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Jaeger, VK, Valentini, G, Hachulla, E et al. (22 more authors) (2018) Smoking in Systemic Sclerosis: A Longitudinal European Scleroderma Trials and Research Group Study. Arthritis and Rheumatology, 70 (11). pp. 1829-1834. ISSN 2326-5191

https://doi.org/10.1002/art.40557

© 2018, American College of Rheumatology. This is the peer reviewed version of the following article: Jaeger, VK, Valentini, G, Hachulla, E et al. (22 more authors) (2018) Smoking in Systemic Sclerosis: A Longitudinal European Scleroderma Trials and ResearchGroup Study. Arthritis and Rheumatology, 70 (11). pp. 1829-1834. ISSN 2326-5191, which has been published in final form at https://doi.org/10.1002/art.40557. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Uploaded in accordance with the publisher's self-archiving policy.

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lead to differences between this version and the Version of Record. Please cite this article as

doi: 10.1002/art.40557

This article is protected by copyright. All rights reserved.

DR. EDOARDO ROSATO (Orcid ID : 0000-0002-7417-8093)

DR. FRANCESCO DEL GALDO (Orcid ID : 0000-0002-8528-2283)

Article type : Brief Report

Running head: Smoking in systemic sclerosis

Title: Smoking in Systemic Sclerosis: a Longitudinal European Scleroderma Trials

and Research Group Study

Veronika K┻ Jaeger MScな┸ Gabriele Valentini MDに┸ Eric (achulla MD┸ PhDぬ┸ Franco Cozzi MDね┸ Oliver Distler MDの┸ Paolo Airó MDは┸ Laszlo Czirják MD┸ PhDば┸ Yannick Allanore MD┸ PhDぱ┸ Elise Siegert MDひ┸ Edoardo Rosato MDなど┸ Marco Matucci┽Cerinic MD┸ PhDなな┸ Cristian Caimmi MDなに┸ Jörg (enes MDなぬ┸ Patricia E┻ Carreira MDなね┸ Vanessa Smith MD┸ PhDなの┸なは┸ Francesco del Galdo MD┸ PhDなば┸ Christopher P┻ Denton MD┸ PhDなぱ┸ Susanne Ullman MDなひ┸ Ellen De Langhe MD┸ PhDにど┸ Valeria Riccieri MD┸ PhDにな┸ Juan J┻ Alegre┽Sancho MD┸ PhDにに┸ Simona Rednic MD┸ PhDにぬ┸ Ulf M“ller┽Ladner MDにね┸ Ulrich A┻ Walker MDな┸ EUSTAR co┽authors な Department of Rheumatology┸ University (ospital Basel┸ Basel┸ Switzerland に Rheumatology Department┸ Second University of Naples┸ Naples┸ )taly ぬ Service de Médecine )nterne┸ (ôpital (uriez┸ Université de Lille┸ Lille┸ France ね Rheumatology Unit┸ Department of Medicine┸ University of Padova┸ Padova┸ )taly の Department of Rheumatology┸ University (ospital Zurich┸ Zurich┸ Switzerland

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は UO Reumatologia ed )mmunologia Clinica┸ Spedali Civili┸ Brescia┸ )taly ば Department of Rheumatology and )mmunology┸ University of Pécs┸ Pécs┸ (ungary ぱ Department of Rheumatology A┸ Paris Descartes University┸ Cochin (ospital┸ France┸ Paris ひ Department of Rheumatology and )mmunology┸ University (ospital Charité┸ Berlin┸ Germany など Department of Clinical Medicine┸ Clinical )mmunology Unit┽Scleroderma Center┸ Sapienza University of Rome┸ Rome┸ )taly なな Department of Experimental and Clinical Medicine┸ University of Florence ┃ Div of Rheumatology AOUC┸ Florence )taly なに Unit of Rheumatology┸ University of Verona┸ Verona┸ )taly なぬ Department of )nternal Medicine ))┸ Eberhard┽Karls┽University T“bingen┸ T“bingen┸ Germany┻ なね Servicio de Reumatologia┸ (ospital Universitario なに de Octubre┸ Madrid┸ Spain なの Faculty of )nternal Medicine┸ Ghent University┸ Ghent┸ Belgium┸ なは Department of Rheumatology┸ Ghent University (ospital┸ Ghent┸ Belgium なば Leeds Musculoskeletal Biomedical Research Unit ゅLMBRUょ┸ University of Leeds┸ Leeds┸ United Kingdom なぱ Department of Rheumatology┸ University College London┸ Royal Free (ospital┸ London┸ United Kingdom なひ Department of Dermatology┸ Bispebjerg (ospital┸ University of Copenhagen┸ Denmark にど Department of Rheumatology┸ University (ospitals Leuven┸ Leuven┸ Belgium┸ にな Rheumatology Unit┸ Department Of )nternal Medicine and Medical Specialities┸ Sapienza University of Rome┸ )taly にに Sección de Reumatología┸ (ospital Universitario Dr Peset┸ Valencia┸ Spain┸

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にぬ Clinica Reumatologie┸ University of Medicine ┃ Pharmacy┸ Cluj┽Napoca┸ Romania にね Department of Rheumatology and Clinical )mmunology┸ Justus┽Liebig┽University of Giessen┸ Kerckhoff┽Klinik┸ Bad Nauheim┸ Germany EUSTAR co-authors: Lidia P┻ Ananieva┸ Florenzo )annone┸ Jörg (┻W┻ Distler┸ Eduardo Kerzberg┸ Bojana Stamenkovic┸ José Antonio Pereira Da Silva┸ )van Catellví┸ Sule Yavuz┸ Kamal Solanki┸ Branimir Anic┸ Esthela Loyo┸ Tim Schmeiser┸ Ruxandra Maria )onescu┸ Peter Villiger┸ Francesco Paolo Cantatore┸ Paloma García de la Peña Lefebvre┸ Carina Mihai┸ Dominique Farge Bancel┸ Pierluigi Meroni┸ Thierry Martin┸ Stefan (eitmann┸ Nicolas (unzelmann┸ Fahrettin Oksel┸ Washington Bianchi┸ Sara Bongiovanni┸ Radim Becvar┸ Thierry Zenone┸ Alexandra Balbir┽Gurman┸ Piotr Wiland┸ Pawel Zebryk┸ François Spertini┸ Lori Chung┸ Alessandra Vacca┸ Carlo Chizzolini┸ Carlo Francesco Selmi┸ Cristina┽Mihaela Tanaseanu┸ )ra Litinsky┸ Frédéric A┻ (oussiau┸ Brigitte Krummel┽Lorenz┸ Vivien M┻ (su┸ Francisca Fontes┸ Alexandra Maria Burlui┸ Duska Martinovic┸ Sergei Popa┸ )tzhak Rosner┸ Carmel Mallia┸ Rosario Foti┸ Luc Mouthon┸ Martin Aringer┸ Jacob van Laar┸ Roger (esselstrand┸ Maria Rosa Pozzi┸ Gabriela Riemekasten┸ Maurizio Cutolo┸ Paul (asler┸ Zea Mendoza Antonio┸ Cord Sunderkötter┸ Codrina Ancuta┸ Jean Sibilia┸ Roberto Caporali┸ Armando Gabrielli┸ Raffaele Pellerito┸ Ariane (errick┸ Øyvind Midtvedt┸ Kilian Eyerich┸ Brigitte Granel┸ Lesley Ann Saketkoo┸ Maura Couto┸ Yael Eizikovits┸ Giuseppina Abignano┻ FUNDING None

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COMPETING INTERESTS None KEYWORDS Systemic sclerosis┸ smoking┸ organ manifestations┸ prevalence┸ progression CORRESPONDING AUTHOR Ulrich A┻ Walker┸ Department of Rheumatology┸ University (ospital Basel┸ Petersgraben ね┸ ねどぬな Basel┸ Switzerland┹ Phone┺ ギねなはなののはのどなな┹ Fax┺ ギねなはなにはのひどにな┹ E┽mail┺ ulrich┻walkerｈusb┻ch

ABSTRACT

Objectives: Data on the role of tobacco exposure in systemic sclerosis ゅSScょ severity and progression are scarce┻ We aimed to assess the effects of smoking on the evolution of pulmonary and skin manifestations in the EUSTAR database┻ Methods: Adult SSc patients with data on smoking history and a なに┽にね months follow┽up visit were included┻ Associations of severity and progression of organ involvement with smoking history and the comprehensive smoking index ゅCS)ょ were assessed using multivariable regression analyses┻ Results: ぬ┸ぬなひ patients were included ゅage のば years┹ ぱのガ femaleょ┸ ははガ were never smokers┹ にぬガ ex┽smokers and ななガ were current smokers┻ Current smokers had a lower percentage of anti┽topoisomerase autoantibodies than previous or never smokers ゅぬなガ vs. ねどガ and ねのガ┸ respectivelyょ┻ Never smokers had a higher baseline forced expiratory volume in one second【forced vital capacity ゅFEVな【FVCょ ratio than previous and current smokers ゅpジど┻どどなょ┻ The FEVな【FVC ratio declined faster in current smokers than in never smokers ゅpサど┻どのょ or ex┽smokers ゅpサど┻どなょ┻

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The baseline modified Rodnan skin score ゅmRSSょ and the mRSS decline were comparable across smoking groups┻ Although heavy smoking ゅmore than にの pack yearsょ increased the odds of digital ulcers by almost のどガ┸ there was no robust adverse association of smoking with digital ulcer development┻ Conclusion: The known adverse effect of smoking on bronchial airways and alveoli is also observed in SSc patients┹ however robust adverse effects of smoking on the progression of SSc┽specific pulmonary or cutaneous manifestations were not observed┻ Systemic sclerosis ゅSScょ is a rare┸ multisystem autoimmune disorder いなう┻ (ypoxia and oxidative stress have been implicated in the pathophysiology of its generalized microangiopathy and fibrosis いなう┻ Although smoking does not appear to confer a risk for SSc development いにう┸ it has vasoconstrictive effects and increases free radical exposure┸ and together with other proinflammatory and immunomodulatory effects may exacerbate SSc manifestations いぬう┻ Data on the role of tobacco exposure with regards to the severity of SSc organ manifestations and progression are however scarce and at times contradictory いねう┻ A Canadian cohort study of はどは patients for example reported an increased frequency of digital ulcers ゅDUょ in smokers いねう┸ whereas a study of なばに Australian patients┸ found no association of smoking history with vascular characteristics いのう┻ Larger studies and robust data assessing the possible effect of smoking on SSc presentations and importantly SSc progression are lacking┻ We therefore assessed the association of tobacco exposure with the prevalence and evolution of SSc organ manifestations┻

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PATIENTS AND METHODS This study is based on the multinational┸ longitudinal European Scleroderma Trials and Research ゅEUSTARょ database いはう┻ Each center obtained local ethical committee approval┹ each patient provided written informed consent┻ Data collection started in にどどね┻ The smoking module┸ however┸ was introduced to the database in にどなぬ┹ hence smoking data were only collected from that date onwards┻ Data for this study were exported in May にどなば┻ Patients were included if they were older than なぱ years┸ fulfilled the なひぱど ACR or にどなぬ ACR【EULAR criteria for SSc┸ and if the smoking status was known┹ additionally┸ patients were required to have a follow┽up visit なに┽にね months after baseline┻ )nformation about the core data collected in EUSTAR can be found elsewhere いはう┻ The EUSTAR smoking module collects patient┽reported smoking status ゅnever【previous【current smokerょ┸ the number of pack┽years┸ and the smoking start and cessation dates┻ The influence of smoking behavior was assessed on several disease parameters┺ forced expiratory volume in one second【forced vital capacity ratio ゅFEVな【FVCょ┸ FVC┸ single breath diffusing capacity for monoxide ゅDLCO【sbょ┸ systolic pulmonary arterial pressure as estimated by echocardiography ゅPAPsysょ┸ modified Rodnan skin score ゅmRSSょ and digital ulcers ゅDUょ┻ Further information about outcome measures as well as variables describing the study population can be found in Supplementary Table な┻ Outcome progression was downscaled to ╅rate of change per なに months╆ unless otherwise stated┻

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Statistical analysis Frequencies【percentages or means【standard deviations ゅSDょ were calculated┹ groups were compared using やに┽tests【Fisher╆s exact tests or t┽tests【ANOVA┻ Multiple linear and logistic regression analyses were applied to adjust outcome【exposure associations with a priori defined potential confounding factors ゅage┸ sex┸ time since the onset of Raynaud╆s phenomenon いRPう and since the first non┽RP manifestation┸ antibody status┸ and skin involvementょ┻ As the SSc specific antibodies might be on the causal pathway between smoking and SSc organ involvement we additionally analyzed the data without adjustment for antibody status┸ these results can be found in the supplementary ゅSupplementary Tables に┸ ぬ┸ ねょ┻ Three smoking metrics were modelled separately┺ ゅModel なょ never【previous【current smoking┸ ゅModel にょ smoking intensity ゅpack┽years┹ never smokers サど pack┽years┸ light smokers サど┽など pack┽years┸ medium smokers サなど┽にの pack┽years┸ heavy smokers サスにの pack┽yearsょ┸ and ゅModel ぬょ comprehensive smoking index ゅCS)ょ┻ The CS) is an index incorporating smoking duration┸ time since cessation and smoking intensity into a single variable いば┸ぱう┻ The CS) depends on two parameters which are estimated for each outcome separately┺ the half┽life┸ i┻e┻ the rate at which the smoking╆s impact decays over time┸ and the lag┽time┸ i┻e┻ the delay between smoking and its impact┻ Never smokers carry a CS) of ど and higher CS) values indicate more smoking┻ The CS) values are estimated separately for each outcome variable and hence the CS)s including their ranges are different for each outcome variable┻ The results from the CS) regression analyses should be interpreted in the following way┺ The beta values represent the additive increase or decrease in the outcome variable per unit increase in the CS)┻ The odds ratio ゅORょ values represent the increase in odds for the presence of the outcome

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variable per unit CS) increase┻ OR values larger than one indicate that increased smoking increases the likelihood of occurrence of the outcome┻ Missing data were imputed using multiple imputation with chained equations いひう┻ The regression analyses shown in this paper are all based on imputed data┹ the results based on a complete case analysis are represented in Supplementary Table は┻ Analyses were performed with Stata【)Cなの┻なゅStataCorp┸ USAょ┻

RESULTS

Patient and smoking characteristics Of the なに┸ひなに adult SSc patients within EUSTAR┸ はなばひゅねぱガょ patients had no smoking data available┹ in ぬねなねゅにはガょ patients had no follow┽up visit in the required time frame┻ Therefore ぬ┸ぬなひゅにはガょ patients fulfilled the inclusion criteria ゅSupplementary Figure なょ┻ The included patients had clinically similar demographic and disease characteristics than the excluded patients ゅSupplementary Table のょ┻ On average┸ a follow┽up visit was recorded な┻ね years ゅSD ど┻ぬぬょ after baseline┻ Patients were on average のば years old and ぱのガ were female┻ Demographic and disease characteristics are shown in Table な┻ ははガ of patients were never smokers┸ にぬガ ex┽smokers and ななガ were current smokers┹ なぬガ of the current smokers ゅな┻のガ of patientsょ stopped smoking during the observation time on average ひ months after the baseline visit┻ The average ex┽smokers had smoked なぱ pack┽years ゅSD になょ during a time of なひ years ゅSD なにょ and ceased smoking なの years ゅSD なぬょ ago┻ ねひガ of the ex┽smokers had ceased smoking before RP onset and のぱガ had quit before the onset of the first non┽RP manifestation┻ The average current smoker had smoked にば pack┽years ゅSD ぬどょ during a time of ぬど years ゅSD なぬょ┻ As patients with interstitial lung disease ゅ)LDょ might be more likely to cease smoking than patients without )LD there might be a higher percentage of )LD patients in the

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previous smoker group possibly leading to worse trajectories in lung function measures┻ Therefore┸ in addition to analyzing the entire study population┸ we also analyzed the progression of lung function measures separately for patients with )LD on high resolution CT ゅ(RCTょ and patients without )LD on (RCT┻ Among all patients┸ ねひガ had signs of )LD on (RCT┻ The smoking behavior patterns were similar in patients with )LD and in patients without )LD┹ はぱガ of patients in both groups were never smokers┸ にぬガ of patients with and にどガ of patients without )LD were previous smokers┸ and ひガ of patients with and なにガ of patients without )LD were current smokers ゅpサど┻どはょ┻ FEV1/FVC ratio Never smokers had a significantly higher baseline FEVな【FVC ratio than previous and current smokers ゅTable なょ┻ These differences in baseline FEVな【FVC ratio were seen in all three smoking models ゅFigure な┹ Table に┹ Supplementary Table ばょ┻ As can be seen in Table に┸ patients had a に┻ば unit lower FEVな【FVC ratio per unit increase in the CS)┻ Medium and heavy smokers had lower baseline FEVな【FVC ratios than never smokers and light smokers ゅall pジど┻どどな┹ Supplementary Table ばょ┻ )n univariable analysis┸ the FEVな【FVC ratio declined similarly across smoking groups ゅpサど┻どはのょ┹ in multivariable analysis┸ the FEVな【FVC ratio however declined faster in current smokers ゅFigure なょ┹ this result was also observed when stratifying the study population into )LD and non┽)LD patients ゅdata not shownょ┻

FVC There was no significant difference in baseline FVC and in the FVC change between the three smoking groups ゅTable なょ┻ This lack of a robust effect of smoking on the baseline FVC and on the FVC change was also observed in all three multivariable models ゅFigure

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な┹ Table に┹ Supplementary Table ばょ┻ This lack was also observed when assessing the FVC changes separately for )LD and non┽)LD patients ゅdata not shownょ┻

DLCO/sb Smokers had lower baseline DLCO【sb levels than never smokers ゅpジど┻どどな┹ Table なょ┹ smoking was associated with low baseline DLCO【sb in all three models ゅFigure な┹ Table に┹ Supplementary Table ばょ┻ The DLCO【sb declined similarly across all three smoking behavior groups in univariable ゅTable なょ and multivariable analysis ゅFigure な┹ Table に┹ Supplementary Table ばょ┸ these results were also true when looking at )LD and non┽)LD patients separately ゅdata not shownょ┻

PAPsys The average baseline PAPsys was slightly higher in never smokers than in current or ex┽smokers ゅTable なょ┻ These differences stayed apparent but to a lesser extent not only when assessing the smoking groups multivariably┸ but also evaluating smoking intensity and the CS) ゅFigure な┹ Table に┹ Supplementary Table ばょ┻ The PAPsys increased similarly in the groups in univariable ゅTable なょ and multivariable analysis ゅFigure な┹ Table に┹ Supplementary Table ばょ┻

Skin involvement No association was evident between the severity of skin fibrosis and the smoking history regardless of the smoking matrices used ゅTable な┹ Figure な┹ Table に┹ Supplementary Table ばょ┻ SSc sine scleroderma┸ however┸ was twice as prevalent in current as in ex┽ or never smokers ゅTable なょ┻

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)n all smoking models┸ no clinically significant difference in mRSS evolution was observed ゅTable な┹ Figure な┹ Table に┹ Supplementary Table ばょ┻

DU The prevalence of DUs was comparable in the smoking behavior groups ゅTable なょ┻ (owever┸ heavy smokers had a greater likelihood of DUs than never smokers in multivariable analysis ゅORサな┻は┸ pサど┻どに┹ Supplementary Table ばょ┹ also┸ a higher CS) was associated with the presence of DUs at baseline ゅORサな┻に┸ pサど┻どどに┸ i┻e┻ for a one unit increase in CS)┸ the odds of having DUs at baseline increases by a factor of な┻なひ┹ Table にょ┻ )n the sub┽group of DU┽naïve patients at baseline┸ なねガ of never smokers developed new DUs in between the two visits┸ compared to なはガ ex┽smokers and ぱガ current smokers ゅpサど┻どのょ┻ Ex┽smokers had comparable odds than never smokers to develop DU between the two visits ゅORサな┻な┸ pサど┻ばょ┹ current smokers developed DUs less often than never smoking patients ゅORサど┻の┸ pサど┻どぬなょ┻ The smoking intensity was not associated with incident DU during the observation period ゅSupplementary Table ばょ┻

DISCUSSION Our study is by far the largest prospectively investigating the effect of smoking on SSc outcomes┻ Smoking was common in our patients┸ however less than in Anglo┽Saxon cohorts and also much lower than the European average of around にぱガいね┸の┸などう┻ The EUSTAR cohort replicated the known adverse effect of smoking on bronchial airways in terms of a decline in FEVな【FVC and DLCO┻ Given the absence of discernible adverse effects of smoking on PAPsys the effect of smoking on diffusion capacity may reflect emphysema rather than precapillary pulmonary vasculopathy┻ Adverse effects of smoking on pulmonary airway obstruction and diffusing capacity were also seen in two

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cohorts of なぬば SSc and なひ smokers いなな┸なにう┻ )n line with one of these cohorts いななう but in contrast to the second study いなにう we found no association between lung compliance ゅFVCょ and smoking status┻ Our study also found no robust effect of smoking on DU prevalence and incidence when assessing the smoking behavior itself or assessing the smoking intensity┸ similar to two smaller studies いなぬ┸なねう┻ We even found a negative association between tobacco exposure and incident DU during the follow┽up in a sub┽group of DU naïve patients ゅORサど┻のょ┻ This effect could not be explained by differences in immunosuppressive and vasoactive medication ゅdata not shownょ┻ (owever┸ when we assessed smoking using the CS) we did find an association of smoking on DU prevalence similar to another┸ however quite smaller study also using the CS) いねう┻ This difference could partially arise due to a ╅healthy smoker effect╆┸ although this bias is partly been accounted for by the CS) いなのう┻ Given these results┸ it is difficult to draw robust conclusions on the effect of smoking on DUs┻ )n our study┸ smokers had a lower prevalence of Scl┽ばど autoantibodies than previous and never smokers┻ This imbalance in autoantibody status is also in line with that found in another study┸ in which Scl┽ばど positive patients were more likely to be never smokers than ever smokers いにう raising the possibility of a aethiopathological link between smoking and Scl┽ばど positivity┻ The question┸ however┸ is if this imbalance is partly due to a link┸ maybe a causal one┸ between smoking and autoantibody status or if this imbalance is partly explained by a ╅healthy smoker effect╆ especially as the prevalence of Scl┽ばど positivity in previous smokers is more comparable to the never smokers than to current smokers┻

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Like all registry┽based studies the EUSTAR cohort has limitations┻ We had no means to verify the smoking information provided by the patients┸ however we were able to demonstrate known adverse effects of smoking on airway obstruction suggesting that the information provided by the patients was not random and that our study was powered to detect meaningful changes in other parameters┻ By requiring the study population to have a follow┽up visit there is a possibility that we excluded sicker patients┸ i┻e┻ that we introduced a selection bias for healthier patients┻ (owever┸ at baseline the patients that were excluded due to the absence of a follow┽up visit within the required time frame were not majorly worse off than the included patients ゅSupplementary Table のょ arguing against a major selection bias┻ )n summary┸ our study demonstrates an adverse effect of smoking on pulmonary airways┸ but no effects on SSc┽specific pulmonary and cutaneous involvement┻ These data argue against a major role of tobacco associated free radicals┸ vasoconstrictory and immunomodulatory effects in the pathogenesis of SSc vasculopathy and fibrosis┻

ACKNOWLEDGEMENTS EUSTAR acknowledges the unconditional support that EULAR has provided in the past for the maintenance of the EUSTAR database and the EUSTAR secretariat and the present support of the World Scleroderma Foundation┻

ETHICAL APPROVAL Ethics approval according to the Declaration of (elsinki has been obtained from all respective contributing local ethics committees┻

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DATA SHARING Data is available from the EUSTAR group upon valid scientific request┻

CONTRIBUTORSHIP VKJ and UAW designed the study┸ analyzed and interpreted the data and wrote the manuscript┸ OD and YA advised in the study design┻ All authors were involved in data acquisition┸ and drafting of the article or revising it critically for important intellectual content┻ All authors approved the final version of the manuscript┻

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EULAR Scleroderma Trials And Research group database┻ Ann Rheum Dis にどどば┹はは┺ばのね‒はぬ┻ ば┻ Leffondre K┸ Abrahamowicz M┸ Xiao Y┻ Modelling smoking history using a comprehensive smoking index贖┺ Application to lung cancer┻ Stat Med にどどは┹にの┺ねなぬに‒ねなねは┻ ぱ┻ Dietrich T┸ (offmann K┻ A Comprehensive )ndex for the Modeling of Smoking (istory in Periodontal Research┻ J Dent Res にどどね┹ぱぬ┺ぱのひ‒ぱはぬ┻ ひ┻ Little RJA┻ Missing┽Data Adjustments in Large Surveys┻ J Bus Econ Stat なひぱぱ┹は┺にぱば┻ など┻ World (ealth Organization┻ Tobacco ┽ Data and statistics┻ にどなば┻ Available at┺ http┺【【www┻euro┻who┻int【en【health┽topics【disease┽prevention【tobacco【data┽and┽statistics┻ Accessed October ぬな┸ にどなば┻ なな┻ Steen VD┸ Owens GR┸ Fino GJ┸ Rodnan GP┸ Medsger TA┻ Pulmonary involvement in systemic sclerosis ゅsclerodermaょ┻ Arthritis Rheum なひぱの┹にぱ┺ばのひ‒ばはば┻ なに┻ Greenwald G)┸ Tashkin DP┸ Gong (┸ Simmons M┸ Duann S┸ Furst DE┸ et al┻ Longitudinal changes in lung function and respiratory symptoms in progressive systemic sclerosis┻ Prospective study┻ Am J Med なひぱば┹ぱぬ┺ぱぬ‒ひに┻ なぬ┻ Alivernini S┸ Santis M De┸ Tolusso B┸ Mannocci A┸ Bosello SL┸ Peluso G┸ et al┻ Skin ulcers in systemic sclerosis┺ Determinants of presence and predictive factors of healing┻ J Am Acad Dermatol にどどひ┹はど┺ねには‒ぬの┻ なね┻ Khimdas S┸ (arding S┸ Bonner A┸ Zummer B┸ Baron M┸ Pope J┻ Associations with digital ulcers in a large cohort of systemic sclerosis┺ Results from the Canadian Scleroderma Research Group registry┻ Arthritis Care Res (Hoboken) にどなな┹はぬ┺なねに‒なねひ┻ なの┻ Becklake MR┸ Lalloo U┻ The ╉healthy smoker╊┺ a phenomenon of health selection╂ Respiration なひひど┹のば┺なぬば‒ねね┻

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Table 1. Baseline demographic and disease characteristics as well as outcome measures by smoking status┻ ACA┸ anticentromere autoantibodies┹ DLCO【sb┸ single breath diffusing capacity for monoxide┹ ESR┸ erythrocyte sedimentation rate┹ FEVな┸ forced expiratory volume in one second┹ FVC┸ forced vital capacity┹ LVEF┸ left ventricular ejection fraction┹ mRSS┸ modified Rodnan skin score┹ NY(A┸ New York heart association┹ PAPsys┸ systolic pulmonary artery pressure as estimated by echocardiography┹ RNAP┽)))┸ anti┽RNA polymerase┽))) autoantibodies┹ RP┸ Raynaud╆s phenomenon┹ Scl┽ばど┸ anti┽topoisomerase autoantibodies┻ こbased on the follow┽up visit┸ not the なに months projection┻ ここThe changes in outcomes are given downscaled to ╉per なに month╊┻ おNumber of patients with available information for each variable┻ Characteristics of the study

population

n# Never

smokers

Ex-

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Current

smokers

p-value

ガ or mean ゅSDょガ or mean ゅSDょガ or mean ゅSDょ N ににどのばのにぬはに Age┹ years ぬぬなひのば┻のゅなね┻なょのば┻にゅなに┻なょのに┻のゅなな┻にょジど┻どどな Male sex ぬぬなひぱにばにひジど┻どどな Disease characteristics Time since RP onset┹ years ぬにぱはなね┻ひゅなな┻ばょなぬ┻ねゅなな┻ぬょなぬ┻ぬゅなな┻ぱょど┻どどな Time since first non┽RP manifestation┹ years にひぱぱなな┻ばゅぱ┻ぱょなど┻のゅぱ┻ばょぱ┻ひゅば┻ぱょジど┻どどな Skin involvement

Sine ぬなどはばぱなのジど┻どどな Limited はねはにのぱ Diffuse にひぬどにば

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mRSS にひねひば┻ばゅば┻ねょば┻ぱゅば┻ひょは┻ひゅば┻ぬょど┻なね Follow┽up mRSSこにぱぬひば┻ねゅば┻にょば┻にゅば┻なょは┻ひゅは┻ひょど┻ねど Change in mRSSここにはぱね ┽ど┻ぬゅぬ┻ねょ ┽ど┻はゅね┻どょ ┽ど┻にゅぬ┻ぬょど┻なに Esophageal symptoms ぬにばのはどははのぱど┻どなど Stomach symptoms ぬにねなにぬにぬになど┻はぱ )ntestinal symptoms ぬにのどにばぬどにひど┻にね Dyspnea┹ NY(A functional class

) ぬななねのばのねはぬど┻どどな )) ぬぬぬねぬな ))) ひなどの )V なにな Digital ulcers┸ current ぬなにのなねなねなはど┻ば Digital ulcers┸ ever ぬなにのねはねぱねのど┻のは LVEF┹ ガにねねぱはに┻ぬゅは┻なょはな┻ばゅは┻ぬょはぬ┻どゅの┻ぱょど┻どなの FEVな【FVC ratio ににのはひば┻のゅなぬ┻のょひの┻ねゅなの┻にょひに┻ぱゅなの┻どょジど┻どどな Follow┽up FEVな【FVC ratioこなひぱぱひば┻なゅなに┻どょひの┻ねゅなね┻のょひど┻のゅなに┻ばょジど┻どどな Change in FEVな【FVC ratioここなはのは ┽ど┻ぬゅなど┻なょど┻ねゅひ┻ねょ ┽な┻はゅば┻ばょど┻どはの FVC┹ ガ of predicted にばにどひは┻なゅにに┻どょひは┻ばゅにな┻ぬょひぱ┻ぬゅなひ┻ばょど┻にの Follow┽up FVCこ┹ ガ of predicted にねぬのひの┻のゅにに┻ぱょひは┻ぬゅにに┻のょひひ┻ぬゅなぱ┻ぱょど┻どぬば

Change in FVCここ┹ ガ of predicted になはは ┽ど┻はゅぱ┻のょ ┽ど┻ねゅば┻ばょど┻なゅひ┻ねょど┻ねの DLCO【sb┹ ガ of predicted にのぱぬはひ┻ぱゅなひ┻はょはは┻ねゅにど┻ねょはば┻なゅなば┻ぱょジど┻どどな Follow┽up DLCO【sbこ┹ ガ of predicted ににのぬはば┻のゅにど┻どょはの┻はゅにど┻どょはね┻ねゅなぱ┻なょど┻どにな Change in DLCO【sbここ┹ ガ of predicted なひばば ┽に┻どゅひ┻なょ ┽な┻ばゅひ┻にょ ┽に┻どゅば┻ぱょど┻ぱは PAPsys┹ mm(g にぬなばにぱ┻ぱゅなは┻ひょには┻どゅな┻どょにね┻ぬゅなに┻のょジど┻どどな

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Follow┽up PAPsysこ┹ mm(g にどののにひ┻にゅなぬ┻はょにぱ┻のゅなね┻なょにね┻ばゅなな┻はょジど┻どどな Change in PAPsysここ┹ mm(g なばどはど┻はゅなど┻のょな┻はゅぱ┻のょど┻にゅぱ┻なょど┻なぱ Laboratory parameters ACA positive にのどぱねばねばはなジど┻どどな Scl┽ばど positive ねのねどぬな RNAP┽))) positive ぬはは ESR┹ mm【hr にばひのにに┻ぱゅなぱ┻ねょなぱ┻ひゅなは┻ばょなぱ┻どゅなね┻のょジど┻どどな

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Table 2. Regression analysis comparing outcomes at baseline and progression of outcomes according to the comprehensive smoking index ゅCS)ょ adjusted for age┸ sex┸ time since the onset of Raynaud╆s phenomenon┸ time since the first non┽Raynaud╆s phenomenon manifestation┸ antibody status and extent of skin involvement┻ The first column illustrates the mean and the range of each outcome╆s CS) based on the imputed dataset┻ (igher CS)s indicate more smoking┹ never smokers carry a CS) of ど┻ The beta values represent the additive increase or decrease in the outcome variable per unit increase in the CS)┻ The OR values represent the increase in odds for the presence of the outcome variable per unit CS) increase┻ OR values larger than one indicate that increased smoking increased the likelihood of occurrence of the outcome┻ The follow┽up part of the table assesses the projected change per なに months of the outcomes┻ C)┸ confidence interval┹ DLCO【sb┸ single breath diffusing capacity for monoxide┹ DU┸ digital ulcers┹ FEVな┸ forced expiratory volume in one second┹ FVC┸ forced vital capacity┹ mRSS┸ modified Rodnan skin score┹ OR┸ odds ratios┹ PAPsys┸ systolic pulmonary artery pressure as estimated by echocardiography┻ Outcomes Mean CSI

(range)

CSI が or OR ひのガC) p┽value Baseline FEVな【FVC ど┻ねのゅど┽ね┻どひょがサ ┽に┻ばな ┽ぬ┻ねは to ┽な┻ひばジど┻どどな FVC ど┻ぬねゅど┽の┻なにょがサど┻ねな ┽ど┻ぬひ to な┻ににど┻ぬに DLCO【sb ど┻にばゅど┽に┻ひねょがサ ┽ね┻ぬぱ ┽の┻ぱひ to ┽に┻ぱぱジど┻どどな PAPsys ど┻にぬゅど┽に┻はなょがサ ┽に┻どぱ ┽ぬ┻のば to ┽ど┻のぱど┻どどは mRSS ど┻ねどゅど┽ば┻どのょがサど┻にど ┽ど┻どぬ to ど┻ねぬど┻どぱぱ

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DU current ど┻ぬのゅど┽ば┻ひねょ ORサな┻なひな┻どば to な┻ぬにど┻どどに Follow-up FEVな【FVC ど┻ぬぬゅど┽は┻はひょがサ ┽ど┻ねの ┽ど┻ひぬ to ど┻どにど┻どのひ FVC ど┻ねはゅど┽は┻ぬはょがサど┻ぬに ┽ど┻どな to ど┻ははど┻どのひ DLCO【SB ど┻ねぬゅど┽ね┻どにょがサど┻ぬば ┽ど┻なは to ど┻ひどど┻なば PAPsys ど┻ぬのゅど┽は┻なひょがサ ┽ど┻にな ┽ど┻ばは to ど┻ぬねど┻ねの mRSS ど┻ねぬゅど┽は┻ぬはょがサ ┽ど┻なは ┽ど┻にひ to ┽ど┻どにど┻どにな DU new btw visits ど┻ぬどゅど┽ぱ┻ぬばょ ORサど┻ぱぬど┻はぱ to な┻どどど┻どのは

Figure 1. Regression analysis comparing outcomes by smoking status adjusted for age┸ sex┸ time since the onset of Raynaud╆s phenomenon┸ time since the first non┽Raynaud╆s phenomenon manifestation┸ antibody status and extent of skin involvement┻ Panel A shows the multiple adjusted baseline levels of the outcome measures and corresponding ひのガ confidence intervals and panel B shows the multiple adjusted change rates in the outcome measures between baseline and the projected なに months follow┽up┻ Light grey represents never smokers┸ medium grey represents ex┽smokers and dark grey represents current smokers┻ DLCO【sb┸ single breath diffusing capacity for monoxide ゅガ of predictedょ┹ FEVな┸ forced expiratory volume in one second┹ FVC┸ forced vital capacity ゅガ of predictedょ┹ mRSS┸ modified Rodnan skin score┹ PAPsys┸ systolic pulmonary artery pressure as estimated by echocardiography ゅmm(gょ┻

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Smoking in Systemic Sclerosis: A Longitudinal European ...eprints.whiterose.ac.uk/136096/1/Jaeger_et_al-2018-Arthritis_%26...This is a repository copy of Smoking in Systemic Sclerosis: