Systemic sclerosis-associated interstitial lung disease in the EUSTAR database: analysis by region

Abstract

Objectives

The prevalence and characteristics of SSc-associated interstitial lung disease (SSc-ILD) vary between geographical regions worldwide. The objectives of this study were to explore the differences in terms of prevalence, phenotype, treatment and prognosis in patients with SSc-ILD from predetermined geographical regions in the EUSTAR database.

Material and methods

Patients were clustered into seven geographical regions. Clinical characteristics and survival of patients with SSc-ILD were compared among these pre-determined regions.

Results

For baseline analyses, 9260 SSc patients were included, with 6732 for survival analyses. The prevalence of SSc-ILD in the overall population was 50.2%, ranging from 44.0% in ‘Western Europe and Nordic countries’ to 67.5% in ‘Eastern European, Russia and Baltic countries’. In all regions, anti-topoisomerase antibodies were associated with SSc-ILD. Management also significantly differed; mycophenolate mofetil was prescribed at baseline in 31.6% of patients with SSc-ILD in ‘America (North and South)’ and 31.7% in ‘Middle East’ but only 4.3% in ‘Asia and Oceania’ (P <0.0001). Patients from ‘America (North and South)’ and ‘Middle East’ had the highest survival rate at the end of follow-up (85.8% and 85.2%, respectively).

Conclusions

Our study highlights key differences among regions in terms of clinical presentation and prognosis of SSc-ILD. This work also demonstrates that the management of SSc-ILD is highly variable among the different regions considered, suggesting that efforts are still needed for the standardization of medical practice in the treatment of this disease.

Introduction

SSc is a chronic autoimmune disease characterized by vascular dysfunction and fibrosis of the skin and internal organs [1]. Autoimmunity in SSc includes the positivity for antinuclear antibodies with different mutually exclusive specificity, such as anti-centromere, or anti-topoisomerase (also called anti-Scl70) antibodies [2]. SSc is the rheumatic disease with the highest individual mortality; interstitial lung disease (ILD) is among the leading SSc-related causes of death [1, 3]. The prevalence of SSc-ILD and the extent of lung damage vary according to the different national registries and databases, suggesting that geographical variations may exist regarding SSc-ILD phenotypes [4, 5]. Moreover, variations in the management of SSc-ILD among different regions may also influence prognosis.

Among risk markers, autoantibodies may have a reproducible prognostic value and could be useful to stratify patients in practice or research evaluating SSc-ILD [6]. American registries have shown that patients with anti-topoisomerase antibodies had more severe pulmonary decline than patients with other specificities [7]. Nonetheless, in the SENSCIS study, a large worldwide randomized controlled trial evaluating the efficacy of nintedanib in SSc-ILD, the predictive value of anti-topoisomerase antibodies was not demonstrated [6]. This result may suggest that the predictive value of autoantibodies may, therefore, vary across geographical regions [8].

Heterogeneity in SSc is of utmost importance and is a challenge for clinical practice and trial design. As SSc is a rare disorder, international studies are needed to obtain a sufficient sample size. To date, there is no study comparing the prevalence and clinical presentation of SSc-ILD among different regions worldwide within the same database. The European Scleroderma Trials and Research (EUSTAR) group database is a multicentric international SSc database that offers the unique opportunity of exploring SSc-ILD at a worldwide scale, notably as patients from Asia and America are now included in this European initiative [9, 10]. Therefore, the objectives of this study were to explore the prevalence, clinical phenotype, management and prognosis of patients with SSc-ILD in different predetermined geographical regions based on the prospective EUSTAR database.

Patients and methods

Patient population and characteristics

Patients aged ≥18 years enrolled since January 2009 in the EUSTAR database and fulfilling the ACR/EULAR classification criteria were included [11, 12]. The local ethics committee of each EUSTAR centre (complete list provided in the supplementary data available at Rheumatology online) specifically approved this cohort study, which complies with the Declaration of Helsinki. Informed written consent was provided by all participants. The data set was extracted from the database on 1 December 2020. Patients were classified as having diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc according to LeRoy classification [13]. The structure of the EUSTAR database, the nature of collected data and definitions of clinical variables have been described previously [14, 15]. Disease duration since SSc onset was defined based on the first non-Raynaud’s phenomenon (RP) symptom. The first visit recorded in EUSTAR was considered as the baseline visit. For longitudinal analyses, only patients with a baseline visit and at least one follow-up visit including survival status were included. Overall mortality during follow-up was considered for survival analyses since the detailed cause of death and ILD-specific mortality were not available in the EUSTAR database. All appropriate items within the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were applied [16, 17].

SSc-ILD definition

ILD was attested by the presence of signs of ILD on high-resolution CT (HRCT) and/or X-rays, or when a date for a diagnosis of ILD was notified by the evaluator any time during the study. Pulmonary function tests (PFT) were conducted in the different centres in accordance with European Respiratory Society guidelines [18, 19]. Extent of lung fibrosis on HRCT was not included due to missing data and the absence of centralized assessment of HRCT.

Predefined geographical regions

EUSTAR inclusion centres were located within 36 different countries that were clustered into seven predefined geographical regions: ‘Southern Europe’, ‘Western Europe and Nordic countries’, ‘Eastern Europe, Russia and Baltic countries’, ‘Central Europe’, ‘Middle East’, ‘America (North and South)’ and ‘Asia and Oceania’. These regions were defined prior to any analyses. The definition of these regions was adapted from a previous study evaluating the risks of rheumatic diseases in first- and second-generation immigrants in Europe, and updated based on more recent data [20, 21].

Statistical analysis

Quantitative variables are presented as mean (s.d.) and qualitative variables as N (%). Univariable associations of baseline qualitative characteristics with SSc-ILD, and overall differences between regions for qualitative parameters, were assessed using the Pearson χ² test. Quantitative parameters were compared using the Mann–Whitney U test. Multiple pairwise comparisons between regions were adjusted using Bonferroni correction. Survival analyses were conducted using the log-rank test, and censored 20 years after SSc onset; no specific adjustment for multiple testing was performed for these analyses. As antibody status may predict the course of SSc-ILD and associated survival, we stratified survival analysis based on antibody status. Only patients with known antibody status were included in this survival analysis. As this was an observational explorative study, no power or sample size calculations were performed. A P-value of P < 0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics Version 24.

Results

Patient population

Within the EUSTAR database, 9260 patients fulfilled inclusion criteria and had data regarding ILD status. Among them, 6732 patients had at least one follow-up visit (Fig. 1 and Supplementary Table S1, available at Rheumatology online). In comparison with patients without data regarding SSc-ILD status (n = 1289), patients with data had more severe disease, most notably when considering baseline dcSSc prevalence (30.1% vs 24.4% in patients with data regarding ILD in comparison with patients without) (Supplementary Table S2, available at Rheumatology online). Among patients with data regarding ILD status, 4648 patients had SSc-ILD (50.2%) (Supplementary Table S3, available at Rheumatology online).

ILD prevalence and associated characteristics in the seven predetermined geographical regions

The numbers of patients with SSc-ILD in all regions and countries are detailed in Table 1. The region with the lowest prevalence of SSc-ILD was ‘Western Europe and Nordic countries’ (prevalence of 44.0%) and the highest prevalence of SSc-ILD was in the region ‘Eastern Europe, Russia and Baltic countries’ (prevalence of 67.5%) (Table 1 and Supplementary Table S3, available at Rheumatology online).

The distribution of all considered parameters showed significant overall variation among the seven geographical regions (Table 2). In terms of demographic characteristics, patients from ‘Asia and Oceania’ had the youngest mean age [51.1 years old (15.1)]. The prevalence of males was highly variable, ranging from 28.1% in ‘Western Europe and Nordic countries’ to 12.0% in ‘America (North and South)’ (P < 0.0001).

Regarding disease characteristics at baseline (Table 2), patients from ‘Asia and Oceania’ had a shorter disease duration since first non-RP symptom [6.0 years (7.0)], and mean disease duration significantly differed from that of patients from all other regions (P < 0.0001) except for ‘Eastern Europe, Russia and Baltic countries’ and ‘Western Europe and Nordic countries’. The prevalence of dcSSc was highest in ‘America (North and South)’ (53.1%) and lowest in ‘Southern Europe’ (40%) (P < 0.0001). Other major phenotypic differences concerned muscle weakness, ranging from 4.4% (‘Asia and Oceania’) to 38.8% (‘Eastern Europe, Russia and Baltic countries’), or joint synovitis, ranging from 8.7% (‘Asia and Oceania’) to 28.1% (‘Middle East’).

The prevalence of autoantibodies also reflected this phenotypic heterogeneity. When considering the entire population (n = 4648 patients with SSc-ILD) regardless of the geographical location of the centre, the overall prevalence of anti-topoisomerase antibodies was 50.6%. This prevalence ranged from 26.9% in ‘America North and South’ to 63.0% in ‘Middle East’ (P < 0.0001) (Table 2). Nonetheless, in all regions, the presence of anti-topoisomerase antibodies was significantly more frequent in patients with SSc-ILD in comparison with patients without (Supplementary Table S3, available at Rheumatology online). Similarly, although the prevalence of anti-centromere antibodies was highly variable (from 12.3% in ‘Asia and Oceania’ to 26.6% in ‘Southern Europe’) (Table 2), they corresponded with lower risk of ILD in all regions (Supplementary Table S3, available at Rheumatology online).

In terms of PFTs, the region with the lowest mean forced vital capacity (FVC) percent predicted (%pred) at baseline was ‘America (North and South)’ [73.2 (21.8)], whereas the mean baseline FVC was highest in ‘Southern Europe’ [90.8 (21.7)] (P < 0.0001). In all regions, baseline FVC (%pred) was significantly lower in patients with SSc-ILD than in patients without (Supplementary Table S3, available at Rheumatology online). Mean diffusing capacity of the lungs for carbon monoxide (%pred) was severely impaired in all regions with the lowest mean value in ‘Eastern Europe, Russia and Baltic countries’ [56.0 (18.0)].

Immunomodulatory therapies in the seven predetermined geographical regions

Management at baseline was also significantly different depending on the region. Immunomodulatory therapies were prescribed at baseline in 61.0% of the patients when considering the entire population (n = 4648 patients with SSc-ILD), with large variations (from 18.6% in ‘Asia and Oceania’ to 79.9% in ‘Middle East’). In all regions, mycophenolate mofetil (MMF) was more frequently prescribed in patients with SSc-ILD than in patients without, except in ‘Asia and Oceania’ (Supplementary Table S3, available at Rheumatology online). ‘Middle East’ and ‘America (North and South)’ had the highest rates of MMF use (31.7% and 31.6%, respectively). This baseline prescription of MMF in ‘America (North and South)’ and ‘Middle East’ was significantly greater in comparison with each region taken separately (P < 0.01 after Bonferroni correction) except for ‘Southern Europe’, where the prevalence was numerically lower (24.9%) but without reaching statistical significance after Bonferroni correction (P > 1.000). The lowest rate of MMF use at baseline was in ‘Asia and Oceania’ (4.3%).

Impact of ILD on survival and overall survival in patients with SSc-ILD across the seven predetermined geographical regions

Patients with SSc-ILD had significantly lower rates of survival than patients without in all regions (P < 0.05), except in ‘America (North and South)’ and ‘Middle East’ (P = 0.559 and P = 0.997, respectively) (Fig. 2). This difference did not reach statistical significance in ‘Eastern Europe, Russia and Baltic countries’ (P = 0.077), although a trend was observed (Fig. 2). Similarly, patients from ‘Middle East’ and ‘America (North and South)’ had the highest survival rate at the end of the follow-up (85.2% and 85.8%, respectively) (Fig. 3). ‘Asia and Oceania’ had the lowest survival rate (66.2%), and survival in this region tended to be lower than in other regions [P < 0.05 in comparison with ‘America (North and South)’ and ‘Middle East’, P < 0.200 in all other regions except with ‘Eastern Europe, Russia and Baltic countries’ (P = 0.445)]. Follow-up durations per region are provided in Supplementary Table S4, available at Rheumatology online.

Impact of antibody status on overall survival in patients with SSc-ILD within the seven predetermined geographical regions

When considering antibody status as dichotomic variables, patients with anti-centromere antibodies had better survival rates than patients negative for this antibody subtype in the overall SSc-ILD population (P = 0.01). Nonetheless, this difference was only observed in ‘Southern Europe’ when regions were considered separately (P = 0.001 in this region and P > 0.100 in all others), and the opposite trend was observed in ‘Asia and Oceania’ (Supplementary Fig. S1, available at Rheumatology online). In the overall SSc-ILD population, there was no difference in terms of survival between patients with and without anti-topoisomerase antibodies (Fig. 4). Nonetheless, when considering each region separately, anti-topoisomerase antibody status significantly discriminated survivors and non-survivors among SSc-ILD patients in ‘America (North and South)’ (P = 0.001 in this region and P > 0.100 in all others except ‘Asia and Oceania’). The opposite trend was observed in ‘Asia and Oceania’ (Fig. 4). Patients with anti-RNA polymerase III antibodies tended to have lower survival rates in the overall SSc-ILD population, and this result reached statistical significance in ‘Western Europe and Nordic counties’ and ‘Eastern Europe, Russia and Baltic countries’ (P = 0.026 and P = 0.027, respectively). The opposite trend was observed in ‘America (North and South)’ (Supplementary Fig. S2, available at Rheumatology online).

When considered as separate variables with pairwise comparison, there was no difference in terms of survival among the populations defined by antibody status in the overall SSc-ILD population (Supplementary Fig. S3 and Supplementary Table S5, available at Rheumatology online). When considering each region separately, discrepancies were observed in the prognostic values of autoantibodies, as detailed in Supplementary Table S5, available at Rheumatology online.

Discussion

The objectives of this study were to explore the differences in terms of prevalence, clinical presentation, prognosis and treatment in patients with SSc-ILD from predetermined geographical regions in the EUSTAR database. Our study highlights the heterogeneity of survival and SSc-ILD prevalence, as its regional prevalence ranged from 44% to 67.5% of patients with SSc. This range is consistent with recent results from national registries and international reviews [4, 22].

Geographical discrepancies may reflect differences in health care organization, access to SSc centres, ILD screening strategies and early management of SSc (including treatments). Our work provides insight into the worldwide regional differences concerning the treatment of SSc-ILD, as about one-third of SSc-ILD patients in ‘America (North and South)’ and ‘Middle East’ used MMF at baseline, whereas this proportion fell to 4.3% in ‘Asia and Oceania’. Such differences could be explained by discrepancies in terms of drug availability or drug validation by the regulatory agencies in these different regions. Organization of healthcare systems may also help to explain geographical disparities, notably including cost compensation system, health insurance policies and early access to expert centres [23].

Regarding phenotype, key risk factors for SSc-ILD onset such as positivity for anti-topoisomerase antibodies (anti-Scl70) were common to all regions when comparing patients with and without SSc-ILD in our study. By contrast, the prognostic values of autoantibodies in terms of survival varied across regions and could not be generalized worldwide based on our data. The heterogeneous predictive value of antibody subtypes in SSc-ILD depending on the region of interest suggests that their predictive value should be considered based on the geographical context [2, 8, 24, 25]. This result may explain the discrepancies between the American registries, where positivity for anti-topoisomerase antibodies (Scl70) was associated with worse prognosis, and the international SENSCIS trial, in which this result was not confirmed [6, 7]. This result may suggest that a double stratification on geographical region and autoantibody status could be useful for randomization in SSc-ILD randomized controlled trials. The variable performances of detection techniques for anti-topoisomerase antibodies that were available in the different regions may also contribute to these differences [26]. Antibody subtypes have been proposed as a relevant marker for a future sub-classification of SSc, beyond the skin-based classification of dcSSc vs limited cutaneous SSc [2]. Their variable prognostic value in SSc-ILD, as illustrated in our study, and the variable availability of the most specific detection techniques across different regions, may suggest that the relevance of such an antibody-based classification should be carefully validated in different regions worldwide before being fully endorsed.

Studies directly comparing patients from different countries have also underscored the variable severity of SSc among patients depending on their geographical origin. For example, review of the EUSTAR database revealed that Iranian patients with SSc more frequently had dcSSc and a lower FVC value than French patients [27]. Similarly, American patients had more severe phenotypes, with a higher prevalence of dcSSc than French patients [8]. In these studies, phenotypic differences were also associated with significant differences in the prevalence of antibody subtypes such as anti-centromere and anti-topoisomerase I antibodies. The prevalence of digital ulcers in multicentre studies also varies depending on the geographical origin [28].

The strengths of our study include its large sample size, its unique worldwide approach in SSc-ILD and its long-term follow-up. The careful evaluation of validated inclusion criteria of SSc by well-trained clinicians is also a strength in comparison with databases based on International Classification of Diseases-10 codes or other unrepresentative identification methods in nationwide databases [11, 12].

Our study has several limitations. We did not include genetic analyses in our results because these data were not available in the EUSTAR database. This could be considered as a limitation because geographical discrepancies may reflect the influence of genetic background on the clinical presentation and clinical trajectories of SSc-ILD patients [29–31]. Nonetheless, recent studies suggest that antibody subtypes could be surrogate markers of genetic differences in patients with SSc [32]. Within the same geographical region, race may also impact the phenotype and antibody subtypes of patients with SSc [33]. Black patients more frequently have SSc-ILD and a lower prevalence of anti-centromere antibodies as compared with white patients [9, 33, 34]. We did not include ethnicity in our study as this question was recently explored in EUSTAR, with a study showing that black patients had more severe disease when considering the prevalence of dcSSc compared with white patients and that the mortality rate was higher in Asian patients than in white patients [9]. Although this result is in accordance with our results on SSc-ILD in ‘Asia and Oceania’, there were no data regarding SSc-ILD prevalence or management in this previous EUSTAR study on ethnic differences, and beyond stratification on centres, only two geographical regions were explored (inside/outside Asia and inside/outside sub-Saharan Africa). Our study fills this gap. Differences in the specificity of autoantibodies may contribute to explaining the variable prevalence of visceral involvement such as SSc-ILD among ethnicities [31, 34, 35]. The severity of SSc-ILD may also be influenced by environmental exposures [36, 37] or socio-demographic factors, which may vary according to regions and/or ethnicities as suggested by recent analyses in African-American patients [38–40]. In our work, 10–15% of patients had SSc-ILD diagnosed by X-rays, and this could be considered as a limitation as HRCT is the reference standard for the diagnosis of ILD. Nonetheless, the majority of patients had available HRCT [>90% in all regions except in Eastern Europe, Russia and Baltic countries (87.9%) and Central Europe (77%)].

Another limitation is that the seven geographical regions delineated in our study could be considered arbitrary, although we based this repartition on previous publications and designed them prior to any analyses [20, 21]. Our results may have been different if the regions had been designed differently. The differences across regions may also be a result of the variable demographical parameters and variable statistical power linked to different sample size in each region. Nonetheless, statistical differences in key parameters such as autoantibodies were observed in regions with a small sample size, suggesting that the statistical power was sufficient to highlight relevant differences. Moreover, all regions had at least 175 patients, which could be considered as a large sample size as SSc-ILD is a rare disease. We only included baseline medications, and treatments such as immunomodulatory drugs may have changed during the course of the disease; this underscores the need to interpret the results on management with caution. We did not include any detailed analysis of HRCT parameters such as ILD patterns as these data were not available in EUSTAR. PFT trajectories were not explored in our work as such data have been recently analysed in EUSTAR, although geographical differences were not assessed [14]. The absence of centralized confirmation of antibody status is also a limitation inherent to the worldwide scale of the database [26].

Conclusions

Our study highlights key differences among regions in terms of prognosis and clinical presentation worldwide. This work also demonstrates that the management of SSc-ILD is highly variable among the different regions considered, suggesting that further efforts are needed for standardization of medical practice in the treatment of SSc-ILD, especially as it remains among the leading causes of SSc-related death. These regional discrepancies suggest that further research is warranted to investigate how potential interplays between genetic background and epigenetic influence exerted by different environmental exposure arising from geographic boundaries may impact SSc-ILD onset, clinical phenotype and the prevalence of associated autoantibodies.

Supplementary data

Supplementary data are available at Rheumatology online.

Data availability statement

The data that support the findings of this study are available upon reasonable request.

Funding

This study was supported by Boehringer Ingelheim International GmbH (BI). BI had no role in the design, analysis or interpretation of the results in this study. BI was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations.

Disclosure statement: D.H. declares support for attending meetings and/or travel from Shire outside of the current study. N.S. is an employee of Boehringer Ingelheim International GmbH. P.A. declares payment or honoraria for presentations from Boehringer Ingelheim International GmbH outside of the current study. J.dV-B. declares consulting fees from Boehringer Ingelheim International GmbH and Abbvie (<€5000) outside of the current study. G.R. declares consulting fees from Boehringer Ingelheim International GmbH and Janssen, speaker honorarium from Boehringer Ingelheim International GmbH outside of the current study. E.H. declares honoraria for lectures from Boehringer Ingelheim International GmbH (<€10 000) outside of the current study. N.H. declares consulting fees from Boehringer Ingelheim International GmbH and honoraria for lectures from Boehringer Ingelheim International GmbH outside of the current study. A-M. H-V. declares grants or contracts from Bayer, Boehringer Ingelheim, consulting fees from Actelion, Boehringer Ingelheim, ARXX, Medscape, Honoraria for lectures, presentations from Actelion, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Lilly, Medscape, support for attending meetings and/or travel from Actelion, Boehringer Ingelheim, Roche, Medscape, declares being a member from the board of EUSTAR, Nordic Pulmonary hypertension group, and declares medical writing from Boehringer Ingelheim. O.D. declares research grants from Kymera and Mitsubishi Tanabe, consulting fees from Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Corbus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Tanabe, MSD, Roche, Roivant, Topadur and UBC, speaker fees from Bayer, Boehringer Ingelheim, Medscape, Novartis, Roche, patent issued ‘mir-29 for the treatment of systemic sclerosis’ (US8247389, EP2331143) outside of the current study. M.C. declares research grants from BMS, Celgene, Pfizer and Boehringer Ingelheim, lecture fees from Janssen, declares that the University of Genova Received equipment, materials, drugs, medical writing, gifts or other services from DS Medica outside of the current study. Y.A. declares consulting fees from Boehringer Ingelheim, Sanofi, Celltrion, Roche, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim and Sanofi outside of the current study. The other authors have nothing to disclose.

Acknowledgements

Collaborators: On behalf of EUSTAR collaborators: Marco Matucci Cerinic (Florence (Italy)); Ulrich Walker (Basel (Switzerland)); Florenzo Iannone (Bari (Italy)); Radim Becvar (Prague (Czech Republic)); Otylia Kowal Bielecka (Bialystok (Poland)); Carmen Pizzorni (Genova (Italy)); Francesco Ciccia (Naples (Italy)); Elise Siegert (Berlin (Germany)); Simona Rednic (Cluj-Napoca (Romania)); P. Vlachoyiannopoulos (Athens (Greece)); Jiri Stork (Prague (Czech Republic)); Murat Inanc (Capa, Istanbul (Turkey)); Patricia E. Carreira (Madrid (Spain)); Srdan Novak (Rijeka (Croatia)); László Czirják (Pecs (Hungary)); Michele Iudici (Geneva (Switzerland)); Eugene J. Kucharz (Katowice (Poland)); Katja Perdan-Pirkmajer (Ljublijana (Slovenia)); Bernard Coleiro (Balzan (Malta)); Gianluca Moroncini (Ancona (Italy)); Dominique Farge Bancel (Paris (France)); Fabian A Mendoza (Philadelphia (USA)) Roger Hesselstrand (Lund (Sweden)); Mislav Radic (Split (Croatia)); Alexandra Balbir-Gurman (Haifa (Israel)); Andrea Lo Monaco (Ferrara (Italy)); Raffaele Pellerito (Torino (Italy)); Alessandro Giollo (Verona (Italy)); Jadranka Morovic-Vergles (Zagreb (Croatia)); Christopher Denton (London (United Kingdom)); Madelon Vonk (Nijmegen (The Netherlands)); Nemanja Damjanov (Belgrade (Serbia & Montenegro)); Jörg Henes (Tübingen (Germany)); Vera Ortiz Santamaria (Granollers, Barcelona (Spain)); Stefan Heitmann (Stuttgart (Germany)); Dorota Krasowska (Lublin (Poland)); Paul Hasler (Aarau (Switzerland)); Michaela Kohm (Frankfurt am Main (Germany)); Ivan Foeldvari (Hamburg (Germany)); Gianluigi Bajocchi (Reggio Emilia (Italy)); Maria João Salvador (Coimbra (Portugal)); Bojana Stamenkovic (Niska Banja (Serbia and Montenegro)); Carlo Francesco Selmi (Rozzano, Milano (Italy)); Mohammed Tikly (Johannesburg (South Africa)); Lidia P. Ananieva (Moscow (Russia)); Ariane Herrick (Salford (United Kingdom)); Ulf Müller-Ladner (Bad Nauheim (Germany)); Klaus Søndergaard (Aarhus N (Denmark)); Francesco Puppo (Genova (Italy)); Merete Engelhart (Hellerup (Denmark)); Gabriela Szücs (Debrecen (Hungary)); Carlos de la Puente (Madrid (Spain)); Valeria Riccieri (Roma (Italy)); Ruxandra Maria Ionescu (Bucharest (Romania)); Ami Sha (Baltimore (USA)); Ana Maria Gheorghiu (Bucharest (Romania)); Cord Sunderkötter (Münster (Germany)); Jörg Distler (Erlangen (Germany)); Francesca Ingegnoli (Milano (Italy)); Luc Mouthon (Paris (France)); Vanessa Smith (Ghent (Belgium)); Francesco Paolo Cantatore (Foggia (Italy)); Susanne Ullman (Copenhagen (Denmark)); Carlos Alberto von Mühlen (Porto Alegre (Brazil)); Maria Rosa Pozzi (Monza (Italy)); Kilian Eyerich (Munich (Germany)); Piotr Wiland (Wroclaw (Poland)); Marie Vanthuyne (Brussels (Belgium)); Juan Jose Alegre-Sancho (Valencia (Spain)); Kristine Herrmann (Dresden (Germany)); Ellen De Langhe (Leuven (Belgium)); Branimir Anic, Marko Baresic, Miroslav Mayer (Zagreb (Croatia)); Maria Üprus, Kati Otsa (Tallin (Estonia)); Sule Yavuz (Altunizade-Istanbul (Turkey)); Brigitte Granel (Marseille (France)); Carolina de Souza Müller (Curitiba (Brazil)); Svetlana Agachi (Chisinau (Republic of Moldova)); Simon Stebbings (Dunedin (New Zealand)); Alessandro Mathieu, Alessandra Vacca (Monserrato (CA) (Italy)); Percival D. Sampaio-Barros (São Paulo (Brazil)); Lisa Stamp (Christchurch (New Zealand)); Kamal Solanki (Hamilton (New Zealand)); Douglas Veale (Dublin (Ireland)); Esthela Loyo, Carmen Tineo (Santiago (Dominican Republic)); Sergio Toloza (Catamarca (Argentina)); Mengtao Li (Beijing (China)); Walid Ahmed Abdel Atty Mohamed (Alexandria (Egypt)); Jacek Olas (Crakow (Poland)); Fahrettin Oksel, Figen Yargucu (Bornova, Izmir (Turkey)); Cristina-Mihaela Tanaseanu (Bucharest (Romania)); Rosario Foti (Catania (Italy)); Codrina Ancuta (Iasi (Romania)); Daniel E. Furst (Los Angeles (USA)); Britta Maurer (Bern (Switzerland)); Jacob van Laar (Middlesbrough (United Kingdom)); Marzena Olesinska (Warsaw (Poland)); Cristiane Kayser (São Paulo (Brazil)); Nihal Fathi (Assiut (Egypt)); Paloma García de la Peña Lefebvre, Jorge Juan Gonzalez Martin (Madrid (Spain)); Patrick Carpentier, Bernard Imbert (Grenoble (France)); Camille Francès, Patricia Senet (Paris (France)); Jean Sibilia (Strasbourg (France)); Ira Litinsky (Tel Aviv (Israel)); Jean Luc Senécal, Martial Koenig, France Joval, Grodzicky Tamara (Montréal (Canada)); Francesco Del Galdo (Leeds (United Kingdom)); Goda Seskute (Vilnius (Lithuania)); Lesley Ann Saketkoo (New Orleans (USA)); Eduardo Kerzberg (Buenos Aires (Argentina)); Washington Bianchi, Breno Valdetaro Bianchi (Rio de Janeiro (Brasil)); Ivan Castellví (Barcelona (Spain)); Jasminka Milas-Ahic, Roberta Visevic (Osijek (Croatia)); Massimiliano Limonta (Bergamo (Italy)); Doron Rimar (Haifa (Israel)); Maura Couto (Viseu (Portugal)); François Spertini (Lausanne (Switzerland)); Antonella Marcoccia (Roma (Italy)); Sarah Kahl (Bad Bramstedt (Germany)); Vivien M. Hsu (New Brunswick (USA)); Thierry Martin (Strasbourg (France)); Sergey Moiseev, Pavel Novikov (Moscow (Russia)); Lorinda S. Chung (Stanford (USA)); Tim Schmeiser (Wuppertal-Elberfeld (Germany)); Dominik Majewski (Poznan (Poland)); Zbigniew Zdrojewski (Gdansk (Poland)); Julia Martínez-Barrio (Madrid (Spain)); Dinesh Khanna (Ann Arbor, Michigan (USA)); Vera Bernardino (Lisboa (Portugal)); Lelita Santo (Coimbra (Portugal)); Yair Levy (Kfar Saba (Israel)); Elena Rezus (Lasi (Romania)); Omer Nuri Pamuk (Edirne (Turkey)); Daniel Brito de Araujo (Pelotas, RS (Brasil)); Piercarlo Sarzi Puttini (Milano (Italy)); Marek Brzosko (Szczecin (Poland)); Hadi Poormoghim (Tehran (Iran)); Marta Maman (Buenos Aires (Argentina)); Ina Kötter (Hamburg (Germany)); Giovanna Cuomo (Naples (Italy)); Francis Gaches (Toulouse (France)); Laura Belloli (Milano (Italy)); Petros Sfikakis (Athens (Greece)); Juliana Markus (Uberlandia (Brazil)); Daniel Furst (Los Angeles (USA)); Ana-Maria Ramazan (Constanta City (Romania)); Marie-Elise Truchetet (Bordeaux (France)); Patrick Jego (Rennes (France)); Lorenzo Dagna (Milano (Italy)); JM van Laar (Utrecht (The Netherlands)); Lidia Rudnicka (Warsaw (Poland)); Susana Oliveira (Amadora (Portugal)); Fabiola Atzeni (Messina (Italy)); Masataka Kuwana (Tokyo (Japan)); Arsene Mekinian (Paris (France)); Mickaël Martin (Poitiers (France)); Yoshiya Tanaka (Kitakyushu (Japan)); Hidekata Yasuoka (Aichi (Japan)); Carmen-Pilar Simeón-Aznar (Barcelona (Spain)); Tatsuya Atsumi (Sapporo (Japan)); Magda Parvu (Bucharest (Romania)); Ines Cordeiro (Lisboa (Portugal)); Nicoletta Del Papa (Milano (Italy)); Thomas Karonitsch (Vienna (Austria)); Anna Bazela-Ostromecka (Grunwaldzka (Poland)); Enrico Selvi (Siena (Italy)); Yasushi Kawaguchi (Tokyo (Japan)); Tomas Soukup (Hradec Kralove (Czech Republic)); Ignasi Rodriguez-Pinto (Barcelona (Spain)); Marija Geroldinger-Simic (Linz (Austria)); Gerard Espinosa (Barcelona (Spain)); Karen Voigt (Hamburg (Germany)); Torsten Kubacki (Köln (Germany)); Olena Garmish (Kiev (Ukraina)); Marta Mosca (Pisa (Italy)); Ulrich Gerth (Rheinfelden (Switzerland)); Ludmila Antonenko (Kiev (Ukraina)).

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment for the development of the manuscript. Editorial support and formatting assistance, in part, were provided by Claire Scott, of MediTech Media, UK, and was contracted and funded by Boehringer Ingelheim International GmbH (BI).

References

Author notes