff" rid="af13">13</xref></contrib><contrib contrib-type="author"><name><surname>Ancuţa</surname><given-names>Codrina</given-names></name><xref ref-type="aff" rid="af14">14</xref></contrib><contrib contrib-type="author"><name><surname>Ong</surname><given-names>Voon H</given-names></name><xref ref-type="aff" rid="af15">15</xref></contrib><contrib contrib-type="author"><name><surname>Farge</surname><given-names>Dominique</given-names></name><xref ref-type="aff" rid="af16">16</xref></contrib><contrib contrib-type="author"><name><surname>Hudson</surname><given-names>Marie</given-names></name><xref ref-type="aff" rid="af17">17</xref></contrib><contrib contrib-type="author"><name><surname>Matucci-Cerinic</surname><given-names>Marco</given-names></name><xref ref-type="aff" rid="af18">18</xref></contrib><contrib contrib-type="author"><name><surname>Balbir-Gurman</surname><given-names>Alexandra</given-names></name><xref ref-type="aff" rid="af19">19</xref></contrib><contrib contrib-type="author"><name><surname>Midtvedt</surname><given-names>Øyvind</given-names></name><xref ref-type="aff" rid="af20">20</xref></contrib><contrib contrib-type="author"><name><surname>Jordan</surname><given-names>Alison C</given-names></name><xref ref-type="aff" rid="af21">21</xref></contrib><contrib contrib-type="author"><name><surname>Jobanputra</surname><given-names>Paresh</given-names></name><xref ref-type="aff" rid="af21">21</xref></contrib><contrib contrib-type="author"><name><surname>Stevens</surname><given-names>Wendy</given-names></name><xref ref-type="aff" rid="af22">22</xref></contrib><contrib contrib-type="author"><name><surname>Moinzadeh</surname><given-names>Pia</given-names></name><xref ref-type="aff" rid="af23">23</xref></contrib><contrib contrib-type="author"><name><surname>Hall</surname><given-names>Frances C</given-names></name><xref ref-type="aff" rid="af24">24</xref></contrib><contrib contrib-type="author"><name><surname>Agard</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="af25">25</xref></contrib><contrib contrib-type="author"><name><surname>Anderson</surname><given-names>Marina E</given-names></name><xref ref-type="aff" rid="af26">26</xref></contrib><contrib contrib-type="author"><name><surname>Diot</surname><given-names>Elisabeth</given-names></name><xref ref-type="aff" rid="af27">27</xref></contrib><contrib contrib-type="author"><name><surname>Madhok</surname><given-names>Rajan</given-names></name><xref ref-type="aff" rid="af28">28</xref></contrib><contrib contrib-type="author"><name><surname>Akil</surname><given-names>Mohammed</given-names></name><xref ref-type="aff" rid="af29">29</xref></contrib><contrib contrib-type="author"><name><surname>Buch</surname><given-names>Maya H</given-names></name><xref ref-type="aff" rid="af30">30</xref></contrib><contrib contrib-type="author"><name><surname>Chung</surname><given-names>Lorinda</given-names></name><xref ref-type="aff" rid="af31">31</xref></contrib><contrib contrib-type="author"><name><surname>Damjanov</surname><given-names>Nemanja</given-names></name><xref ref-type="aff" rid="af32">32</xref></contrib><contrib contrib-type="author"><name><surname>Gunawardena</surname><given-names>Harsha</given-names></name><xref ref-type="aff" rid="af33">33</xref></contrib><contrib contrib-type="author"><name><surname>Lanyon</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="af34">34</xref></contrib><contrib contrib-type="author"><name><surname>Ahmad</surname><given-names>Yasmeen</given-names></name><xref ref-type="aff" rid="af35">35</xref></contrib><contrib contrib-type="author"><name><surname>Chakravarty</surname><given-names>Kuntal</given-names></name><xref ref-type="aff" rid="af36">36</xref></contrib><contrib contrib-type="author"><name><surname>Jacobsen</surname><given-names>Søren</given-names></name><xref ref-type="aff" rid="af37">37</xref></contrib><contrib contrib-type="author"><name><surname>MacGregor</surname><given-names>Alexander J</given-names></name><xref ref-type="aff" rid="af38">38</xref></contrib><contrib contrib-type="author"><name><surname>McHugh</surname><given-names>Neil</given-names></name><xref ref-type="aff" rid="af39">39</xref></contrib><contrib contrib-type="author"><name><surname>Müller-Ladner</surname><given-names>Ulf</given-names></name><xref ref-type="aff" rid="af40">40</xref></contrib><contrib contrib-type="author"><name><surname>Riemekasten</surname><given-names>Gabriela</given-names></name><xref ref-type="aff" rid="af41">41</xref></contrib><contrib contrib-type="author"><name><surname>Becker</surname><given-names>Michael</given-names></name><xref ref-type="aff" rid="af42">42</xref></contrib><contrib contrib-type="author"><name><surname>Roddy</surname><given-names>Janet</given-names></name><xref ref-type="aff" rid="af43">43</xref></contrib><contrib contrib-type="author"><name><surname>Carreira</surname><given-names>Patricia E</given-names></name><xref ref-type="aff" rid="af44">44</xref></contrib><contrib contrib-type="author"><name><surname>Fauchais</surname><given-names>Anne Laure</given-names></name><xref ref-type="aff" rid="af45">45</xref></contrib><contrib contrib-type="author"><name><surname>Hachulla</surname><given-names>Eric</given-names></name><xref ref-type="aff" rid="af46">46</xref></contrib><contrib contrib-type="author"><name><surname>Hamilton</surname><given-names>Jennifer</given-names></name><xref ref-type="aff" rid="af47">47</xref></contrib><contrib contrib-type="author"><name><surname>İnanç</surname><given-names>Murat</given-names></name><xref ref-type="aff" rid="af48">48</xref></contrib><contrib contrib-type="author"><name><surname>McLaren</surname><given-names>John S</given-names></name><xref ref-type="aff" rid="af49">49</xref></contrib><contrib contrib-type="author"><name><surname>van Laar</surname><given-names>Jacob M</given-names></name><xref ref-type="aff" rid="af50">50</xref></contrib><contrib contrib-type="author"><name><surname>Pathare</surname><given-names>Sanjay</given-names></name><xref ref-type="aff" rid="af51">51</xref></contrib><contrib contrib-type="author"><name><surname>Proudman</surname><given-names>Susannah</given-names></name><xref ref-type="aff" rid="af52">52</xref></contrib><contrib contrib-type="author"><name><surname>Rudin</surname><given-names>Anna</given-names></name><xref ref-type="aff" rid="af53">53</xref></contrib><contrib contrib-type="author"><name><surname>Sahhar</surname><given-names>Joanne</given-names></name><xref ref-type="aff" rid="af54">54</xref></contrib><contrib contrib-type="author"><name><surname>Coppere</surname><given-names>Brigitte</given-names></name><xref ref-type="aff" rid="af55">55</xref></contrib><contrib contrib-type="author"><name><surname>Serratrice</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="af56">56</xref></contrib><contrib contrib-type="author"><name><surname>Sheeran</surname><given-names>Tom</given-names></name><xref ref-type="aff" rid="af57">57</xref></contrib><contrib contrib-type="author"><name><surname>Veale</surname><given-names>Douglas J</given-names></name><xref ref-type="aff" rid="af58">58</xref></contrib><contrib contrib-type="author"><name><surname>Grange</surname><given-names>Claire</given-names></name><xref ref-type="aff" rid="af59">59</xref></contrib><contrib contrib-type="author"><name><surname>Trad</surname><given-names>Georges-Selim</given-names></name><xref ref-type="aff" rid="af60">60</xref></contrib><contrib contrib-type="author"><name><surname>Denton</surname><given-names>Christopher P</given-names></name><xref ref-type="aff" rid="af15">15</xref></contrib></contrib-group><aff id="af1"><label>1</label><institution>Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></aff><aff id="af2"><label>2</label><addr-line>NIHR Manchester Musculoskeletal Biomedical Research Unit</addr-line>,<institution>Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></aff><aff id="af3"><label>3</label><institution>Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></aff><aff id="af4"><label>4</label><addr-line>Department of Rheumatology</addr-line>,<institution>Lund University</institution>,<addr-line>Lund</addr-line>,<country>Sweden</country></aff><aff id="af5"><label>5</label><addr-line>Service de Médecine Interne</addr-line>,<institution>Hôpital Cochin, Centre de Référence pour les Vascularites Nécrosantes et la Sclérodermie Systémique, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris (AP-HP)</institution>,<addr-line>Paris</addr-line>,<country>France</country></aff><aff id="af6"><label>6</label><addr-line>Nuffield Department of Orthopaedics</addr-line>,<institution>Rheumatology and Musculoskeletal Sciences,University of Oxford</institution>,<addr-line>Oxford</addr-line>,<country>UK</country></aff><aff id="af7"><label>7</label><institution>Member of Steering Committee, contact via Professor Herrick, The University of Manchester</institution>,<addr-line>Manchester</addr-line>,<country>UK</country></aff><aff id="af8"><label>8</label><addr-line>Department of Rheumatology and Immunology</addr-line>,<institution>Medical Center, University of Pécs</institution>,<addr-line>Pecs</addr-line>,<country>Hungary</country></aff><aff id="af9"><label>9</label><addr-line>Department of Internal Medicine 3</addr-line>,<institution>University of Erlangen-Nuremberg</institution>,<addr-line>Erlangen</addr-line>,<country>Germany</country></aff><aff id="af10"><label>10</label><addr-line>Department of Rheumatology</addr-line>,<institution>University of Zurich</institution>,<addr-line>Zurich</addr-line>,<country>Switzerland</country></aff><aff id="af11"><label>11</label><institution>Royal Free London NHS Foundation Trust</institution>,<addr-line>London</addr-line>,<country>UK</country>.</aff><aff id="af12"><label>12</label><addr-line>Rehabilitation Services</addr-line>,<institution>Salford Royal NHS Foundation Trust</institution>,<addr-line>Salford</addr-line>,<country>UK</country></aff><aff id="af13"><label>13</label><addr-line>Department of the Rheumatic Diseases</addr-line>,<institution>Radboud University Nijmegen Medical Centre</institution>,<addr-line>Nijmegen</addr-line>,<country>The Netherlands</country></aff><aff id="af14"><label>14</label><addr-line>Rheumatology 2 Department</addr-line>,<institution>“Grigore T. Popa” University of Medicine and Pharmacy, Clinical Rehabilitation Hospital</institution>,<addr-line>Iași</addr-line>,<country>Romania</country></aff><aff id="af15"><label>15</label><addr-line>UCL Division of Medicine</addr-line>,<institution>Centre for Rheumatology and Connective Tissue Diseases</institution>,<addr-line>London</addr-line>,<country>UK</country></aff><aff id="af16"><label>16</label><addr-line>Unité Clinique de Médecine Interne</addr-line>,<institution>Maladies Auto-immunes et Pathologie Vasculaire, UF 04, Hôpital Saint-Louis, AP-HP Assistance Publique des Hôpitaux de Paris, INSERM UMRS 1160, Paris Denis Diderot University,</institution><country>France</country></aff><aff id="af17"><label>17</label><institution>Jewish General Hospital, Lady Davis Institute and McGill University</institution>,<addr-line>Montreal</addr-line>,<country>Canada</country></aff><aff id="af18"><label>18</label><addr-line>Department Experimental and Clinical Medicine, Division of Rheumatology AOUC</addr-line>,<institution>University of Florence</institution>,<addr-line>Florence</addr-line>,<country>Italy</country></aff><aff id="af19"><label>19</label><addr-line>Shine Rheumatology Unit</addr-line>,<institution>Rambam Heath Care Campus; Rappaport Faculty of Medicine</institution>,<addr-line>Haifa</addr-line>,<country>Israel</country></aff><aff id="af20"><label>20</label><addr-line>Rheumatology Unit</addr-line>,<institution>Oslo University Hospital Rikshospitalet</institution>,<addr-line>Oslo</addr-line>,<country>Norway</country></aff><aff id="af21"><label>21</label><institution>Queen Elizabeth Hospital Birmingham, UHB Foundation Trust</institution>,<addr-line>Birmingham</addr-line>,<country>UK</country></aff><aff id="af22"><label>22</label><institution>St Vincent's Hospital</institution>,<addr-line>Melbourne</addr-line>,<country>Australia</country></aff><aff id="af23"><label>23</label><addr-line>Department for Dermatology</addr-line>,<institution>University of Cologne Kerpenerstr. 62</institution>,<addr-line>Köln</addr-line>,<country>Germany</country></aff><aff id="af24"><label>24</label><institution>Cambridge University NHS Hospital Foundation Trust</institution>,<addr-line>Cambridge</addr-line>,<country>UK</country></aff><aff id="af25"><label>25</label><addr-line>Department of Internal Medicine</addr-line>,<institution>Hôtel-Dieu Hospital</institution>,<institution>University of Nantes</institution>,<addr-line>Nantes</addr-line>,<country>France</country></aff><aff id="af26"><label>26</label><institution>University of Liverpool, Aintree University Hospital</institution>,<addr-line>Liverpool</addr-line>,<country>UK</country></aff><aff id="af27"><label>27</label><addr-line>Service de Médecine Interne</addr-line>,<institution>Hôpital Bretonneau Tours</institution><addr-line>Cedex</addr-line>,<country>France</country></aff><aff id="af28"><label>28</label><institution>Centre for Rheumatic Diseases</institution>,<addr-line>Glasgow Royal Infirmary, Glasgow</addr-line>,<country>UK</country></aff><aff id="af29"><label>29</label><institution>Sheffield Teaching Hospitals</institution>,<addr-line>Sheffield</addr-line>,<country>UK</country></aff><aff id="af30"><label>30</label><institution>Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust</institution>,<country>UK</country></aff><aff id="af31"><label>31</label><institution>Stanford University</institution>,<addr-line>Stanford, California</addr-line>,<country>USA</country>.</aff><aff id="af32"><label>32</label><institution>University of Belgrade School of Medicine, Institute of Rheumatology</institution>,<addr-line>Belgrade</addr-line>,<country>Serbia</country></aff><aff id="af33"><label>33</label><institution>Clinical and Academic Rheumatology, North Bristol NHS Trust</institution>,<addr-line>Bristol</addr-line>,<country>UK</country></aff><aff id="af34"><label>34</label><institution>Nottingham University Hospitals NHS Trust, and Nottingham NHS Treatment Centre</institution>,<addr-line>Nottingham</addr-line>,<country>UK</country></aff><aff id="af35"><label>35</label><institution>Peter Maddison Rheumatology Centre</institution>,<addr-line>Llandudno</addr-line>,<country>UK</country></aff><aff id="af36"><label>36</label><institution>Queens Hospital</institution>,<addr-line>Romford</addr-line>,<country>UK</country></aff><aff id="af37"><label>37</label><institution>University of Copenhagen, Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Rigshospitalet</institution>,<addr-line>Copenhagen</addr-line>,<country>Denmark</country></aff><aff id="af38"><label>38</label><institution>Norwich Medical School, University of East Anglia</institution>,<addr-line>Norwich</addr-line>,<country>UK</country></aff><aff id="af39"><label>39</label><institution>Royal National Hospital for Rheumatic Diseases</institution>,<addr-line>Bath</addr-line>,<country>UK</country></aff><aff id="af40"><label>40</label><addr-line>Department of Rheumatology and Clinical Immunology</addr-line>,<institution>Justus-Liebig University Giessen</institution>,<addr-line>Bad Nauheim</addr-line>,<country>Germany</country></aff><aff id="af41"><label>41</label><addr-line>Department of Rheumatology</addr-line>,<institution>University of Lübeck</institution>,<addr-line>Lübeck</addr-line>,<country>Germany</country></aff><aff id="af42"><label>42</label><addr-line>Department of Rheumatology and Clinical Immunology</addr-line>,<institution>University Hospital Charité Berlin</institution>,<addr-line>Berlin</addr-line>,<country>Germany</country></aff><aff id="af43"><label>43</label><addr-line>Department of Rheumatology</addr-line>,<institution>Royal Perth Hospital</institution>,<addr-line>Perth</addr-line>,<country>Australia</country></aff><aff id="af44"><label>44</label><institution>Servicio de Reumatologia. Hospital Universitario 12 de Octubre</institution>,<addr-line>Madrid</addr-line>,<country>Spain</country></aff><aff id="af45"><label>45</label><addr-line>Internal Medicine Unit</addr-line>,<institution>Limoges University Hospital</institution>,<country>France</country></aff><aff id="af46"><label>46</label><addr-line>Département de Médecine Interne et Immunologie Clinique</addr-line>,<institution>Centre National de Référence Maladies Systémiques etAuto-immunes Rares, Université de Lille, Inserm, U995, FHU Immune-Mediated Inflammatory Diseases and Targeted Therapies,</institution><addr-line>Lille</addr-line>,<country>France</country></aff><aff id="af47"><label>47</label><institution>Gateshead Hospitals Foundation Trust</institution>,<addr-line>Gateshead</addr-line>,<country>UK</country></aff><aff id="af48"><label>48</label><addr-line>Department of Internal Medicine, Division of Rheumatology</addr-line>,<institution>Istanbul University</institution>,<addr-line>Istanbul</addr-line>,<country>Turkey</country></aff><aff id="af49"><label>49</label><addr-line>Fife Rheumatic Diseases Unit</addr-line>,<institution>Whyteman's Brae Hospital</institution>,<addr-line>Kirkcaldy</addr-line>,<country>UK</country></aff><aff id="af50"><label>50</label><addr-line>Department of Rheumatology and Clinical Immunology</addr-line>,<institution>UMC Utrecht</institution>,<addr-line>Utrecht</addr-line>,<country>The Netherlands</country></aff><aff id="af51"><label>51</label><institution>James Cook University Hospital</institution>,<addr-line>Middlesbrough</addr-line>,<country>UK</country></aff><aff id="af52"><label>52</label><addr-line>Rheumatology Unit</addr-line>,<institution>Royal Adelaide Hospital, and Discipline of Medicine, University of Adelaide</institution>,<addr-line>Adelaide</addr-line>,<country>South Australia</country></aff><aff id="af53"><label>53</label><addr-line>Department of Rheumatology and Inflammation Research</addr-line>,<institution>The Sahlgrenska Academy at Gothenburg University</institution>,<addr-line>Gothenburg</addr-line>,<country>Sweden</country></aff><aff id="af54"><label>54</label><institution>Monash Centre for Inflammatory Diseases, Monash University</institution>,<addr-line>Clayton, Melbourne</addr-line>,<country>Australia</country></aff><aff id="af55"><label>55</label><addr-line>Department of Internal Medicine</addr-line>,<institution>Hôpital Edouard Herriot</institution>,<addr-line>Lyon</addr-line>,<country>France</country></aff><aff id="af56"><label>56</label><addr-line>Department of Internal Medicine</addr-line>,<institution>Foundation Hospital Saint Joseph</institution>,<addr-line>Marseille</addr-line>,<country>France</country></aff><aff id="af57"><label>57</label><institution>Cannock Chase Hospital</institution>,<addr-line>Cannock</addr-line>,<country>UK</country></aff><aff id="af58"><label>58</label><institution>St Vincent's University Hospital</institution>,<addr-line>Dublin</addr-line>,<country>Ireland</country></aff><aff id="af59"><label>59</label><addr-line>Department of Internal Medicine</addr-line>,<institution>Centre Hospitalier Lyon Sud</institution>,<addr-line>Pierre Benite</addr-line>,<country>France</country></aff><aff id="af60"><label>60</label><addr-line>Internal Medecine</addr-line>,<institution>Ambroise Paré Hospital</institution>,<addr-line>Boulogne Billancourt</addr-line>,<country>France</country></aff><author-notes><fn><p><bold>Handling editor</bold> Tore K Kvien</p></fn><corresp><label>Correspondence to</label> Professor Ariane Herrick, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9PT, UK; <email>ariane.herrick@manchester.ac.uk</email></corresp></author-notes><pub-date pub-type="ppub"><month>7</month><year>2017</year></pub-date><pub-date pub-type="epub"><day>9</day><month>6</month><year>2017</year></pub-date><volume>76</volume><issue>7</issue><fpage>1207</fpage><lpage>1218</lpage><history><date date-type="received"><day>12</day><month>9</month><year>2016</year></date><date date-type="rev-recd"><day>24</day><month>11</month><year>2016</year></date><date date-type="accepted"><day>25</day><month>11</month><year>2016</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://www.bmj.com/company/products-services/rights-and-licensing/</copyright-statement><copyright-year>2017</copyright-year><license license-type="open-access"><license-p>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 and the use is non-commercial. See: <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">http://creativecommons.org/licenses/by-nc/4.0/</ext-link></license-p></license></permissions><self-uri xlink:title="pdf" xlink:href="annrheumdis-2016-210503.pdf"></self-uri><abstract><sec><title>Objectives</title><p>The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.</p></sec><sec><title>Methods</title><p>This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.</p></sec><sec><title>Results</title><p>Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: −4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months.</p></sec><sec><title>Conclusions</title><p>These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed.</p></sec><sec><title>Trial registration number</title><p>NCT02339441.</p></sec></abstract><kwd-group><kwd>Systemic Sclerosis</kwd><kwd>Treatment</kwd><kwd>Cyclophosphamide</kwd><kwd>Methotrexate</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 sec-type="intro" id="s1"><title>Introduction</title><p>The diffuse cutaneous subtype of systemic sclerosis (dcSSc) is rare (SSc incidence is around 10–20/million/year,<xref rid="R1" ref-type="bibr">1</xref> of whom approximately 25% will have diffuse disease) but carries high morbidity and mortality due to early internal organ involvement and rapidly progressive, painful skin thickening. Also, 5-year and 10-year survival rates, although improving, are in the order of 68% and 50%, respectively.<xref rid="R2" ref-type="bibr">2</xref><xref rid="R3" ref-type="bibr">3</xref></p><p>At present, there is no drug known to favourably influence disease course. Randomised controlled trials (RCTs) have historically been confounded by disease rarity (only small numbers of patients are recruited, often over long periods) and strict entry criteria meaning that severe cases are often excluded.<xref rid="R4" ref-type="bibr">4</xref> These strict criteria further restrict sample sizes and limit generalisability. Therefore, although RCTs represent a gold standard for assessing drug efficacy, results may not be applicable to real-life clinical settings.<xref rid="R5" ref-type="bibr">5</xref> Small trials run the risk of being underpowered, thus potentially yielding false-negative results.<xref rid="R6" ref-type="bibr">6</xref> The past three decades have seen a number of promising treatments for early dcSSc failing to meet efficacy end points in RCTs: examples include methotrexate (multinational, 71 patients)<xref rid="R7" ref-type="bibr">7</xref> and anti-transforming growth factor β1 antibody therapy (multinational, 45 patients).<xref rid="R8" ref-type="bibr">8</xref></p><p>A further difficulty in recruiting into RCTs of early dcSSc is that many clinicians have reservations about placebo therapy in a potentially life-threatening disease and favour immunosuppression, consistent with the European League Against Rheumatism (EULAR) recommendations, which advocate methotrexate for skin manifestations<xref rid="R9" ref-type="bibr">9</xref> in early dcSSc, although this agent has been shown to be of only limited efficacy.<xref rid="R7" ref-type="bibr">7</xref> Immunosuppressants are potentially hazardous, especially in patients prone to internal organ disease and infection.</p><p>Against this background, our aim was to compare, using an observational approach, the effectiveness of standard treatment approaches (mainly immunosuppressant treatments but including a ‘no immunosuppressant’ option to reflect that some patients or clinicians may choose this approach) in the early management of patients with dcSSc, capturing entry and outcome data in a systematic way. Modern statistical approaches allow robust interrogations of prospective observational studies, as an adjunct to, or even substitute for, RCTs in rare diseases,<xref rid="R10" ref-type="bibr">10</xref> although the potential of these novel approaches has not yet been realised.<xref rid="R11" ref-type="bibr">11</xref></p></sec><sec sec-type="methods" id="s2"><title>Methods</title><sec id="s2a"><title>Study design</title><p>The European Scleroderma Observational Study (ESOS) was a prospective, observational cohort study (ClinicalTrials.gov identifier: NCT02339441), in which standardised data were collected at study entry and at follow-up visits, and entered electronically by investigators at each centre into an electronic case record form. All data were checked by the project coordinator and any inconsistencies were discussed with the chief investigator and (if appropriate) the local principal investigator. The main inclusion criteria were early dcSSc (skin involvement proximal to elbow, knee, face, neck<xref rid="R12" ref-type="bibr">12</xref> and within three years of the onset of skin thickening) and age >18 years. Exclusion criteria were previous stem cell transplantation, previous immunosuppressant treatment for >4 months or use of any immunosuppressant drug other than methotrexate, mycophenolate mofetil (MMF) or cyclophosphamide within the month prior to study entry.</p><p>Clinicians selected the protocol of their choice for each patient. The recommended treatment protocols, as decided by the Steering Committee to reflect international best clinical practice, were
<list list-type="order"><list-item><p>Methotrexate (oral or subcutaneous with a target dose of 20–25 mg weekly).</p></list-item><list-item><p>MMF (500 mg twice daily for 2 weeks increasing to 1 g twice daily).</p></list-item><list-item><p>Cyclophosphamide.</p><p>Possible regimens included:</p><list list-type="roman-lower"><list-item><p>Intravenous. Minimum monthly dose 500 mg/m<sup>2</sup> with a recommended duration of 6–12 months.</p></list-item><list-item><p>Oral. 1–2 mg/kg/day with a recommended duration of 12 months. Patients treated with cyclophosphamide were then usually ‘transferred’ to a maintenance immunosuppressive drug (methotrexate, MMF or azathioprine) as per the treating clinician's choice.</p></list-item></list></list-item><list-item><p>No immunosuppressant treatment, to give the option of including patients in whom immunosuppression was not felt indicated or appropriate (or declined by the patient).</p></list-item></list></p><p>Patients were assessed at baseline, with subsequent visits scheduled three-monthly for 24 months (or between 12 and 24 months for those patients recruited after September 2013).</p><p>To have 80% power to detect a difference between two treatment arms of five modified Rodnan skin score (mRSS) units at 12 months would require 63 patients per protocol. Allowing 20% loss to follow-up, and varying numbers recruited to the different protocols, recruitment target was 316 patients.</p></sec><sec id="s2b"><title>Patients</title><p>Patients were recruited between July 2010 and September 2014. Demographic characteristics including age, gender, smoking habit, ethnicity, antibody status (anti-topoisomerase-1 (anti-Scl70), anti-RNA III polymerase, anticentromere) and presence of visceral organ involvement were recorded for all patients. The algorithms to determine the presence of different types of organ involvement are summarised in online <xref ref-type="supplementary-material" rid="SM1">supplementary table</xref> S1.</p><supplementary-material content-type="local-data" id="SM1"><object-id pub-id-type="doi">10.1136/annrheumdis-2016-210503.supp1</object-id><label>Supplementary tables</label><p><inline-supplementary-material id="ss1" mimetype="application" mime-subtype="pdf" xlink:href="annrheumdis-2016-210503supp001.pdf" content-type="local-data"></inline-supplementary-material></p></supplementary-material></sec><sec id="s2c"><title>Outcome measures</title><p>The primary outcome measure, assessed at each visit, was the change in mRSS over time. All mRSS assessments were performed by those experienced in skin scoring. The mRSS is assessed clinically at 17 body sites on a 0–3 scale (maximum score 51) and measures the extent of skin thickening.<xref rid="R13" ref-type="bibr">13</xref> It is the most commonly used primary outcome measure in RCTs of dcSSc,<xref rid="R4" ref-type="bibr">4</xref><xref rid="R7" ref-type="bibr">7</xref><xref rid="R8" ref-type="bibr">8</xref> reflecting disease severity and predicting mortality.<xref rid="R14" ref-type="bibr">14</xref> All other outcomes/recorded variables were mainly part of routine clinical practice and are summarised in online <xref ref-type="supplementary-material" rid="SM1">supplementary table</xref> S2. Secondary end points included pulmonary function (forced vital capacity (FVC: % predicted) and carbon monoxide diffusing capacity (DLCO: % predicted)), quality of life<xref rid="R15" ref-type="bibr">15–18</xref> (including the Health Assessment Questionnaire Disability Index (HAQ-DI)<xref rid="R15" ref-type="bibr">15</xref> and Cochin Hand Function Scale<xref rid="R18" ref-type="bibr">18</xref>), occurrence of side effects and survival.</p></sec><sec id="s2d"><title>Statistical analysis</title><p>In an observational study, patient characteristics differ between groups and any differences in outcomes might be driven by those characteristics rather than the treatments (confounding by indication). In each of the analyses (for the different outcome measures), all variables associated with the outcome were considered as confounders.<xref rid="R19" ref-type="bibr">19</xref><xref rid="R20" ref-type="bibr">20</xref></p><sec id="s2d1"><title>Differences between protocols at baseline</title><p>Kruskal-Wallis test was applied for continuous variables and Fisher's test for categorical variables.</p></sec><sec id="s2d2"><title>Influence of baseline characteristics on mRSS at baseline and over time</title><p>The association between baseline variables and mRSS was assessed by simple linear regressions, entering each characteristic separately as a predictor of mRSS. To examine how each variable affected the progression of mRSS, the regression equation was modified by adding a term for time and its interaction with the baseline predictor value.</p></sec><sec id="s2d3"><title>Differences in the changes between groups for all outcomes</title><p>Inverse probability of treatment (IPT) weights equalise the distributions of confounders between the treatment groups, thus removing confounding by indication.<xref rid="R21" ref-type="bibr">21</xref> Treatment probabilities were computed using multinomial logistic regressions, with the baseline values of the selected confounders as predictors.<xref rid="R22" ref-type="bibr">22</xref> Censoring weights rebalance the data such that the distributions of confounders remain unchanged throughout the study. For each observation, the probability of remaining uncensored given the baseline values of the confounders, the initial protocol and a cubic spline for time was calculated using a pooled logistic regression model.<xref rid="R23" ref-type="bibr">23</xref> Multiplying both weights yielded the IPT and inverse probability of censoring (IPTC) weights. Weights >20 were truncated at that value.<xref rid="R24" ref-type="bibr">24</xref></p><p>Treatment effects were assessed using IPTC-weighted linear regression models, which include an intercept, a time term, indicator variables for treatment groups and interactions between time and treatments. The model followed an intention-to-treat approach. Differences in the interaction terms reflected differences in the evolution of outcome.</p><p>Cochin hand function data were log-transformed (after adding one to each value) to correct for a highly left-skewed distribution. CIs for the difference of logs were back-transformed, yielding a percentage difference between predicted baseline and 12-month levels.</p><p>Because of missing data at baseline for confounders, multiple imputation by chained equations was applied with STATA V.13.1. Imputations were performed separately for each different outcome model. Moreover, each analysis was restricted to the subset of patients with available outcome data at baseline.</p></sec><sec id="s2d4"><title>Survival analysis</title><p>Kaplan-Meier curves, adjusted using IPT weights, provide estimates of the cumulative probability of surviving in each of the protocols. An IPT-weighted Cox regression, including indicator variables for the protocols, was used to test for differences in survival between protocols. Both overall and adverse event-free survival were examined.</p></sec></sec></sec><sec sec-type="results" id="s3"><title>Results</title><p>In total, 326 patients from 50 centres (19 countries) were recruited into the study (<xref ref-type="fig" rid="ANNRHEUMDIS2016210503F1">figure 1</xref>): 160 from mainland Europe and the Middle East, 134 from the UK, 15 from Australia and 17 from North America (six centres from Australia and North America joined after the initial recruitment wave). Not being a randomised study, the number of patients starting on each protocol differed: 65 (19.9%) methotrexate, 118 (36.2%) MMF, 87 (26.7%) cyclophosphamide and 56 (17.2%) no immunosuppressant treatment. Median (IQR) doses are shown in online <xref ref-type="supplementary-material" rid="SM1">supplementary table</xref> S3.</p><fig id="ANNRHEUMDIS2016210503F1" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Progression of patients through the study.</p></caption><graphic xlink:href="annrheumdis-2016-210503f01"></graphic></fig><sec id="s3a"><title>Baseline characteristics of patients</title><p>The median mRSS (21, IQR 16–27) and its distribution did not differ across all four treatment groups (p=0.306) (<xref ref-type="table" rid="ANNRHEUMDIS2016210503TB1">table 1</xref>). There were significant differences between treatment groups in gender (patients in the cyclophosphamide group less likely to be female, p=0.003) and duration of skin thickening (the ‘no immunosuppressant’ group had the longest, p=0.001). Also, patients in the cyclophosphamide group were more likely to have had previous immunosuppression (p=0.007) or steroid treatment (p=0.001). At baseline, 94 (28.8%) patients were taking oral corticosteroids, with a median dose of 10 mg/day (range 2.5–60 mg/day).</p><table-wrap id="ANNRHEUMDIS2016210503TB1" orientation="portrait" position="float"><label>Table 1</label><caption><p>Baseline characteristics and differences between protocols</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col></colgroup><tbody><tr><td rowspan="1" colspan="1"><inline-graphic xlink:href="annrheumdis-2016-210503t01a.jpg"></inline-graphic><inline-graphic xlink:href="annrheumdis-2016-210503t01b.jpg"></inline-graphic></td></tr></tbody></table><table-wrap-foot><fn><p>Median (IQR) unless otherwise indicated.</p></fn><fn><p>*p indicates significance of Kruskal-Wallis test (for continuous variables) or Fisher's exact test (for categorical variables).</p></fn><fn><p>†Of the 26 patients who had previously received immunosuppressant therapy, in 2 patients this was for cancer.</p></fn><fn><p>‡86 patients had a sPAP/RVSP value assumed to be normal and thus not measured. If those cases are omitted, only 38 values of sPAP/RVSP are missing (11.7%). Median values are ‘falsely’ high because calculation omits unmeasured (normal) values.</p></fn><fn><p>§Renal involvement is defined as renal crisis and/or moderate-to-severe renal impairment.</p></fn><fn><p>¶Despite the significant p-value for the Kruskal-Wallis test, post hoc tests reject any between-group differences in the SF36 mental scores.</p></fn><fn><p>** Cochin hand function scores were not performed in all centres because of translational issues.</p></fn><fn><p>CRP, C reactive protein; DLCO, carbon monoxide diffusing capacity; eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate; FACIT, Functional Assessment of Chronic Illness Therapy; FVC, forced vital capacity; GI, gastrointestinal; HAQ-DI, Health Assessment Questionnaire Disability Index; mRSS, modified Rodnan skin score (17 sites); RVSP, right ventricular systolic pressure; SF36, Short-Form 36; sPAP, systolic pulmonary artery pressure.</p></fn></table-wrap-foot></table-wrap><sec id="s3a1"><title>Organ involvement</title><p>There were significant differences between groups for presence of pulmonary fibrosis, cardiac, renal and muscle involvement. Patients on cyclophosphamide were more likely to have pulmonary fibrosis (p=0.036 across groups) or cardiac involvement (p=0.009 across groups). Patients in the ‘no immunosuppressant’ group were more likely to have renal involvement (p=0.039), and the methotrexate group had more frequent muscle involvement (p=0.002).</p></sec><sec id="s3a2"><title>Functional ability</title><p>Scores for the HAQ-DI, Functional Assessment of Chronic Illness Therapy (FACIT) fatigue and Short-Form 36 (SF36) physical and mental indexes did not differ significantly between groups. However, there were significant differences across groups in the cochin hand function scale (CHFS), which was poorest in the cyclophosphamide group (p=0.025).</p></sec><sec id="s3a3"><title>Concomitant medications</title><p>As anticipated in a study of patients with early dcSSc, there was substantial use of concomitant medications (see online <xref ref-type="supplementary-material" rid="SM1">supplementary table</xref> S4).</p></sec></sec><sec id="s3b"><title>Progression through the study</title><p><xref ref-type="fig" rid="ANNRHEUMDIS2016210503F1">Figure 1</xref> shows how patients progressed through the study. Overall, 276 patients (84.7%) remained in the study at 12 months of follow-up and 234 (71.7%) completed 24 months (or reached the last study visit date of 30 September 2015).</p><sec id="s3b1"><title>Changes in protocol</title><p>A total of 60 (18.4%), 12 (3.7%) and 1 (0.3%) patients changed protocol one, two or three times during the study. Among patients still in the study, adherence to initial protocol at 24 months for the different cohorts was 76.2% (methotrexate), 79.7% (MMF), 79.2% (cyclophosphamide) and 73.3% (no immunosuppressant) (see online <xref ref-type="supplementary-material" rid="SM2">supplementary figure</xref> S1). In the no immunosuppressant cohort, 10 out of 56 patients commenced an immunosuppressant (<xref ref-type="fig" rid="ANNRHEUMDIS2016210503F1">figure 1</xref>).</p><supplementary-material content-type="local-data" id="SM2"><object-id pub-id-type="doi">10.1136/annrheumdis-2016-210503.supp2</object-id><label>Supplementary figures</label><p><inline-supplementary-material id="ss2" mimetype="application" mime-subtype="pdf" xlink:href="annrheumdis-2016-210503supp002.pdf" content-type="local-data"></inline-supplementary-material></p></supplementary-material></sec><sec id="s3b2"><title>Withdrawals and deaths</title><p>In total, 35 patients (10.7%) died and 42 (12.9%) withdrew from the study (including lost to follow-up). Of the 35 deceased patients, 31 cases were primarily attributed to SSc-related causes (26 most likely primarily cardiorespiratory, 2 renal crises, 2 gastrointestinal (one aspiration) and 1 peritonitis (on peritoneal dialysis following renal crisis)), 3 died of cancer (1 nasopharyngeal, 1 rectal, 1 colorectal) and in 1 case the cause was unknown.</p></sec></sec><sec id="s3c"><title>Influence of baseline variables on the initial skin score and on skin score trajectory</title><p><xref ref-type="table" rid="ANNRHEUMDIS2016210503TB2">Table 2</xref> summarises the effect of different characteristics on the initial mRSS and its subsequent trajectory, as analysed with linear regression.</p><p>Using the associations described by <xref ref-type="table" rid="ANNRHEUMDIS2016210503TB2">table 2</xref>, the confounders identified for the skin score were age, duration of skin thickening, current or previous steroid use, anti-topoisomerase, anti-RNA polymerase III, pulmonary fibrosis, pulmonary hypertension, cardiac, renal and muscle involvement, as well as HAQ-DI, Cochin hand function and FACIT fatigue scores (see online <xref ref-type="supplementary-material" rid="SM1">supplementary table</xref> S5 for lists of confounders and online <xref ref-type="supplementary-material" rid="SM1">supplementary table</xref>s S6– S13 for each model's confounder selection process).</p><table-wrap id="ANNRHEUMDIS2016210503TB2" orientation="portrait" position="float"><label>Table 2</label><caption><p>Associations between baseline characteristics and skin score</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col></colgroup><tbody><tr><td rowspan="1" colspan="1"><inline-graphic xlink:href="annrheumdis-2016-210503t02.jpg"></inline-graphic></td></tr></tbody></table><table-wrap-foot><fn><p>Example for interpretation of results: the presence of anti-RNA polymerase III is associated with (A) a higher mRSS by 4.5 units at baseline and (B) losing an extra 2.1 units per year compared with an average of −3.0 units per year for all patients.</p></fn><fn><p>*Renal involvement is defined as renal crisis and/or moderate-to-severe renal impairment.</p></fn><fn><p>p<sup>(1)</sup>: Significance p value for characteristic coefficient in linear regression of baseline mRSS on baseline predictor.</p></fn><fn><p>p<sup>(2)</sup>: Significance p value for interaction coefficient between time and baseline characteristic in a longitudinal regression model.</p></fn><fn><p>CRP, C reactive protein; DLCO, carbon monoxide diffusing capacity; ESR, erythrocyte sedimentation rate; FACIT, Functional Assessment of Chronic Illness Therapy; FVC, forced vital capacity; GI, gastrointestinal; HAQ-DI, Health Assessment Questionnaire Disability Index; mRSS, modified Rodnan skin score (17 sites); SF36, Short-Form 36.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3d"><title>Changes in skin score over time in the different treatment groups</title><p>The mean change in mRSS after 12 and 24 months was −2.9 and −6.7 units. Based on a weighted regression model, there were statistically significant reductions in mRSS in all four treatment groups at 12 months (−4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for the no immunosuppressant group), but the differences between treatments were not significant (p=0.346) (<xref ref-type="table" rid="ANNRHEUMDIS2016210503TB3">table 3</xref> and <xref ref-type="fig" rid="ANNRHEUMDIS2016210503F2">figure 2</xref>).</p><table-wrap id="ANNRHEUMDIS2016210503TB3" orientation="portrait" position="float"><label>Table 3</label><caption><p>Predicted yearly changes in outcomes and survival rates according to initial protocol, with and without adjusting (95% CI)</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col></colgroup><tbody><tr><td rowspan="1" colspan="1"><inline-graphic xlink:href="annrheumdis-2016-210503t03.jpg"></inline-graphic></td></tr></tbody></table><table-wrap-foot><fn><p>Significance p: Fisher's test for equality of change rates between protocols, for each outcome variable.</p></fn><fn><p>*Results are reported in terms of changes after 12 months. However, all study data (from baseline to the 24-month end point) were used in estimation. To obtain 24-month changes, multiply results above by 2.</p></fn><fn><p>†For the subanalysis involving the subset of patients with pulmonary fibrosis at baseline, patients with definite bibasal pulmonary fibrosis confirmed on HRCT were included, irrespective of FVC value. If no HRCT scan was performed at baseline, an FVC<55%, DLCO<55% predicted or definite bibasal shadowing on X-ray was also a basis for inclusion.</p></fn><fn><p>‡Changes expressed in units for the Cochin regression are an approximation derived from the 95% CI of percentage changes between baseline and 12 months (on a scale shifted by one unit), applied to the predicted baseline values for each group in the original scale.</p></fn><fn><p>DLCO, carbon monoxide diffusing capacity; FVC, forced vital capacity; HAQ-DI, Health Assessment Questionnaire Disability Index; HRCT, high-resolution CT; mRSS, modified Rodnan skin score (17 sites); PF, pulmonary fibrosis.</p></fn></table-wrap-foot></table-wrap><fig id="ANNRHEUMDIS2016210503F2" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Modified Rodnan skin score (mRSS) during baseline and follow-up visits, by initial protocol. For each group of patients, according to their initial protocol, the distribution of the skin score is illustrated on the left-hand side by box and whisker plots (indicating the median and IQR) at baseline, 12 and 24 months. On the right-hand side, the distribution of individual 1-year changes in the skin score is described by histograms and a kernel density estimate. In addition, a vertical green line indicates the value of the average 1-year change in the skin score, irrespective of treatment choice. The bottom panel in the figure describes the estimated changes in mRSS (with 95% CI) according to initial protocol, based on the results from the adjusted model (described in <xref ref-type="table" rid="ANNRHEUMDIS2016210503TB3">table 3</xref>).</p></caption><graphic xlink:href="annrheumdis-2016-210503f02"></graphic></fig></sec><sec id="s3e"><title>Changes in secondary outcomes over time in the different treatment groups</title><sec id="s3e1"><title>Lung function</title><p>After adjusting for potential confounders, the change rates of FVC and DLCO were not significantly different in the four treatment groups (p=0.460 and 0.505) (<xref ref-type="table" rid="ANNRHEUMDIS2016210503TB3">table 3</xref>).</p><p>However, in a subset of patients with pulmonary fibrosis or suspected pulmonary fibrosis (cases confirmed on high-resolution CT (HRCT) irrespective of FVC or DLCO, or with one of the following if HRCT not performed: FVC or DLCO under 55% predicted or definite bibasal shadowing on X-ray), there was a significant difference in the change rate of FVC over time (p=0.035). Patients initially prescribed cyclophosphamide demonstrated 7.4% absolute increase in FVC (% predicted) compared with 2.0% decrease for methotrexate, 3.2% increase for MMF and 4.0% increase for the ‘no immunosuppressant’ group (<xref ref-type="table" rid="ANNRHEUMDIS2016210503TB3">table 3</xref>).</p></sec><sec id="s3e2"><title>Functional ability and hand function</title><p>Changes over time for the HAQ-DI and CHFS did not differ between protocols (p=0.130 and 0.073), regardless of adjusting (<xref ref-type="table" rid="ANNRHEUMDIS2016210503TB3">table 3</xref>).</p></sec><sec id="s3e3"><title>Development of internal organ involvement</title><p>This is described in online <xref ref-type="supplementary-material" rid="SM2">supplementary figure</xref> S2.</p></sec></sec><sec id="s3f"><title>Comparison of survival between treatment protocols</title><p>Survival was lowest in the no immunosuppressant group at both 12 and 24 months but differences between protocols were not statistically significant either before (p=0.389) or after weighting (p=0.440). In the adjusted model, at 24 months, those in the no immunosuppressant group had a predicted survival rate of 84.0% compared with 94.1% for methotrexate, 88.8% for MMF and 90.1% for cyclophosphamide (<xref ref-type="fig" rid="ANNRHEUMDIS2016210503F3">figure 3</xref>). Patients with lung involvement (pulmonary fibrosis and/or hypertension) at baseline had significantly poorer survival than those without: at 24 months, their predicted survival rate was 74.6% versus 91.7% (p<0.0005) and similarly for cardiac involvement, 71.6% versus 90.7% (p<0.0005).</p><fig id="ANNRHEUMDIS2016210503F3" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Kaplan-Meier estimated survival curves by treatment group.</p></caption><graphic xlink:href="annrheumdis-2016-210503f03"></graphic></fig></sec><sec id="s3g"><title>Adverse effects</title><p>Of the 75, 182 and 101 patients who were ever on methotrexate, MMF or cyclophosphamide, respectively, 29 (38.7%), 40 (22.0%) and 23 (22.8%) were reported to have had side effects, necessitating drug discontinuation in 9 (12.0%), 14 (7.7%) and 5 (4.5%) patients, respectively. A survival analysis on protocol exits due to adverse effects showed no differences in the tolerability of the three treatments (p=0.212) (see online <xref ref-type="supplementary-material" rid="SM2">supplementary figure</xref> S3).</p></sec></sec><sec sec-type="discussion" id="s4"><title>Discussion</title><p>Our main findings were, first, that there were no significant differences in outcome between the four treatment protocols (methotrexate, MMF, cyclophosphamide, no immunosuppression), although there may be a signal in favour of immunosuppression for early dcSSc. Although skin score improved in all treatment groups, this was least in the no immunosuppressant category, who also had the highest mortality. Second, ESOS confirms the relative effectiveness of cyclophosphamide in patients with pulmonary fibrosis.<xref rid="R25" ref-type="bibr">25</xref><xref rid="R26" ref-type="bibr">26</xref></p><p>An important point when interpreting our findings (and therefore a note of caution) is that the ‘no immunosuppressant’ group was not a control group. Patients in this group had a longer disease duration than the other three groups and were more likely to have renal involvement.</p><p>Our findings lend support to two recently published studies (the Autologous Stem Cell Transplantation International Scleroderma trial (ASTIS) trial of autologous stem cell transplantation<xref rid="R27" ref-type="bibr">27</xref> and the Scleroderma Lung Study (SLS) II (comparing MMF and cyclophosphamide),<xref rid="R26" ref-type="bibr">26</xref> which suggest benefit, including in mRSS, from immunosuppression (as did SLS 1<xref rid="R25" ref-type="bibr">25</xref>). In ASTIS, those patients randomised to cyclophosphamide had an 8.8 unit fall in mRSS (from 25.8) at 24 months (compared with 3.3 in ESOS over 12 months), but the cyclophosphamide protocol was more intense, and the patients had more severe disease (patients with the highest mRSS at baseline tend to improve most quickly<xref rid="R4" ref-type="bibr">4</xref> as also demonstrated by our own findings (<xref ref-type="table" rid="ANNRHEUMDIS2016210503TB2">table 2</xref>)). MRSS fell by 19.9 units in those patients randomised to stem cell transplantation<xref rid="R27" ref-type="bibr">27</xref> (and therefore intensive immunosuppression). In SLS 1,<xref rid="R25" ref-type="bibr">25</xref> patients with dcSSc randomised to cyclophosphamide experienced a 5.3 unit fall in mRSS at 12 months (compared with 3.3 in ESOS), whereas mRSS fell by 1.7 on placebo (compared with 2.2 units in the ESOS ‘no immunosuppressant’ group). In SLS II,<xref rid="R26" ref-type="bibr">26</xref> mRSS at 24 months fell 4.9 units on MMF (compared with 4.1 units in ESOS at 12 months) and by 5.4 after 12 months treatment with cyclophosphamide, although these values are not directly comparable because they relate to patients with limited cutaneous and dcSSc combined.</p><p>The methodological strength of ESOS, which built upon experience gained in a previous, smaller observational study,<xref rid="R28" ref-type="bibr">28</xref> was its design: its standardised protocols emulated the conditions of a clinical trial, and although not randomised, patients were enrolled into four homogenous treatment arms with well-defined interventions and a systematic record of protocol changes and exits. Entry criteria were deliberately inclusive: RCTs often exclude patients with internal organ involvement and for whom immunosuppression is most likely to be beneficial. By recruiting 326 patients from 50 centres, ESOS represents a large cohort of patients with very early dcSSc (median duration of skin thickening 11.9 months): its data will serve as a benchmark when designing and interpreting future clinical trials. This is especially relevant with a number of novel treatment approaches currently being explored including biological agents. For example, in a recent RCT of tocilizumab,<xref rid="R29" ref-type="bibr">29</xref> mRSS fell over 24 weeks by 3.9 units from 26 in the 43 tocilizumab-treated patients and by 1.2 units from 26 in the 44 placebo-treated patients, this latter fall comparable to the ESOS ‘no immunosuppressant’ response. In comparing between these studies, the higher baseline mRSS in the tocilizumab study should be borne in mind.</p><p>The main weakness of observational studies is that each patient's outcome on her/his treatment arm cannot be completely disentangled from her/his initial characteristics. For instance, ESOS has verified that patients with lung and cardiac involvement tend to be prescribed cyclophosphamide. However, adjusting using IPT weights minimises the problem of confounding by indication.</p><p>In conclusion, observational studies offer a rich population-wide perspective assessing treatment effects in a real-world setting. ESOS achieved its aim of following a large international cohort of patients with early dcSSc over 2 years, each of whom was treated according to one of four protocols. The message for clinicians is that there is a weak signal to support using immunosuppressants for early dcSSc (and in particular cyclophosphamide for patients with pulmonary fibrosis). However, it is clear that there remains a pressing need for the development of more effective and targeted treatments.</p></sec></body><back><ack><p>The authors are grateful to Dr Holly Ennis for study set-up and to her and Dr Graham Dinsdale for project coordination during the earlier phases of the study. Thanks also to members of the independent oversight board: Stephen Cole, Dinesh Khanna and Frank Wollheim.</p></ack><fn-group><fn><p><bold>Contributors:</bold> ALH, ML, RH, LM, AS, EB, LC, JHWD, OD, KF, WJG, RO, MV and CPD were members of the Steering Committee and designed the study. ALH, RH, LM, LC, JHWD, OD, MV, CA, VHO, DF, MH, MM-C, AB-G,OM, ACJ, PJ, WS, PM, FCH, CA, MEA, ED, RM, MA, MHB, LC, ND, HG, PL, YA, KC, SJ, AJM, NM, UM-L, GR, MB, JR, PEC, AF, EH, JH, MI, JSM, J van L, SP, SP, AR, JS, BC, CS, TS, DJV, CG, GT and CPD were principal investigators at the different sites and recruited patients. XP was study coordinator. SP and ML were responsible for the statistical analysis. ALH, XP, SP, ML, RH, LM, AS and CPD wrote the draft report, and all authors reviewed the report, provided comments and approved the final report.</p></fn><fn><p><bold>Funding:</bold> ESOS was funded by a grant from the European League Against Rheumatism (EULAR) Orphan Disease Programme. Additional funding from Scleroderma and Raynaud's UK allowed a 1-year extension of the study.</p></fn><fn fn-type="COI-statement"><p><bold>Competing interests:</bold> ALH has done consultancy work for Actelion, served on a Data Safety Monitoring Board for Apricus, received research funding and speaker's fees from Actelion, and speaker's fees from GSK. JHWD has consultancy relationships and/or has received research funding from Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma, Active Biotech, Galapagos, Inventiva, Medac, Pfizer, Anamar and RuiYi and is stock owner of 4D Science GmbH. OD has received consultancy fees from 4D Science, Actelion, Active Biotech, Bayer, Biogenidec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare Foundation, Genentech/Roche, GSK, Inventiva, Lilly, Medac, Medimmune, Pharmacyclics, Pfizer, Serodapharm, and Sinoxa and received research grants from Actelion, Bayer, Boehringer Ingelheim, Ergonex, Pfizer and Sanofi, and has a patent mir-29 for the treatment of systemic sclerosis licenced. WG has received teaching fees from Pfizer. FH has received research funding from Actelion. MEA has undertaken advisory board work and received honoraria from Actelion, and received speaker's fees from Bristol-Myers Squibb. LC has done advisory board work for Gilead and served Data Safety Monitoring Boards for Cytori and Reata. HG has done consultancy work and received honoraria from Actelion. UM-L is funded in part bu EUSTAR/EULAR. JMvL has received honoraria from Eli Lilly, Pfizer, Roche, MSD and BMS. AR receives funding from AstraZeneca. CPD has done consultancy for GSK, Actelion, Bayer, Inventiva and Merck-Serono, received research grant funding from GSK, Actelion, CSL Behring and Inventiva, received speaker's fees from Bayer and given trial advice to Merck-Serono.</p></fn><fn><p><bold>Patient consent:</bold> Obtained.</p></fn><fn><p><bold>Ethics approval:</bold> The Ethics Committee of each centre approved the study.</p></fn><fn><p><bold>Provenance and peer review:</bold> Not commissioned; externally peer reviewed.</p></fn><fn><p><bold>Data sharing statement:</bold> At present, unpublished data from the study are not available for sharing. This position may change in 6–12 months time.</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 name-style="western"><surname>Nikpour</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Stevens</surname><given-names>WM</given-names></name>, <name name-style="western"><surname>Herrick</surname><given-names>AL</given-names></name>, <etal>et al</etal></person-group><article-title>Epidemiology of systemic sclerosis</article-title>. <source>Best Practice Res Clin Rheumatol</source><year>2010</year>;<volume>24</volume>:<fpage>857</fpage>–<lpage>69</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.berh.2010.10.007">doi:10.1016/j.berh.2010.10.007</ext-link></mixed-citation></ref><ref id="R2"><label>2</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Rubio-Rivas</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Royo</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Simeon</surname><given-names>CP</given-names></name>, <etal>et al</etal></person-group><article-title>Mortality and survival in systemic sclerosis : systematic review and meta-analysis</article-title>. <source>Sem Arthritis Rheum</source><year>2014</year>;<volume>44</volume>:<fpage>208</fpage>–<lpage>19</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.semarthrit.2014.05.010">doi:10.1016/j.semarthrit.2014.05.010</ext-link></mixed-citation></ref><ref id="R3"><label>3</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Nihtyanova</surname><given-names>SI</given-names></name>, <name name-style="western"><surname>Schreiber</surname><given-names>BE</given-names></name>, <name name-style="western"><surname>Ong</surname><given-names>VH</given-names></name>, <etal>et al</etal></person-group><article-title>Prediction of pulmonary complications and long-term survival in systemic sclerosis</article-title>. <source>Arthritis Rheum</source><year>2014</year>;<volume>66</volume>:<fpage>1625</fpage>–<lpage>35</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/art.38390">doi:10.1002/art.38390</ext-link></mixed-citation></ref><ref id="R4"><label>4</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Merkel</surname><given-names>PA</given-names></name>, <name name-style="western"><surname>Silliman</surname><given-names>NP</given-names></name>, <name name-style="western"><surname>Clements</surname><given-names>PJ</given-names></name>, <etal>et al</etal></person-group><article-title>Patterns and predictors of change in outcome measures in clinical trials in scleroderma: An individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis</article-title>. <source>Arthritis Rheum</source><year>2012</year>;<volume>64</volume>:<fpage>3420</fpage>–<lpage>9</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/art.34427">doi:10.1002/art.34427</ext-link><pub-id pub-id-type="pmid">22328195</pub-id></mixed-citation></ref><ref id="R5"><label>5</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Silverman</surname><given-names>SL</given-names></name></person-group><article-title>From randomized controlled trials to observational studies</article-title>. <source>Am J Med</source><year>2009</year>;<volume>122</volume>:<fpage>114</fpage>–<lpage>20</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/j.amjmed.2008.09.030">doi:10.1016/j.amjmed.2008.09.030</ext-link><pub-id pub-id-type="pmid">19185083</pub-id></mixed-citation></ref><ref id="R6"><label>6</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Halpern</surname><given-names>SD</given-names></name>, <name name-style="western"><surname>Karlawish</surname><given-names>JT</given-names></name>, <name name-style="western"><surname>Berlin</surname><given-names>JA</given-names></name></person-group><article-title>The continuing unethical conduct of underpowered clinical trials</article-title>. <source>JAMA</source><year>2002</year>;<volume>288</volume>:<fpage>358</fpage>–<lpage>62</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1001/jama.288.3.358">doi:10.1001/jama.288.3.358</ext-link><pub-id pub-id-type="pmid">12117401</pub-id></mixed-citation></ref><ref id="R7"><label>7</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Pope</surname><given-names>JE</given-names></name>, <name name-style="western"><surname>Bellamy</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Seibold</surname><given-names>JR</given-names></name>, <etal>et al</etal></person-group><article-title>A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma</article-title>. <source>Arthritis Rheum</source><year>2001</year>;<volume>44</volume>:<fpage>1351</fpage>–<lpage>8</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/1529-0131(200106)44:6<1351::AID-ART227>3.0.CO;2-I">doi:10.1002/1529-0131(200106)44:6<1351::AID-ART227>3.0.CO;2-I</ext-link><pub-id pub-id-type="pmid">11407694</pub-id></mixed-citation></ref><ref id="R8"><label>8</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Denton</surname><given-names>CP</given-names></name>, <name name-style="western"><surname>Merkel</surname><given-names>PA</given-names></name>, <name name-style="western"><surname>Furst</surname><given-names>DE</given-names></name>, <etal>et al</etal></person-group><article-title>Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis: a multicentre, randomized, placebo-controlled Phase I/II trial of CAT-192</article-title>. <source>Arthritis Rheum</source><year>2007</year>;<volume>56</volume>:<fpage>323</fpage>–<lpage>3</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/art.22289">doi:10.1002/art.22289</ext-link><pub-id pub-id-type="pmid">17195236</pub-id></mixed-citation></ref><ref id="R9"><label>9</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Kowal-Bielecka</surname><given-names>O</given-names></name>, <name name-style="western"><surname>Landewé</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Avouac</surname><given-names>J</given-names></name>, <etal>et al</etal></person-group><article-title>EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research Group (EUSTAR)</article-title>. <source>Ann Rheum Dis</source><year>2009</year>;<volume>68</volume>:<fpage>620</fpage>–<lpage>8</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1136/ard.2008.096677">doi:10.1136/ard.2008.096677</ext-link><pub-id pub-id-type="pmid">19147617</pub-id></mixed-citation></ref><ref id="R10"><label>10</label><mixed-citation publication-type="book"><person-group person-group-type="author"><name name-style="western"><surname>Rawlins</surname><given-names>MD</given-names></name></person-group><source>The Harveian Oration of 2008: On the evidence for decisions about the use of therapeutic interventions</source>. <publisher-loc>London</publisher-loc>: <publisher-name>Royal College of Physicians</publisher-name>, <year>2008</year>.</mixed-citation></ref><ref id="R11"><label>11</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Gagne</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Thompson</surname><given-names>L</given-names></name>, <name name-style="western"><surname>O'Keefe</surname><given-names>K</given-names></name>, <etal>et al</etal></person-group><article-title>Innovative research methods for studying treatments for rare diseases: methodological review</article-title>. <source>BMJ</source><year>2014</year>;<volume>349</volume>:<fpage>g6802</fpage><ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1136/bmj.g6802">doi:10.1136/bmj.g6802</ext-link><pub-id pub-id-type="pmid">25422272</pub-id></mixed-citation></ref><ref id="R12"><label>12</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>LeRoy</surname><given-names>EC</given-names></name>, <name name-style="western"><surname>Black</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Fleischmajer</surname><given-names>R</given-names></name>, <etal>et al</etal></person-group><article-title>Scleroderma (systemic sclerosis): classification, subsets and pathogenesis</article-title>. <source>J Rheumatol</source><year>1988</year>;<volume>15</volume>:<fpage>202</fpage>–<lpage>5</lpage>.<pub-id pub-id-type="pmid">3361530</pub-id></mixed-citation></ref><ref id="R13"><label>13</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Clements</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Lachenbruch</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Siebold</surname><given-names>J</given-names></name>, <etal>et al</etal></person-group><article-title>Inter- and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis</article-title>. <source>J Rheumatol</source><year>1995</year>;<volume>22</volume>:<fpage>1281</fpage>–<lpage>5</lpage>.<pub-id pub-id-type="pmid">7562759</pub-id></mixed-citation></ref><ref id="R14"><label>14</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Clements</surname><given-names>PJ</given-names></name>, <name name-style="western"><surname>Hurwitz</surname><given-names>EL</given-names></name>, <name name-style="western"><surname>Wong</surname><given-names>WK</given-names></name>, <etal>et al</etal></person-group><article-title>Skin thickness score as a predictor and correlate of outcome in systemic sclerosis</article-title>. <source>Arthritis Rheum</source><year>2000</year>;<volume>43</volume>:<fpage>2445</fpage>–<lpage>54</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/1529-0131(200011)43:11<2445::AID-ANR11>3.0.CO;2-Q">doi:10.1002/1529-0131(200011)43:11<2445::AID-ANR11>3.0.CO;2-Q</ext-link><pub-id pub-id-type="pmid">11083267</pub-id></mixed-citation></ref><ref id="R15"><label>15</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Steen</surname><given-names>VD</given-names></name>, <name name-style="western"><surname>Medsger</surname><given-names>TA</given-names></name></person-group><article-title>The value of the health assessment questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time</article-title>. <source>Arthritis Rheum</source><year>1997</year>;<volume>40</volume>:<fpage>1984</fpage>–<lpage>91</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/art.1780401110">doi:10.1002/art.1780401110</ext-link><pub-id pub-id-type="pmid">9365087</pub-id></mixed-citation></ref><ref id="R16"><label>16</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Webster</surname><given-names>K</given-names></name>, <name name-style="western"><surname>Cella</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Yost</surname><given-names>K</given-names></name></person-group><article-title>The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation</article-title>. <source>Health Qual Life Outcomes</source><year>2003</year>;<volume>1</volume>:<fpage>79</fpage><ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1186/1477-7525-1-79">doi:10.1186/1477-7525-1-79</ext-link><pub-id pub-id-type="pmid">14678568</pub-id></mixed-citation></ref><ref id="R17"><label>17</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Harel</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Thombs</surname><given-names>BD</given-names></name>, <name name-style="western"><surname>Hudson</surname><given-names>M</given-names></name>, <etal>et al</etal></person-group><article-title>Measuring fatigue in SSc: a comparison of the Short Form-36 Vitality subscale and Functional Assessment of Chronic Illness Therapy–Fatigue scale</article-title>. <source>Rheumatol</source><year>2012</year>;<volume>51</volume>:<fpage>2177</fpage>–<lpage>85</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1093/rheumatology/kes206">doi:10.1093/rheumatology/kes206</ext-link></mixed-citation></ref><ref id="R18"><label>18</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Rannou</surname><given-names>F</given-names></name>, <name name-style="western"><surname>Poiraudeau</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Berezne</surname><given-names>A</given-names></name>, <etal>et al</etal></person-group><article-title>Assessing disability and quality of life in systemic sclerosis: construct validities of the Cochin Hand Function Scale, Health Assessment Questionnaire (HAQ), Systemic Sclerosis HAQ, and Medical Outcomes Study 36-Item Short Form Health Survey</article-title>. <source>Arthritis Rheum</source><year>2007</year>;<volume>57</volume>:<fpage>94</fpage>–<lpage>102</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/art.22468">doi:10.1002/art.22468</ext-link><pub-id pub-id-type="pmid">17266096</pub-id></mixed-citation></ref><ref id="R19"><label>19</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Brookhart</surname><given-names>MA</given-names></name>, <name name-style="western"><surname>Schneeweiss</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Rothman</surname><given-names>KJ</given-names></name>, <etal>et al</etal></person-group><article-title>Variable selection for propensity score models</article-title>. <source>Amer J Epidemiol</source><year>2006</year>;<volume>163</volume>:<fpage>1149</fpage>–<lpage>56</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1093/aje/kwj149">doi:10.1093/aje/kwj149</ext-link><pub-id pub-id-type="pmid">16624967</pub-id></mixed-citation></ref><ref id="R20"><label>20</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Austin</surname><given-names>PC</given-names></name>, <name name-style="western"><surname>Grootendorst</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Normand</surname><given-names>S-LT</given-names></name>, <etal>et al</etal></person-group><article-title>Conditioning on the propensity score can result in biased estimation of common measures of treatment effect: a Monte Carlo study</article-title>. <source>Stat Med</source><year>2007</year>;<volume>26</volume>:<fpage>754</fpage>–<lpage>68</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1002/sim.2618">doi:10.1002/sim.2618</ext-link><pub-id pub-id-type="pmid">16783757</pub-id></mixed-citation></ref><ref id="R21"><label>21</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Sato</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Matsuyama</surname><given-names>Y</given-names></name></person-group><article-title>Marginal structural models as a tool for standardization</article-title>. <source>Epidemiology</source><year>2003</year>;<volume>14</volume>:<fpage>680</fpage>–<lpage>6</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1097/01.EDE.0000081989.82616.7d">doi:10.1097/01.EDE.0000081989.82616.7d</ext-link><pub-id pub-id-type="pmid">14569183</pub-id></mixed-citation></ref><ref id="R22"><label>22</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Imbens</surname><given-names>G</given-names></name></person-group><article-title>The role of the propensity score in estimating dose-response functions</article-title>. <source>Biometrika</source><year>2000</year>;<volume>87</volume>:<fpage>706</fpage>–<lpage>10</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1093/biomet/87.3.706">doi:10.1093/biomet/87.3.706</ext-link></mixed-citation></ref><ref id="R23"><label>23</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Fewell</surname><given-names>Z</given-names></name>, <name name-style="western"><surname>Hernan</surname><given-names>MA</given-names></name>, <name name-style="western"><surname>Wolfe</surname><given-names>F</given-names></name>, <etal>et al</etal></person-group><article-title>Controlling for time-dependant confounding using marginal structural models</article-title>. <source>Stata J</source><year>2004</year>;<volume>4</volume>:<fpage>402</fpage>–<lpage>20</lpage>.</mixed-citation></ref><ref id="R24"><label>24</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Cole</surname><given-names>SR</given-names></name>, <name name-style="western"><surname>Hernán</surname><given-names>MA</given-names></name></person-group><article-title>Constructing inverse probability weights for marginal structural models</article-title>. <source>Amer J Epidemiol</source><year>2008</year>;<volume>168</volume>:<fpage>656</fpage>–<lpage>64</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1093/aje/kwn164">doi:10.1093/aje/kwn164</ext-link><pub-id pub-id-type="pmid">18682488</pub-id></mixed-citation></ref><ref id="R25"><label>25</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Tashkin</surname><given-names>DP</given-names></name>, <name name-style="western"><surname>Elashoff</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Clements</surname><given-names>PJ</given-names></name>, <etal>et al</etal></person-group><article-title>Cyclophosphamide versus placebo in scleroderma lung disease</article-title>. <source>N Eng J Med</source><year>2006</year>;<volume>354</volume>:<fpage>2655</fpage>–<lpage>66</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1056/NEJMoa055120">doi:10.1056/NEJMoa055120</ext-link></mixed-citation></ref><ref id="R26"><label>26</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Tashkin</surname><given-names>DP</given-names></name>, <name name-style="western"><surname>Roth</surname><given-names>MD</given-names></name>, <name name-style="western"><surname>Clements</surname><given-names>PJ</given-names></name>, <etal>et al</etal></person-group><article-title>Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomsed controlled, double-blind, parallel group trial</article-title>. <source>Lancet Respir Med</source><year>2016</year>;<volume>4</volume>:<fpage>708</fpage>–<lpage>19</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/S2213-2600(16)30152-7">doi:10.1016/S2213-2600(16)30152-7</ext-link><pub-id pub-id-type="pmid">27469583</pub-id></mixed-citation></ref><ref id="R27"><label>27</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Van Laar</surname><given-names>JM</given-names></name>, <name name-style="western"><surname>Farge</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Sont</surname><given-names>JK</given-names></name>, <etal>et al</etal></person-group><article-title>Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis</article-title>. <source>JAMA</source><year>2014</year>;<volume>311</volume>:<fpage>2490</fpage>–<lpage>8</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1001/jama.2014.6368">doi:10.1001/jama.2014.6368</ext-link><pub-id pub-id-type="pmid">25058083</pub-id></mixed-citation></ref><ref id="R28"><label>28</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Herrick</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Lunt</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Whidby</surname><given-names>N</given-names></name>, <etal>et al</etal></person-group><article-title>Observational study of treatment outcome in early diffuse cutaneous systemic sclerosis</article-title>. <source>J Rheumatol</source><year>2010</year>;<volume>37</volume>;<fpage>116</fpage>–<lpage>24</lpage>.<pub-id pub-id-type="pmid">19955050</pub-id></mixed-citation></ref><ref id="R29"><label>29</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Khanna</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Denton</surname><given-names>CP</given-names></name>, <name name-style="western"><surname>Jahreis</surname><given-names>A</given-names></name>, <etal>et al</etal></person-group><article-title>Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised controlled trial</article-title>. <source>Lancet</source><year>2016</year>;<volume>387</volume>:<fpage>2630</fpage>–<lpage>40</lpage>. <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1016/S0140-6736(16)00232-4">doi:10.1016/S0140-6736(16)00232-4</ext-link><pub-id pub-id-type="pmid">27156934</pub-id></mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002260 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 002260 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Asie
|area= AustralieFrV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:5530354
|texte= Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:28188239" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a AustralieFrV1
| This area was generated with Dilib version V0.6.33. |  |