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Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry.
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MedLine Citation:
PMID:  22247218     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc).
METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers.
RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group.
CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies.
Authors:
Christopher P Denton; Thomas Krieg; Loic Guillevin; Barbara Schwierin; Daniel Rosenberg; Mariabeth Silkey; Maurice Zultak; Marco Matucci-Cerinic;
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Publication Detail:
Type:  Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't     Date:  2012-01-12
Journal Detail:
Title:  Annals of the rheumatic diseases     Volume:  71     ISSN:  1468-2060     ISO Abbreviation:  Ann. Rheum. Dis.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-11     Completed Date:  2012-05-31     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0372355     Medline TA:  Ann Rheum Dis     Country:  England    
Other Details:
Languages:  eng     Pagination:  718-21     Citation Subset:  IM    
Affiliation:
Centre for Rheumatology and Connective Tissue Diseases, Department of Inflammation, Division of Medicine, UCL Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. cdenton@medsch.ucl.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Adult
Antibodies, Antinuclear / blood
Cohort Studies
Databases, Factual
Europe
Female
Fingers / pathology*
Humans
Male
Registries* / statistics & numerical data
Scleroderma, Systemic / immunology,  pathology*
Skin Ulcer / immunology,  pathology*
Time Factors
Chemical
Reg. No./Substance:
0/Antibodies, Antinuclear; 0/anticentromere antibody
Investigator
Investigator/Affiliation:
M Stetter / ; K Lackner / ; N Tomi / ; F Hafner / ; M Brodmann / ; M Kuen-Spiegel / ; H Kolle / ; B Raffier / ; N Hamberger / ; S Metz / ; C Siebel / ; M Trummer / ; R Thonhofer / ; X Illmer / ; F Trautinger / ; P Schmidt / ; B Rintelen / ; J Sautner / ; A Willfort-Ehringer / ; C Margeta / ; B Monshi / ; D Pirkhammer / ; L Richter / ; G Holzer / ; G Minmair / ; H Broll / ; M Takacs / ; M Hirschl / ; P Mesaric / ; R Feldmann / ; K Semmelweis / ; M Hundstorfer / ; V Reinhart / ; B Maurer / ; D Verner / ; O Distler / ; R Schmidt-Bosshard / ; J Bohmova / ; L Prochazkova / ; P Nemec / ; Z Fojtik / ; T Soukup / ; A Smrzova / ; D Suchy / ; I Zemanova / ; R Becvar / ; A Gawlik / ; M Koch / ; T Rauen / ; B Voss / ; R Kurthen / ; A Unholzer / ; H Starz / ; J Welzel / ; K Plaumann / ; B Merk / ; H H Bloching / ; F Moosig / ; P Frey / ; S Kahl / ; H Schleenbecker / ; K Storck-Mueller / ; A Schwarting / ; A Hazenbiller / ; V Nichelmann / ; W Flaig / ; C Rumbaur / ; I Boesenberg / ; T Schmeiser / ; J Marx / ; L Mayer / ; T Stein / ; W Ochs / ; C Rasche / ; M Worm / ; G Riemekasten / ; K Deuschle / ; M Becker / ; H J Kleiner / ; K Schulze / ; C Tiggers / ; J Peters / ; J Kirschke / ; C Schaefer / ; M Monshausen / ; T Mengden / ; F Sadeghlar / ; M Seidel / ; C Hillebrecht / ; J Andresen / ; R Reemtsen / ; F Stoeckl / ; S Sperling / ; M Podda / ; N Wagner / ; J Guenzel / ; I Wuerzburg / ; K Luethke / ; M Enderlein / ; M Kayser / ; A Gerber / ; M Haust / ; N P Hoff / ; R Mota / ; S Akanay-Diesel / ; K Jahnke / ; S Mettler / ; S Toeller / ; S Zwenger / ; E Klein / ; K Hahn / ; C Beyer / ; J Distler / ; A Katzemich / ; C Erfurt-berge / ; M Sticherling / ; F Schuch / ; P Rapp / ; A Mitchell / ; C Freundlieb / ; U Rushentsova / ; A Himsel / ; U Henkemeier / ; P Eilbacher / ; C Ullrich-Guenther / ; S Neul / ; M Oelsner / ; G Hermanns / ; M Fiene / ; A Gause / ; C Mensing / ; D Klings / ; H Mensing / ; J Messall / ; R Zuper / ; D May / ; L Bruckner / ; N Sheikh / ; P Aries / ; S Kirchberg / ; A Funkert / ; N Blank / ; S Lupaschko / ; M Schwuerzer-Voit / ; L Meier / ; U Herr / ; U Meier / ; G Neek / ; H Wernitzsch / ; C Pfoehler / ; G Assmann / ; J Vosswinkel / ; B Krog / ; E Wollersdorfer / ; J Oltmann-Schroeder / ; R Zeuner / ; S Uhlig / ; S Barth / ; R Huegel / ; R Glaeser / ; B Rabe / ; J Schuster / ; J Scholz / ; K Kremer / ; M Robakidze-Torbahn / ; P Moinzadeh / ; M Mittag / ; A Dohse / ; A Muhlack / ; L Schultz / ; S Schult / ; Y Frambach / ; A Kettenbach / ; I Fell / ; K Schweda / ; K Steinbrink / ; M Podobinska / ; W Harmuth / ; C Nielen / ; A Kaczmarczyk / ; C Kellner / ; J von Oelhafen / ; P B von Bildering / ; S Kunze / ; A Niedermeier / ; G Messer / ; M Sardy / ; V Bekou / ; B Belloni / ; B Huettig / ; M Ziai / ; R Hein / ; A Hallecker / ; M Gaubitz / ; C Hallermann / ; K Schmidt / ; I Herrgott / ; B Hildebrandt / ; E Eiden / ; I Guertler / ; E Gernot Scheibl / ; H Brand / ; U Kaeding / ; E Weiss / ; N Reischel / ; S Kern / ; C Baumann / ; B Hellmich / ; C Loeffler / ; J Pflugfelder / ; P Karaenke / ; J Ruchenburg / ; J Blume / ; M Zabel / ; N Deppermann / ; S Chromik / ; C Metzler / ; E Krupp / ; H Rumpel / ; J-O Krause Rostock / ; C Kneitz / ; I Federow / ; K Schneider / ; M Semmler / ; S Hapke / ; A Barnd / ; M Linke / ; E Kampe-Juzak / ; K Knoebel / ; K Niefanger / ; H U Wilhelm / ; B Lauterwein / ; G Fierlbeck / ; S Schanz / ; C Pfeiffer / ; R Hassel / ; H Wahn / ; K Schildt / ; A von Elling / ; D Boro / ; J Ebel / ; K Ahmadi / ; D Moritz / ; S Dietl / ; J Dyballa / ; B Alsheimer / ; N Schuetz / ; T Schuart / ; C Mueglich / ; H P Tony / ; P Marina / ; F Deininger / ; F Hartmann / ; A B Olsen / ; K H Sondergaard / ; Y Naderi / ; L V Iversen / ; T Karlsmark / ; J B Knudsen / ; J G Gil / ; J C F Lopez / ; J A P Tasende / ; M F Gonzales / ; A A Sandoval / ; M del Carmen Torres Martin / ; M Corteguera / ; B A Barca / ; I C Montes / ; R G de la Torre / ; M Victoria Egurbide / ; A Pros / ; J Munoz / ; C P Simeon / ; G Espinosa / ; G Espinposa / ; M A P Rodriguez / ; I Castellvi / ; J M Mascaro / ; D Bellido / ; V S Manzanedo / ; M P Huertas / ; M D M Sanchez / ; M S S Trenado / ; P V Garcia / ; F Gines Martinez / ; M Angeles Aquirre / ; A H del Rio / ; J L G Vazquez / ; J V Coleman / ; M R Lopez / ; P S Sanchez / ; E M F Aizpuru / ; F J N Mateo / ; J L Callejas / ; N Ortego / ; I Castellvi / ; M P Santo / ; M Rubio / ; I Martin / ; A Cruz / ; M Crespo / ; P C Ramos / ; A S-A Fernandez / ; J A M Filloy / ; T R V Rodriguez / ; A R Marhuenda / ; J J R Blanco / ; M G B Hernan / ; A Z Mendoza / ; C De la Puente / ; E V Rabaneda / ; R G de Vicuna / ; M del Mar Ripoll Macias / ; P G del la Pena Lefebvre / ; E de Ramon / ; M T Camps / ; C Fernandez / ; R Miguelez / ; J Uson / ; E G Delgado / ; V Villaverde / ; F Maceiras / ; J Cruz / ; J A Mosquera / ; A Mera / ; E P Pampin / ; J S Blanco / ; J R Maneiro / ; J J Diaz / ; L Losada / ; M Caamano / ; S Fernandez / ; S A Insua / ; C U Laurin / ; J Sanchez / ; N C Fernandez / ; N D Becerra / ; A Garcia / ; G M Nicolas / ; M del Carmen Ortega de la O / ; A Rueda / ; J Calvo / ; J Roman Ivorra / ; J J Sancho Alegre / ; J Barbado / ; J Montes / ; L Saez / ; A Kaarto / ; H Makinen / ; S Madaule / ; A Dadban / ; C Lok / ; D Ferrandiz / ; M P Moiton / ; N Magy-Bertrand / ; A Taieb / ; C Droitcourt / ; E Belin / ; S Balquiere / ; S Prey / ; C Boulon / ; J Constans / ; C Richez / ; B Sassolas / ; L Misery / ; M Greco / ; E collet / ; S Berthier / ; V Leguy-Seguin / ; B Imbert / ; P Carpentier / ; S Blaise / ; H Maillard / ; N Beneton / ; D Launay / ; E Hachulla / ; G Woijtasik / ; H Charlanne / ; M Lambert / ; N Jourdain / ; P Y Hatron / ; S Morell / ; A Spars / ; A Couraud / ; V Doeffel-hantz / ; A L Fauchais / ; E Vidal / ; G Goudran / ; H Bezanahary / ; N Boussely / ; P Manea / ; S Dumonteil / ; V Loustaud-ratti / ; A Hot / ; B Coppere / ; H Desmurs-Clavel / ; J Ninet / ; M H Girard-Madoux / ; B Granel / ; A Keynote / ; A Khau van Kien / ; P Rullier / ; A Le Quellec / ; S Riviere / ; D Bessis / ; J D Cohen / ; C Farcas / ; F Granel-brocard / ; C Agard / ; C Durant / ; J G Fuzibet / ; V Queyrel / ; A Berezne / ; L Guillevin / ; L Mouthon / ; C Frances / ; C Toledano / ; J Cabane / ; K Tiev / ; D Farge / ; H Keshtmand / ; I Lazareth / ; P Priollet / ; U Michon-Pasturel / ; J Wipff / ; N Assous / ; O Cartry / ; E Kostrzwewa / ; M S Doutre / ; L Blum / ; Z Reguiai / ; A Letremy / ; A Perlat / ; C Cazalets-lacoste / ; O Decaux / ; P Jego / ; A B Duval-modeste / ; O Deboves / ; C Sordet / ; E Chatelus / ; H Chiffot / ; J Sibillia / ; B Couret / ; G Moulis / ; L Sailler / ; D Adoue / ; F Gaches / ; E Diot / ; F Skowron / ; T Zenone / ; T Quemeneur / ; X Kyndt / ; D Wahl / ; S Zuily / ; T Moline / ; V Bravetti / ; N Galanopoulos / ; D Vasilopoulos / ; P Vlachoyannopoulos / ; I Kritikos / ; N Tsifetaki / ; A Koutroumbas / ; A Garyfallos / ; P Athanassiou / ; S Aslanidis / ; S Kamali / ; T Dimitroulas / ; V Galanopoulo / ; A Elezoglou / ; A Grier / ; M Murray / ; M O'Rourke / ; A Gabrielli / ; G Lapadula / ; L Serafino / ; N Terlizzi / ; S Bellissimo / ; S Stisi / ; N Malavolta / ; P Airo / ; A Vacca / ; E Battaglia / ; R Foti / ; S Mazzuca / ; A Bortoluzzi / ; F Trotta / ; F Galluccio / ; A Marucci / ; F Cantatore / ; R Bucci / ; F Puppo / ; R De Angeli / ; W Grassi / ; P Cipriani / ; A Mazzone / ; P Faggioli / ; A Severino / ; R Scorza / ; L Belloli / ; N Ughi / ; M Antivalle / ; N Del Papa / ; W Maglione / ; S Zeni / ; C Ferri / ; M Colaci / ; G Varcasia / ; G Cuomo / ; F Cozzi / ; G Triolo / ; S Gatti / ; C M Montecucco / ; M Doveri / ; A Nigro / ; I Olivieri / ; G Bajoochi / ; E Rosato / ; F Salsano / ; F Faustini / ; G Ferraccioli / ; L Colonna / ; S Pallotta / ; V Riccieri / ; A Mussi / ; F Bellisai / ; M Galeazzi / ; E Fusaro / ; M Saracco / ; R Pellerito / ; P Masolini / ; S De Vita / ; S Lombardi / ; C Lunardi / ; J D Moolenburgh / ; A H M Heurkens / ; A Voskuyl / ; A E Hak / ; E S K Stroes / ; J Remans / ; V Gerdes / ; J M van Woerkom / ; A J L de Long / ; H A H Kaasjager / ; H Visser / ; M Janssen / ; C Van Guldener / ; F Van Neer / ; P Vos / ; A J Peters / ; H Hulsmans / ; K Ronday / ; R Goekoop / ; J Ewals / ; R Valentijn / ; M de Bois / ; M L Westedt / ; D Siewertsz van Reesema / ; E Knifjj-Dutmer / ; J N Stolk / ; H Willems / ; D G Kuiper-geertsma / ; P Baudaoin / ; P Fretter / ; R Westra / ; P B J Sonnaville / ; A SMIT / ; H Bootsma / ; L Brouwer / ; M Bijl / ; N Molders / ; C Lebrun / ; M J van der Veen / ; M Noordzij / ; H Houben / ; R M B Landewe / ; W Vercoutere / ; Z N Jahangier de Veen / ; T R Zijlstra / ; F Ubels / ; G Bruyn / ; P Jansen / ; A Schuerwegh / ; T W J Huizinga / ; P Paassen / ; T Hurkens / ; M Geurts / ; F van den Hoogen / ; M Vonk / ; P J C Jacobs / ; J H L M Groenendael / ; P Seys / ; D van Zeben / ; H van Paassen / ; J Groenendael / ; K H Han / ; M Wlarvens / ; M van Hagen / ; P van Daele / ; R Dolhain / ; A H Gerards / ; P van der Lubbe / ; M D E Kanter / ; W H Muller / ; E Ton / ; M Van Krugten / ; I van Gameren / ; P Lanting / ; C den Hengst / ; C G Gjessdal / ; S L Hjertaker / ; T M Madland / ; A Bendvold / ; H Bitter / ; A M Hoffmann-Vold / ; O Midtvedt / ; G Bakland / ; H K Aslkaksen / ; M Seip / ; S Kalstad / ; W Koldingsnes / ; B Grandauent / ; B Y Nordvag / ; E K Stran / ; J Skomsvoll / ; M Andersen / ; R S Thomsen / ; T Pedersen / ; V Bakkeheim / ; A Cordeiro / ; J Alves / ; S Oliveira / ; P Coelho / ; C Resende / ; C Ponte / ; I Almeida / ; I Silva / ; C Santos / ; I Camara / ; J Costa / ; H Hellstrom / ; A Mohammad / ; I Lind / ; K Lind / ; T Bracin / ; E Liljequist / ; T Vingren / ; A Ostenson / ; E Hermansson / ; C Thorsson / ; M Soderlin / ; A Nordin / ; E Waldheim / ; K Vengemyr / ; K Albertsson / ; M L Karlsson / ; Y Rydvald / ; M Rizk / ; A S Dolnicar / ; J Lukac / ; J James / ; N Mchugh / ; S Cole / ; S Brown / ; A Hamilton / ; A Faizal / ; F Hall / ; K Murphy / ; S Skingle / ; H Harris / ; F Madhok / ; R Hampson / ; E Baguley / ; O Ogunbambi G / ; J Lamb / ; M Anderson / ; R Moots / ; B White-Alao / ; C Morrison / ; J Dobson / ; P Gordon / ; R Salerno / ; C Denton / ; L Parker / ; R Ochiel / ; R Vincent / ; S Zimba / ; T Ngcozana / ; Y Xu / ; D D'Cruz / ; L M Choong / ; A Herrick / ; E Wragg / ; J Manning / ; T Moore / ; C Kelsey / ; K Chakravarty / ; H Skyes / ; P Athiveer /
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Journal Information
Journal ID (nlm-ta): Ann Rheum Dis
Journal ID (iso-abbrev): Ann. Rheum. Dis
Journal ID (hwp): annrheumdis
Journal ID (publisher-id): ard
ISSN: 0003-4967
ISSN: 1468-2060
Publisher: BMJ Group, BMA House, Tavistock Square, London, WC1H 9JR
Article Information
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Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions
open-access:
Received Day: 19 Month: 8 Year: 2011
Accepted Day: 11 Month: 12 Year: 2011
collection publication date: Day: 1 Month: 5 Year: 2012
Electronic publication date: Day: 12 Month: 1 Year: 2012
Volume: 71 Issue: 5
First Page: 718 Last Page: 721
ID: 3329234
PubMed Id: 22247218
Publisher Id: annrheumdis-2011-200631
DOI: 10.1136/annrheumdis-2011-200631

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry
Christopher P Denton1
Thomas Krieg2
Loic Guillevin3
Barbara Schwierin4
Daniel Rosenberg4
Mariabeth Silkey4
Maurice Zultak4
Marco Matucci-Cerinic5* On behalf of: on behalf of the DUO Registry investigators
1Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital, London, UK
2Department of Dermatology, University of Cologne, Cologne, Germany
3Department of Internal Medicine, Paris Descartes University, Paris, France
4Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
5Department of Medicine, University of Florence, Florence, Italy
Correspondence: Correspondence to Christopher P Denton, Centre for Rheumatology and Connective Tissue Diseases, Department of Inflammation, Division of Medicine, UCL Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK; cdenton@medsch.ucl.ac.uk
*The complete list of DUO Registry investigators is provided as online supplement Appendix 1.

Systemic sclerosis (SSc) is a multisystem autoimmune disease characterised by microvascular damage and excessive fibrosis of the skin and various internal organs. Limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) subsets are also associated with the presence of a number of autoantibodies, the expression of which can be useful in the diagnosis, prognosis and SSc disease management.1

The European Medicines Agency (EMA) requested the establishment of a prospective registry of patients with ongoing digital ulcers associated with SSc as a licensing requirement for bosentan in this indication. The Digital Ulcers Outcome (DUO) Registry enrols patients with digital ulcer disease regardless of their treatment status; however, a large proportion are receiving bosentan. This study provides valuable insights into this patient group and here we describe the clinical and autoantibody characteristics of these patients at enrolment.


Methods

The DUO Registry was initiated in April 2008 as an EMA postapproval commitment (after approval of a new indication for bosentan ‘to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease’).2 Participating centres received approval from relevant national and local ethics committees, data protection and health authorities. In line with an observational study design, physicians were asked to enter all consenting consecutive patients with ongoing digital ulcers associated with SSc, irrespective of treatment regimen. Patients received standard medical care and follow-up as determined by their physician. Data definitions were informed by literature3 and scientific committee consensus. Data collection included demographics, SSc disease duration, underlying disease classification (lcSSc, dcSSc, overlap SSc/mixed connective tissue disease and other), internal organ manifestations, autoantibodies, history of interventions/complications related to digital ulcers, ongoing complications related to digital ulcers, and ongoing medications and functional assessment based on a disease-specific questionnaire. The presence of antinuclear antibodies, anti-scleroderma-70 antibodies, anticentromere antibodies (ACA), anti-RNA polymerase 3, anti-U1 ribonucleoprotein and anti-U3 ribonucleoprotein were recorded. All serology tests and other data collection parameters were collected if performed. Quality assurance comprised automatic online quality checks and annual source data verification on 10% of the patients.

Data analysis

Enrolment data for the antibody subsets were analysed cross-sectionally for differences by group. SAS statistical software was used for analysing the data. Descriptive statistics (mean, median, SD, 95% CI, minimum, maximum) are provided for numerical variables. Categorical variables are summarised by counts and percentages and 95% CI.


Results

As of 19 November 2010, a total of 2439 patients had been enrolled into the DUO Registry from 271 participating centres in 18 European countries (Austria, Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Italy, The Netherlands, Norway, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland and UK).

Study cohort characteristics

The mean age of the patients enrolled was 54.6 years (SD 14.1) and the majority were women. Age at first Raynaud's phenomenon was on average 39.8 years and age at first digital ulcer was 46.7 years. At the time of enrolment, 60.0% (1426/2377) had at least one digital ulcer (data were missing for 62 patients). All patients who had no current digital ulcers at enrolment had a history of digital ulcer disease. Overall, 52.2% of the patients were classified as lcSSc, 36.9% as dcSSc, 6.8% as overlap SSc/mixed connective tissue disease, and 4.1% had other diseases (eg, systemic lupus erythematosus, dermatomyositis, vasculitis or SSc not further specified) (data were missing for 44 patients).

At enrolment, gastrointestinal tract manifestations had occurred in more than half of the patients (55.7%). Also common were lung fibrosis (41.3%), pulmonary arterial hypertension (PAH) (15.0%) and heart manifestations (10.7%). Almost half of all patients (47.4%) were receiving treatment with bosentan or another ERA (endothelin receptor antagonist), with a similar proportion receiving calcium antagonists and approximately one third receiving prostanoids (see supplementary table S1, available online only).

Antibody distribution

Almost all, 95.7%, (2085/2179) of patients tested were positive for antinuclear antibodies, 45.2% (854/1888) for anti-scleroderma-70 antibodies, 43.6% (775/1778) for ACA, 9.9% (86/867) for anti-RNA polymerase 3, 9.7% (120/1243) for anti-U1 ribonucleoprotein and 4.9% (39/799) for anti-U3 ribonucleoprotein. Few patients had a combination of antibodies. The combination with the highest occurrence was anti-scleroderma-70 plus ACA, 2.3% (56/2439), followed by anti-scleroderma-70 plus anti-U1 ribonucleoprotein, 1.8% (43/2439), anti-scleroderma-70 plus anti-RNA polymerase 3, 1.5% (36/2439), ACA plus anti-U1 ribonucleoprotein, 1.4% (34/2439), ACA plus anti-RNA polymerase 3, 1.4% (34/2439) and anti-U1 ribonucleoprotein plus anti-U3 ribonucleoprotein, 1.3% (31/2439).

SSc disease characteristics by antibody status

Patients positive for ACA were predominantly classified as lcSSc (82.9%; table 1). From the patients positive for anti-scleroderma-70 antibodies, a high proportion were classified as dcSSc (66.6%) and a lower proportion were classified as lcSSc (29.4%). Lung fibrosis was most frequent in the anti-scleroderma-70 subset (62.2%) compared with other antibody subsets (22.3–41.9%). Gastrointestinal manifestations showed a similar high proportion in all antibody subgroups, except for patients who were anti-U3 ribonucleoprotein positive. The frequencies of PAH and kidney manifestations were generally similar across the antibody subsets, although the proportion among patients with anti-U3 ribonucleoprotein was slightly higher; heart manifestations were highest in patients with anti-scleroderma-70 and anti-U1 ribonucleoprotein and lowest in patients with ACA (table 2). The proportion of patients with previous digital ulcer complications and interventions was broadly similar in the anti-scleroderma-70 subgroup and the ACA subgroup; the most marked exception was for surgical amputation, which occurred almost twice as frequently in patients with ACA (14.6%) compared with anti-scleroderma-70-positive patients (7.9%) (table 3).

Onset of disease manifestations by antibody status

In anti-scleroderma-70-positive patients, the first digital ulcer occurred at a mean age of 44.7 years (95% CI 43.6 to 45.7), whereas in ACA-positive patients, the first digital ulcer occurred approximately 6 years later, at 50.1 years (95% CI 48.9 to 52.3).

Compared with ACA-positive patients, anti-scleroderma-70-positive patients were younger at the onset of first Raynaud's phenomenon symptoms (anti-scleroderma-70: 38.5 years (95% CI 37.5 to 39.6); ACA: 41.1 years (95% CI 39.9 to 42.3)) and had shorter time periods from the onset of Raynaud's phenomenon to the first digital ulcer (anti-scleroderma-70: 6.0 years (95% CI 5.4 to 6.6); ACA: 8.1 years (95% CI 7.3 to 9.0)) (table 1).


Discussion

The findings of the DUO Registry regarding the burden of disease in SSc patients with digital ulcers confirm the findings of other large cohort studies.4, 5 Organ manifestations are common, with gastrointestinal manifestations being the most frequently reported, followed by lung fibrosis, PAH and heart manifestations.

Complications associated with digital ulcers, such as infection requiring systemic antibiotics, gangrene and amputation occurred frequently in all major SSc subsets. Anti-scleroderma-70-positive patients were younger at the onset of the first digital ulcer and had approximately double the rate of lung fibrosis compared with ACA-positive patients, these data are in line with findings from the European League Against Rheumatism Scleroderma Trials and Research.4 Furthermore, heart manifestations were also more common in the anti-scleroderma-70-positive group. Taken together, these findings confirm the association between anti-scleroderma-70 and more severe disease seen in other studies.1

The data show that anti-scleroderma-70-positive patients have fewer surgical amputations than ACA-positive patients but more autoamputation. As patients with this antibody have more SSc disease manifestations, the physician may be more reluctant to perform surgical interventions with the patient being more likely to be left to autoamputation; whereas ACA-positive patients may have a phenotype that leads to a decision to amputate surgically.

The proportion of anti-U1 ribonucleoprotein in patients with SSc, at approximately 30% in both lcSSc and dcSSc, was much higher than the previously reported figures.1 In contrast to other studies, the presence of anti-U1 ribonucleoprotein did not appear to have a greater association with PAH or with gastrointestinal manifestations than other autoantibodies.1

The proportion of patients reported here as anti-U3 ribonucleoprotein positive was low (4.9%), a finding similar to that reported in other studies.1 In addition, the complications associated with anti-U3 ribonucleoprotein positivity were similar as in previous studies.610

There are a number of limitations in this study. The DUO Registry is an observational study and not all data fields were completed for every patient; for example, the number of digital ulcers at enrolment was missing for 62 patients and few patients were tested for anti-RNA polymerase 3 or for anti-U3 ribonucleoprotein antibodies. Central testing was not performed and therefore potential variations between different analysis methods should be considered when interpreting the data.

In addition, at enrolment, differential recall bias for data recorded in the past may confound interpretation.

Almost half of all patients were being treated with bosentan. This is likely to be a reflection of the fact that the DUO Registry was initiated following EMA approval of bosentan,2 and it is possible that patient entry into the registry was biased towards patients receiving bosentan. Therefore, there are limitations in the application of these data to the wider SSc population. Nevertheless, this study provides, and will continue to provide, valuable prospectively collected data from a large cohort of over 2000 SSc patients. The strengths include the prospective nature of data collection and the strong framework of research governance compared with that of previous studies. The multinational and multicentre nature of this registry offers the potential for comparison of different patient populations and healthcare systems.


Conclusion

This report provides the first analysis of data from the large, multinational DUO Registry confirming the high clinical burden of digital ulcers in patients with SSc across antibody subsets, with early occurrence and high frequency in patients with dcSSc. The feasibility and utility of the DUO Registry is confirmed by the findings of this study.


Supplementary Material Supplemental Table
Click here for additional data file (ard-71-5-0718-s1.pdf)


Notes

Contributors Registry design: CPD, TK, LG, BS, DR, MS, MZ, MMC; data acquisition: CPD, TK, LG, MMC; manuscript preparation: CPD, TK, LG, BS, DR, MS, MZ, MMC; statistical analysis: MS, DR. All authors were involved in the drafting and reviewing of the manuscript and approved the final version.

Funding This registry was sponsored by Actelion Pharmaceuticals Ltd. The registry sponsor was involved in the registry design, and in the collection, analysis and interpretation of data.

Competing interests BS, DR, MS and MZ are employees of Actelion Pharmaceuticals Ltd, the manufacturers of bosentan. The non-Actelion employees who are authors of this manuscript have received consultancy fees or research grant funding from Actelion Pharmaceuticals Ltd.

Provenance and peer review Not commissioned; externally peer reviewed.

Correction notice This article has been corrected since it was published Online First. The author list has been amended.

The authors gratefully acknowledge all investigators involved in this registry. The authors would like to thank Lisa Thomas, Elements Communications Ltd, for providing editorial assistance, funded by Actelion Pharmaceuticals Ltd.


References
1. Hamaguchi Y. Autoantibody profiles in systemic sclerosis: predictive value for clinical evaluation and prognosis. J DermatolYear: 2010;37:42–5320175839
2. Tracleer (bosentan) Summary of Product Characteristics. http://www.medicines.org.uk/EMC/medicine/20423/SPC/Tracleer+(bosentan)+125mg+film-coated+tablets/Accessed 17 August 2011
3. Nihtyanova SI,Brough GM,Black CM,et al. Mycophenolate mofetil in diffuse cutaneous systemic sclerosis–a retrospective analysis. Rheumatology (Oxford)Year: 2007;46:442–516899504
4. Walker UA,Tyndall A,Czirják L,et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum DisYear: 2007;66:754–6317234652
5. Mayes MD,Lacey JV Jr,Beebe-Dimmer J,et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis RheumYear: 2003;48:2246–5512905479
6. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis RheumYear: 2005;35:35–4216084222
7. Sacks DG,Okano Y,Steen VD,et al. Isolated pulmonary hypertension in systemic sclerosis with diffuse cutaneous involvement: association with serum anti-U3RNP antibody. J RheumatolYear: 1996;23:639–428730118
8. Arnett FC,Reveille JD,Goldstein R,et al. Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic, serologic, and clinical analysis. Arthritis RheumYear: 1996;39:1151–608670324
9. Hamaguchi Y,Hasegawa M,Fujimoto M,et al. The clinical relevance of serum antinuclear antibodies in Japanese patients with systemic sclerosis. Br J DermatolYear: 2008;158:487–9518205876
10. Aggarwal R,Lucas M,Fertig N,et al. Anti-U3 RNP autoantibodies in systemic sclerosis. Arthritis RheumYear: 2009;60:1112–1819333934

Tables
[TableWrap ID: T1] Table 1 

Demographics and clinical features by antibody status


ANA* (N=2085) Anti-Scl-70 (N=854) Anti-RNA Pol 3 (N=86) ACA (N=775) Anti-U1 RNP (N=120) Anti-U3 RNP (N=39)
Tested positive/tests performed (%) 2085/2179 (95.7) 854/1888 (45.2) 86/867 (9.9) 775/1778 (43.6) 120/1243 (9.7) 39/799 (4.9)
Female, n/N (%) 1719/2085 (82.4) 676/854 (79.2) 70/86 (81.4) 677/775 (87.4) 91/120 (75.8) 31/39 (29.5)
dcSSc, n/N (%) (95% CI) 776/2070 (37.5) (35.4 to 39.6) 557/848 (65.7) (62.4 to 68.9) 37/85 (43.5) (32.8 to 54.7) 91/770 (11.8) (9.6 to 14.3) 34/119 (28.6) (20.7 to 37.6) 10/38 (26.3) (13.4 to 43.1)
lcSSc, n/N (%) (95% CI) 1071/2070 (51.7) (49.6 to 53.9) 249/848 (29.4) (26.3 to 32.6) 28/85 (32.9) (23.1 to 44.0) 638/770 (82.9) (80.0 to 85.5) 38/119 (31.9) (23.7 to 41.1) 15/38 (39.5) (24.0 to 56.6)
Overlap SSc/mCTD, n/N (%) (95% CI) 149/2070 (7.2) (6.1 to 8.6) 17/848 (2.0) (1.2 to 3.2) 14/85 (16.5) (9.3 to 26.1) 23/770 (3.0) (1.9 to 4.5) 40/119 (33.6) (25.2 to 42.8) 12/38 (31.6) (17.5 to 48.7)
Age at enrolment, years, mean (95% CI) 54.4 (53.8 to 55.0) 52.4 (51.4 to 53.3) 51.3 (48.4 to 54.2) 58.1 (57.2 to 59.1) 49.9 (47.4 to 52.5) 48.5 (44.0 to 53.0)
Age at RP onset, years, mean (95% CI) 39.7 (39.0 to 40.5) 38.5 (37.5 to 39.6) 37.6 (34.7 to 40.6) 41.1 (39.9 to 42.3) 35.7 (32.9 to 38.6) 33.7 (28.5 to 38.9)
Age at first digital ulcer, years, mean (95% CI) 46.6 (45.9 to 47.4) 44.7 (43.6 to 45.7) 44.1 (41.1 to 47.2) 50.1 (48.9 to 51.3) 42.6 (39.6 to 45.5) 38.8 (33.6 to 44.0)
Time from onset of RP to first digital ulcer, years, mean (95% CI) 6.6 (6.2 to 7.0) 6.0 (5.4 to 6.6) 6.1 (4.4 to 7.8) 8.1 (7.3 to 9.0) 6.5 (4.9 to 8.0) 6.9 (3.5 to 10.4)
Time from first non-RP to first digital ulcer manifestation, years, mean (95% CI) 3.6 (3.3 to 3.9) 3.2 (2.9 to 3.6) 3.6 (2.5 to 4.8) 3.9 (3.4 to 4.5) 3.8 (2.7 to 4.9) 4.6 (1.9 to 7.4)

The denominator N varies according to the number of available observations.

*Antibody subsets are not mutually exclusive: one patient can have several antibodies and therefore contribute to several groups.

ACA, anticentromere antibodies; ANA, antinuclear antibodies; anti-Scl-70, anti-scleroderma-70 antibodies; anti-RNA Pol 3, anti-RNA polymerase 3; anti-U1 RNP, anti-U1 ribonucleoprotein; anti-U3 RNP, anti-U3 ribonucleoprotein; dcSSc, diffuse cutaneous systemic sclerosis; lcSSc, limited cutaneous systemic sclerosis; mCTD, mixed connective tissue disease; RP, Raynaud's phenomenon; SSc, systemic sclerosis.


[TableWrap ID: T2] Table 2 

Disease manifestations by antibody status


ANA (N=2085) Anti-Scl-70 (N=854) Anti-RNA Pol 3 (N=86) ACA (N=775) Anti-U1 RNP (N=120) Anti-U3 RNP (N=39)
Lung fibrosis, n/N (%) (95% CI) 873/2085 (41.9) (39.7 to 44.0) 531/854 (62.2) (58.8 to 65.4) 36/86 (41.9) (31.3 to 53.0) 173/775 (22.3) (19.4 to 25.4) 50/120 (41.7) (32.7 to 51.0) 16/39 (41.0) (25.6 to 57.9)
PAH, n/N (%) (95% CI) 307/2085 (14.7) (13.2 to 16.3) 133/854 (15.6) (13.2 to 18.2) 12/86 (14.0) (7.4 to 23.1) 120/775 (15.5) (13.0 to 18.2) 19/120 (15.8) (9.8 to 23.6) 9/39 (23.1) (11.1 to 39.3)
Kidney manifestations, n/N (%) (95% CI) 105/2085 (5.0) (4.1 to 6.1) 43/854 (5.0) (3.7 to 6.7) 7/86 (8.1) (3.3 to 16.1) 26/775 (3.4) (2.2 to 4.9) 10/120 (8.3) (4.1 to 14.8) 5/39 (12.8) (4.3 to 27.4)
Gastrointestinal manifestations, n/N (%) (95% CI) 1192/2085 (57.2) (55.0 to 59.3) 498/854 (58.3) (56.4 to 63.9) 51/86 (59.3) (47.9 to 70.8) 440/775 (56.8) (53.2 to 60.3) 63/120 (52.5) (43.2 to 61.7) 15/39 (38.5) (23.4 to 55.4)
Heart manifestations, n/N (%) (95% CI) 220/2085 (10.6) (9.3 to 12.0) 105/854 (12.3) (10.2 to 14.7) 6/86 (7.0) (2.6 to 14.6) 47/775 (6.1) (4.5 to 8.0) 16/120 (13.3) (7.8 to 20.7) 3/39 (7.7) (1.6 to 20.9)

The denominator N varies according to the number of available observations.

*Antibody subsets are not mutually exclusive: one patient can have several antibodies and therefore contribute to several groups.

ACA, anticentromere antibodies; ANA, antinuclear antibodies; anti-Scl-70, anti-scleroderma-70 antibodies; anti-RNA Pol 3, anti-RNA polymerase 3; anti-U1 RNP, anti-U1 ribonucleoprotein; anti-U3 RNP, anti-U3 ribonucleoprotein; PAH, pulmonary arterial hypertension.


[TableWrap ID: T3] Table 3 

Previous digital ulcer complications and interventions by antibody status


ANA* (N=2085) Anti-Scl-70 (N=854) Anti-RNA Pol 3 N=86 ACA (N=775) Anti-U1 RNP (N=120) Anti-U3 RNP (N=39)
Previous digital ulcer complications
Previous critical digital ischaemia, n/N* (%) (95% CI) 459/867 (52.9) (49.6 to 56.3) 174/340 (51.2) (45.7 to 56.6) 13/19 (68.4) (43.4 to 87.4) 178/321 (55.5) (49.8 to 61.0) 25/47 (53.2) (38.1 to 67.9) 12/17 (70.6) (44.0 to 89.7)
Previous gangrene, n/N* (%) (95% CI) 442/1960 (22.6) (20.7 to 24.5) 171/792 (21.6) (18.8 to 24.6) 14/83 (16.9) (9.5 to 26.7) 181/739 (24.5) (21.4 to 27.8) 28/114 (24.6) (17.0 to 33.5) 11/38 (28.9) (15.4 to 45.9)
Previous autoamputation, n/N* (%) (95% CI) 169/1965 (8.6) (7.4 to 9.9) 86/796 (10.8) (8.7 to 13.2) 4/82 (4.9) (1.3 to 12.0) 51/740 (6.9) (5.2 to 9.0) 9/115 (7.8) (3.6 to 14.3) 4/38 (10.5) (2.9 to 24.8)
Previous soft tissue infection requiring systemic antibiotics, total, n/N* (%) 601/1876 (32.0) (29.9 to 34.2) 243/768 (31.6) (28.4 to 35.1) 18/78 (23.1) (14.3 to 34.0) 257/712 (36.1) (32.6 to 39.7) 30/109 (27.5) (19.4 to 36.9) 14/35 (40.0) (23.9 to 57.9)
Previous osteomyelitis, n/N* (%) (95% CI) 69/1952 (3.5) (2.8 to 4.5) 31/793 (3.9) (2.7 to 5.5) 1/82 (1.2) (0.03 to 6.6) 33/735 (4.5) (3.1 to 6.3) 6/114 (5.3) (2.0 to 11.1) 5/37 (13.5) (4.5 to 28.8)
Previous digital ulcer interventions
Previous hospitalisation for digital ulcer, n/N* (%) (95% CI) 870/1974 (44.1) (41.9 to 46.3) 340/805 (42.2) (38.8 to 45.7) 30/80 (37.5) (26.9 to 49.0) 356/743 (47.9) (44.3 to 51.6) 53/111(47.7) (38.2 to 57.4) 16/35 (45.7) (28.8 to 63.4)
Previous upper limb sympathectomy, n/N* (%) (95% CI) 74/1922 (3.9) (3.0 to 4.8) 21/768 (2.7) (1.7 to 4.2) 3/82 (3.7) (0.8 to 10.3) 43/720 (6.0) (4.4 to 8.0) 4/113 (3.5) (1.0 to 8.8) 1/36 (2.8) (0.1 to 14.5)
Previous digital sympathectomy, n/N* (%) (95% CI) 40/1921 (2.1) (1.5 to 2.8) 15/767 (2.0) (1.1 to 3.2) 3/82 (3.7) (0.8 to 10.3) 22/721 (3.1) (1.9 to 4.6) 2/113 (1.8) (0.2 to 6.3) 1/36 (2.8) (0.1 to 14.5)
Previous arterial reconstruction, n/N* (%) (95% CI) 20/1918 (1.0) (0.6 to 1.6) 6/767 (0.8) (0.3 to 1.7) 2/82 (2.4) (0.3 to 8.5) 12/716 (1.7) (0.9 to 2.9) 2/113 (1.8) (0.2 to 6.3) 1/36 (3.0) (0.1 to 15.8)
Previous arthrodesis, n/N* (%) (95% CI) 31/1642 (1.9) (1.3 to 2.7) 12/638 (1.9) (1.0 to 3.3) 1/70 (1.4) (0.04 to 7.7) 10/607 (1.6) (0.8 to 3.0) 2/99 (2.0) (0.3 to 7.1) 1/33 (3.0) (0.1 to 15.8)
Previous debridement, n/N* (%) (95% CI) 189/1644 (11.5) (10.0 to 13.1) 49/491 (10.0) (8.2 to 13.1) 8/71 (11.3) (5.0 to 21.0) 90/608 (14.8) (12.1 to 17.9) 10/97 (10.3) (5.1 to 18.1) 3/33 (9.1) (1.9 to 24.3)
Previous surgical amputation, n/N* (%) (95% CI) 158/1661 (9.5) (8.1 to 11.0) 51/642 (7.9) (6.0 to 10.3) 6/72 (8.3) (3.1 to 17.3) 90/618 (14.6) (11.9 to 17.6) 10/103 (9.7) (4.8 to 17.1) 4/34 (11.8) (3.3 to 27.5)
Previous use of parenteral prostanoids, n/N* (%) 95% CI) 1112/1907 (58.3) (56.1 to 60.5) 462/775 (59.6) (56.1 to 63.1) 37/81 (45.7) (34.6 to 57.1) 411/707 (58.1) (54.4 to 61.8) 62/113 (54.9) (45.2 to 64.2) 15/36 (41.7) (25.5 to 59.2)

The denominator N varies according to the number of available observations.

*Antibody subsets are not mutually exclusive: one patient can have several antibodies and therefore contribute to several groups.

ACA, anticentromere antibodies; ANA, antinuclear antibodies; anti-Scl-70, anti-scleroderma-70 antibodies; anti-RNA Pol 3, anti-RNA polymerase 3; anti-U1 RNP, anti-U1 ribonucleoprotein; anti-U3 RNP, anti-U3 ribonucleoprotein.



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