Dorian Parisis

Charlie Bernier

François Chasset

Laurent Arnaud
email: laurent.arnaud@chru-strasbourg.fr

Authors ' Affiliations

Pr Laurent

Impact of tobacco smoking upon disease risk, activity and therapeutic response in systemic lupus erythematosus: A systematic review and meta-analysis

Keywords: Systemic Lupus Erythematosus, tobacco, cigarette smoking, risk, meta-analysis, systematic review

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INTRODUCTION

Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course and prognosis. As others systemic auto-immune diseases, pathogenesis of SLE remains unknown, but has been shown to result from complex multifactorial interactions between genetic, hormonal and environmental factors that result in the loss of self-tolerance.

Tobacco smoking is one the most prevalent habit and a well-known environmental factor associated with COPD, cancers and cardiovascular diseases. Its involvement in the induction and exacerbation of multiples systemic autoimmune diseases has been the subject of many publications in the past [START_REF] Perricone | Smoke and autoimmunity: The fire behind the disease[END_REF].

Despite the inherent limitations of studies design and heterogeneity, there is currently evidences for the role of tobacco smoking in diseases such as rheumatoid arthritis, Grave's disease, multiple sclerosis or Crohn's disease [START_REF] Perricone | Smoke and autoimmunity: The fire behind the disease[END_REF][START_REF] Arnson | Effects of tobacco smoke on immunity, inflammation and autoimmunity[END_REF]. Moreover, in lupus patients, tobacco also increases comorbidities, such as atherosclerosis, with a similar risk as diabetes mellitus [START_REF] Tektonidou | Subclinical atherosclerosis in Systemic Lupus Erythematosus: Comparable risk with Diabetes Mellitus and Rheumatoid Arthritis[END_REF].

To date, published studies present conflicting data on the impact of cigarette smoking on SLE risk, auto-antibody profile, disease activity, damages and treatment response [START_REF] Perricone | Smoke and autoimmunity: The fire behind the disease[END_REF]. We performed a systematic review with meta-analysis (TABALUP) to investigate the relationship between smoking and lupus risk, antibodies profile and treatment efficacy in SLE patients.

MATERIALS & METHODS

This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), and the Meta-analysis of Observational studies in Epidemiology (MOOSE) guidelines. Given that the study did not involve primary data collection or analysis, the study was considered exempt from ethical committee review.

RESEARCH STRATEGY AND DATA SOURCES

We searched MEDLINE (via PubMed), EMBASE and the Cochrane Database of Systematic Reviews databases from inception to October 2017 for studies examining the association of lupus with tobacco smoking, without language restriction or additional filter. The search strategy used a combination of text words and thesaurus terms (supplementary document). The search was completed by the bibliography review of relevant paper to identify additional studies not indexed by the electronic databases. Attempts were made to contact authors to collect more information from potentially eligible abstracts but none of them sent additional data.

STUDY ELIGIBILITY

All original studies investigating the relationship between smoking and SLE were included in TABALUP. Studies were included in the analysis if: (i) they investigated the relationship between smoking habits and lupus (case-control or cohort study); (ii) contained original data; and (iii) contained sufficient data to calculate odds ratios (ORs). We excluded the following: (i) studies containing duplicate or overlapping data; and (ii) case reports, case series, reviews, and letters to the editors.

STUDY SELECTION

We merged search results obtained from different databases using EndNote software, and removed duplicate references. Every titles and abstracts were independently screened by two investigators (DP and CB) to match the inclusion and exclusion criteria. If the information was insufficient, the decision was based on reading the full text of the article. First authors independently reviewed fulltext of selected manuscripts to determine final study eligibility. In case of disagreement, the article was evaluated closely to reach a consensus. Remaining disagreements between the reviewers were resolved by a third party (LA).

STUDY QUALITY ASSESSMENT

The quality of each included paper was reviewed by the first two authors independently using the Newcastle-Ottawa Scale. In this meta-analysis, the studies with seven star-items or more were considered high-quality studies and those with six star-items or less were considered low quality studies.

DATA EXTRACTION

The following information was extracted from each paper by a reviewer (DP): author, year of publication, study population, demographics, sample size, smoking status, effect size data (OR or RR) and adjustment factors. When the data of interest could not be found in the articles, we contacted corresponding authors to request further information. When possible, smoking status was regarded as past, current or never smoked. If we could not obtain effect size data adjusted with other confounders, we estimated the crude OR from sample size data. For different studies of the same population (e.g., studies conducted on the same registry with overlapping years), we used the results of the most recent and detailed study. Extracted information was confirmed by a second reviewer (CB).

STATISTICAL ANALYSIS

Crude measures of effect or adjusted measures of effect were extracted from the individual studies.

When possible, ORs and 95% confidence intervals (CI) were estimated for each study. Due to inherent biases in observational study designs, the random effect model was used to obtain the combined OR and its standard error (SE). To assess heterogeneity among the studies included in meta-analysis, we used the I 2 statistics. A value of I 2 of 0-25% represents insignificant heterogeneity, 26-50% represents low heterogeneity, 51-75% represents moderate heterogeneity, and more than 75% represents high heterogeneity. Publication bias was assessed by visual inspection of funnel plot.

The leave-1-out sensitivity analysis was conducted to determine whether our assumptions or decisions had a major effect on the results of the review by omitting each study. All statistical analyses were completed using both JMP13 (SAS institute, Cary NC, USA) and MedCalc (MedCalc Softwares, Belgium) softwares. The criterion for statistical significance was considered to be twosided p-value < 0.05.

RESULTS

FLOW CHART AND CHARACTERISTICS OF INCLUDED STUDIES

The flow diagram of study selection process is depicted in Figure 1. A total of 2493 potentially eligible references were identified using the described search strategy. After the exclusion of 604 duplicated articles, titles and abstracts of 1889 articles were reviewed. The remaining 229 papers were screened for eligibility. We excluded 78 references because they did not meet our inclusion criteria. Finally, 151 articles were included for further analysis.

TOBACCO SMOKING AND SLE RISK

Of the 151 studies identified by our literature search, 19 were selected for detailed review regarding this topic . Two studies on the association of prenatal and early-life smoke exposure with SLE risk were set apart [START_REF] Conde | Are prematurity and environmental factors determinants for developing childhood-onset systemic lupus erythematosus?[END_REF][START_REF] Simard | Exposure to maternal smoking and incident SLE in a prospective cohort study[END_REF]. Another study on CYP1A1 and GSTM1 polymorphisms, smoking and SLE risk by Kiyohara et al. [START_REF] Kiyohara | Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of cigarette smoking and systemic lupus erythematosus in a Japanese population[END_REF] was discussed separately. Two duplicate publications were excluded [START_REF] Aggarwal | Lupus risk and age of onset related to smoking[END_REF][START_REF] Conde | Are prematurity and environmental factors determinants for developing childhood-onset systemic lupus erythematousus?[END_REF] and one study [START_REF] Sánchez-Guerrero | Hair dye use and the risk of developing systemic lupus erythematosus[END_REF] was also ignored because it was conducted on the same registry than Barbhaiya et al. [START_REF] Barbhaiya | Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts[END_REF].

A total of 15 published articles (13 case-control studies and 2 cohort studies) examined the association of (active) smoking status with SLE risk [START_REF] Reidenberg | Acetylation phenotypes and environmental chemical exposure of people with idiopathic systemic lupus erythematosus[END_REF][START_REF] Aggarwal | Age of systemic lupus erythematosus onset among cigarette smokers[END_REF][START_REF] Barbhaiya | Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts[END_REF][START_REF] Kiyohara | Cigarette Smoking, Alcohol Consumption, and Risk of Systemic Lupus Erythematosus: A Case-control Study in a Japanese Population[END_REF][START_REF] Ghaussy | Cigarette smoking, alcohol consumption, and the risk of systemic lupus erythematosus: a case-control study[END_REF][START_REF] Kiyohara | Cigarette smoking, STAT4 and TNFRSF1b polymorphisms, and systemic lupus erythematosus in a japanese population[END_REF][START_REF] Zou | Prevalence of systemic lupus erythematosus and risk factors in rural areas of Anhui Province[END_REF][START_REF] Bengtsson | Risk factors for developing systemic lupus erythematosus: a case-control study in southern Sweden[END_REF][START_REF] Washio | Risk factors for development of systemic lupus erythematosus among Japanese females: medical history and reproductive factors[END_REF][START_REF] Ekblom-Kullberg | Smoking and the risk of systemic lupus erythematosus[END_REF][START_REF] Cooper | Smoking and use of hair treatments in relation to risk of developing systemic lupus erythematosus[END_REF][START_REF] Hardy | Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study[END_REF][START_REF] Nakano | Smoking history, alcohol consumption, sports activity and the risk of developing systemic lupus erythematosus in a Japanese population[END_REF][START_REF] Formica | Smoking, alcohol consumption, and risk of systemic lupus erythematosus in the Black Women's Health Study[END_REF][START_REF] Nagata | Systemic lupus erythematosus: a case-control epidemiologic study in Japan[END_REF]. Nine studies examined this association in former-smokers vs non-smokers [START_REF] Barbhaiya | Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts[END_REF][START_REF] Kiyohara | Cigarette Smoking, Alcohol Consumption, and Risk of Systemic Lupus Erythematosus: A Case-control Study in a Japanese Population[END_REF][START_REF] Ghaussy | Cigarette smoking, alcohol consumption, and the risk of systemic lupus erythematosus: a case-control study[END_REF][START_REF] Kiyohara | Cigarette smoking, STAT4 and TNFRSF1b polymorphisms, and systemic lupus erythematosus in a japanese population[END_REF][START_REF] Ekblom-Kullberg | Smoking and the risk of systemic lupus erythematosus[END_REF][START_REF] Cooper | Smoking and use of hair treatments in relation to risk of developing systemic lupus erythematosus[END_REF][START_REF] Hardy | Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study[END_REF][START_REF] Formica | Smoking, alcohol consumption, and risk of systemic lupus erythematosus in the Black Women's Health Study[END_REF][START_REF] Nagata | Systemic lupus erythematosus: a case-control epidemiologic study in Japan[END_REF]. Two case-control studies had been published as abstracts only [START_REF] Aggarwal | Age of systemic lupus erythematosus onset among cigarette smokers[END_REF][START_REF] Nakano | Smoking history, alcohol consumption, sports activity and the risk of developing systemic lupus erythematosus in a Japanese population[END_REF]. General characteristics as geographic location, sample size, OR with 95% CI for risk of SLE, as well as adjusted factors to evaluate the risk of SLE in the selected articles are presented in Table 1.

Five out of 15 studies were conducted in Japan [START_REF] Kiyohara | Cigarette Smoking, Alcohol Consumption, and Risk of Systemic Lupus Erythematosus: A Case-control Study in a Japanese Population[END_REF][START_REF] Kiyohara | Cigarette smoking, STAT4 and TNFRSF1b polymorphisms, and systemic lupus erythematosus in a japanese population[END_REF][START_REF] Washio | Risk factors for development of systemic lupus erythematosus among Japanese females: medical history and reproductive factors[END_REF][START_REF] Nakano | Smoking history, alcohol consumption, sports activity and the risk of developing systemic lupus erythematosus in a Japanese population[END_REF][START_REF] Nagata | Systemic lupus erythematosus: a case-control epidemiologic study in Japan[END_REF] and 5 in the US [START_REF] Reidenberg | Acetylation phenotypes and environmental chemical exposure of people with idiopathic systemic lupus erythematosus[END_REF][START_REF] Barbhaiya | Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts[END_REF][START_REF] Ghaussy | Cigarette smoking, alcohol consumption, and the risk of systemic lupus erythematosus: a case-control study[END_REF][START_REF] Cooper | Smoking and use of hair treatments in relation to risk of developing systemic lupus erythematosus[END_REF][START_REF] Formica | Smoking, alcohol consumption, and risk of systemic lupus erythematosus in the Black Women's Health Study[END_REF]. The remaining studies were done in Europe (Sweden [START_REF] Bengtsson | Risk factors for developing systemic lupus erythematosus: a case-control study in southern Sweden[END_REF], UK [START_REF] Hardy | Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study[END_REF] and Finland [START_REF] Ekblom-Kullberg | Smoking and the risk of systemic lupus erythematosus[END_REF]) and one in China [START_REF] Zou | Prevalence of systemic lupus erythematosus and risk factors in rural areas of Anhui Province[END_REF].

Tobacco exposure was assessed by structured non-blinded interview [START_REF] Reidenberg | Acetylation phenotypes and environmental chemical exposure of people with idiopathic systemic lupus erythematosus[END_REF][START_REF] Ghaussy | Cigarette smoking, alcohol consumption, and the risk of systemic lupus erythematosus: a case-control study[END_REF][START_REF] Zou | Prevalence of systemic lupus erythematosus and risk factors in rural areas of Anhui Province[END_REF][START_REF] Ekblom-Kullberg | Smoking and the risk of systemic lupus erythematosus[END_REF][START_REF] Cooper | Smoking and use of hair treatments in relation to risk of developing systemic lupus erythematosus[END_REF][START_REF] Hardy | Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study[END_REF] or selfadministered questionnaires [START_REF] Barbhaiya | Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts[END_REF][START_REF] Kiyohara | Cigarette Smoking, Alcohol Consumption, and Risk of Systemic Lupus Erythematosus: A Case-control Study in a Japanese Population[END_REF][START_REF] Kiyohara | Cigarette smoking, STAT4 and TNFRSF1b polymorphisms, and systemic lupus erythematosus in a japanese population[END_REF][START_REF] Bengtsson | Risk factors for developing systemic lupus erythematosus: a case-control study in southern Sweden[END_REF][START_REF] Washio | Risk factors for development of systemic lupus erythematosus among Japanese females: medical history and reproductive factors[END_REF][START_REF] Formica | Smoking, alcohol consumption, and risk of systemic lupus erythematosus in the Black Women's Health Study[END_REF][START_REF] Nagata | Systemic lupus erythematosus: a case-control epidemiologic study in Japan[END_REF]. Smoker status was defined as smoking at least one cigarette per day for at least 3 months in 3 studies [START_REF] Ghaussy | Cigarette smoking, alcohol consumption, and the risk of systemic lupus erythematosus: a case-control study[END_REF][START_REF] Cooper | Smoking and use of hair treatments in relation to risk of developing systemic lupus erythematosus[END_REF][START_REF] Hardy | Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study[END_REF] and as smoking at least one cigarette per day for at least 12 months in 4 others studies [START_REF] Kiyohara | Cigarette Smoking, Alcohol Consumption, and Risk of Systemic Lupus Erythematosus: A Case-control Study in a Japanese Population[END_REF][START_REF] Kiyohara | Cigarette smoking, STAT4 and TNFRSF1b polymorphisms, and systemic lupus erythematosus in a japanese population[END_REF][START_REF] Ekblom-Kullberg | Smoking and the risk of systemic lupus erythematosus[END_REF][START_REF] Formica | Smoking, alcohol consumption, and risk of systemic lupus erythematosus in the Black Women's Health Study[END_REF]. Smoking definition was not clearly defined in 7 studies [START_REF] Aggarwal | Age of systemic lupus erythematosus onset among cigarette smokers[END_REF][START_REF] Barbhaiya | Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts[END_REF][START_REF] Zou | Prevalence of systemic lupus erythematosus and risk factors in rural areas of Anhui Province[END_REF][START_REF] Bengtsson | Risk factors for developing systemic lupus erythematosus: a case-control study in southern Sweden[END_REF][START_REF] Washio | Risk factors for development of systemic lupus erythematosus among Japanese females: medical history and reproductive factors[END_REF][START_REF] Nakano | Smoking history, alcohol consumption, sports activity and the risk of developing systemic lupus erythematosus in a Japanese population[END_REF][START_REF] Nagata | Systemic lupus erythematosus: a case-control epidemiologic study in Japan[END_REF]. The evaluation of degree of exposure in each study varied significantly from study to study. In five studies, degree of exposure was not measured [START_REF] Reidenberg | Acetylation phenotypes and environmental chemical exposure of people with idiopathic systemic lupus erythematosus[END_REF][START_REF] Aggarwal | Age of systemic lupus erythematosus onset among cigarette smokers[END_REF][START_REF] Zou | Prevalence of systemic lupus erythematosus and risk factors in rural areas of Anhui Province[END_REF][START_REF] Washio | Risk factors for development of systemic lupus erythematosus among Japanese females: medical history and reproductive factors[END_REF][START_REF] Nakano | Smoking history, alcohol consumption, sports activity and the risk of developing systemic lupus erythematosus in a Japanese population[END_REF]. In all casecontrol studies, smoking status of cases was restricted to smoking exposures that preceded the date of diagnosis of SLE.

Lupus cases definition was based on the ACR 1997 classification criteria in all but one study [START_REF] Bengtsson | Risk factors for developing systemic lupus erythematosus: a case-control study in southern Sweden[END_REF].

Among those studies, 9 were appropriate for inclusion in our meta-analysis (table 2). All studies included in our analysis were case-control studies. We excluded 2 abstracts [START_REF] Aggarwal | Age of systemic lupus erythematosus onset among cigarette smokers[END_REF][START_REF] Nakano | Smoking history, alcohol consumption, sports activity and the risk of developing systemic lupus erythematosus in a Japanese population[END_REF], 2 cohort studies [START_REF] Barbhaiya | Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts[END_REF][START_REF] Formica | Smoking, alcohol consumption, and risk of systemic lupus erythematosus in the Black Women's Health Study[END_REF] and 2 studies based on patients from the same study cohort (KYSS study) [START_REF] Kiyohara | Cigarette smoking, STAT4 and TNFRSF1b polymorphisms, and systemic lupus erythematosus in a japanese population[END_REF][START_REF] Nakano | Smoking history, alcohol consumption, sports activity and the risk of developing systemic lupus erythematosus in a Japanese population[END_REF]. A total of 1738 cases and 3209 controls were included in the analysis. The forest plots of cumulative metaanalysis for the relationship between smoking status and SLE risk are shown in Figures 2A and2B.

For of the risk of SLE in current smokers versus never-smokers, the pooled OR was 1.49 (95%CI: 1.06-2.08) with significant heterogeneity (I²=78%, p=0.01). For the risk of SLE in ever-smokers versus never-smokers, the pooled OR was 1.54 (95%CI: 1.06-2.23) with significant heterogeneity (I²=86%, p<0.0001). For the risk of SLE in former-smokers versus never-smokers, the pooled OR was 0.97 (95%CI: 0.68-1.38) with significant heterogeneity (I²=63%, p=0.01). The funnel plots demonstrated potential publication bias on this topic, as some small negatives studies were not identified in the published literature.

Ten out of 15 studies investigated the dose-effect of cigarette smoking. Only 4 of them, which included 3 original case-controls studies, showed such effect [START_REF] Kiyohara | Cigarette Smoking, Alcohol Consumption, and Risk of Systemic Lupus Erythematosus: A Case-control Study in a Japanese Population[END_REF][START_REF] Kiyohara | Cigarette smoking, STAT4 and TNFRSF1b polymorphisms, and systemic lupus erythematosus in a japanese population[END_REF][START_REF] Hardy | Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study[END_REF][START_REF] Nagata | Systemic lupus erythematosus: a case-control epidemiologic study in Japan[END_REF].

TOBACCO SMOKING AND AUTOANTIBODY PROFILES

Of the 151 studies identified by our literature search, 15 were selected for detailed review regarding this topic [START_REF] Bourré-Tessier | Association of Smoking With Cutaneous Manifestations in Systemic Lupus Erythematosus: Smoking and Cutaneous Involvement in SLE[END_REF][START_REF] Sanchez-Guerrero | Association between smoking status and the clinical and serological characteristics at the onset of systemic lupus erythematosus. an inception cohort analysis[END_REF][START_REF] Freemer | Association of smoking with dsDNA autoantibody production in systemic lupus erythematosus[END_REF][START_REF] Xu | Chinese Systemic Lupus Erythematosus Treatment and Research Group Registry VI: Effect of Cigarette Smoking on the Clinical Phenotype of Chinese Patients with Systemic Lupus Erythematosus[END_REF][START_REF] Barbhaiya | Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts[END_REF][START_REF] Gustafsson | Cigarette smoking, antiphospholipid antibodies and vascular events in Systemic Lupus Erythematosus[END_REF][START_REF] Jolly | Cigarette smoking, disease activity, damage and anti-dsDNA antibodies in SLE[END_REF][START_REF] Arroyo-Ávila | Clinical associations of anti-Smith antibodies in PROFILE: a multi-ethnic lupus cohort[END_REF][START_REF] Rubin | Effect of cigarette smoke on autoimmunity in murine and human systemic lupus erythematosus[END_REF][START_REF] Montes | Smoking and Its Association With Morbidity in Systemic Lupus Erythematosus Evaluated by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index: Preliminary Data and Systematic Review: ASSOCIATION OF SMOKING AND THE SDI SCORE IN SLE[END_REF][START_REF] James | Smoking is not associated with autoantibodies in unaffected first-degree relatives of SLE patients[END_REF][START_REF] Young | Smoking is not associated with autoantibody production in systemic lupus erythematosus patients, unaffected first-degree relatives, nor healthy controls[END_REF][START_REF] Gustafsson | Smoking, autoantibodies and vascular events in systemic lupus erythematosus[END_REF][START_REF] Ekblom-Kullberg | Smoking, disease activity, permanent damage and dsDNA autoantibody production in patients with systemic lupus erythematosus[END_REF][START_REF] Smith | The effects of smoking on age of onset, autoantibodies and interferon-in systemic lupus erythematosus[END_REF]. Characteristics of those studies are presented in table 3. Two of them were duplicate publications of previous results found in two others selected references, leading to additional information. Nine of them provided data suitable for the meta-analysis. Our meta-analysis did not demonstrate an increased risk of anti-dsDNA, anti-Sm or Anti-SSA positivity according to smoking status (Figure 3). For the odds of SLE anti-dsDNA positivity in current-smokers versus eversmokers, the pooled OR was 0.90 (95% CI: 0.42-1.93) with significant heterogeneity (I²=91%, p<0.0001). In ever-smokers vs never-smokers, the pooled OR was 1.03 (95% CI: 0.85-1.25) without heterogeneity (I²=13%, p=0.33). In former-smokers vs never-smokers, the pooled OR was 1.06 (95% CI: 0.62-1.82) with significant heterogeneity (I²=73%, p=0.01).

For the odds of SLE anti-Sm positive in current-smokers versus never-smokers, the pooled OR was 0.58 (95%CI: 0.32-1.05) with significant heterogeneity (I²=85%, p=0.001). Funnel Plot is suggestive of potential publication bias. The odds ratio of ever-smokers vs never-smokers and former-smokers vs never-smokers studies were not significant (data not shown).

For the odds of SLE anti-SSA positive in current-smokers versus non-smokers, the pooled OR was 0.79 (95%CI: 0.50-1.25) with significant heterogeneity (I²=69%, p=0.04). Funnel Plot is not suggestive of potential publication bias. The odds ratio of ever-smokers vs never-smokers and former-smokers vs never-smokers studies were not significant (date not shown).

Four studies out of 13 were not included in this meta-analysis, either because data were missing or were provided as graphs, odd-ratios or ANA titers, not suitable to be pooled with others studies [START_REF] Freemer | Association of smoking with dsDNA autoantibody production in systemic lupus erythematosus[END_REF][START_REF] Young | Smoking is not associated with autoantibody production in systemic lupus erythematosus patients, unaffected first-degree relatives, nor healthy controls[END_REF][START_REF] Ekblom-Kullberg | Smoking, disease activity, permanent damage and dsDNA autoantibody production in patients with systemic lupus erythematosus[END_REF][START_REF] Smith | The effects of smoking on age of onset, autoantibodies and interferon-in systemic lupus erythematosus[END_REF].

TOBACCO SMOKING AND TREATMENTS EFFICACY

Of the 151 studies identified by our literature search, 17 were selected [START_REF] Wahie | Clinical and pharmacogenetic influences on response to hydroxychloroquine in discoid lupus erythematosus: a retrospective cohort study[END_REF][START_REF] Jallouli | Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus: determinants of hcq blood concentration in SLE[END_REF][START_REF] Mok | Factors determining hydroxychloroquine serum levels in a cohort of chinese patients with systemic lupus erythematosus[END_REF][START_REF] Lee | Factors related to blood hydroxychloroquine concentration in patients with systemic lupus erythematosus: hcq concentration in SLE patients[END_REF][START_REF] Piette | Impact of smoking in cutaneous lupus erythematosus[END_REF][START_REF] Lardet | Influence du tabagisme sur l'efficacité des antipaludéens de synthèse (APS) sur les lésions cutanées de sujets atteints de lupus : évaluation à travers une étude prospective[END_REF][START_REF] Kuhn | Influence of smoking on disease severity and antimalarial therapy in cutaneous lupus erythematosus: analysis of 1002 patients from the EUSCLE database[END_REF][START_REF] Frances | Low blood concentration of Hydroxychloroquine is associated with failure of Hydroxychloroquine treatment in patients with cutaneous lupus: Results of a prospective study[END_REF][START_REF] Kreuter | Lupus erythematosus tumidus: response to antimalarial treatment in 36 patients with emphasis on smoking[END_REF][START_REF] Kosi | Lupus Erythmetosus and smoking: the impact on clinical presentation and therapeutic response[END_REF][START_REF] Jewell | Patients with cutaneous lupus erythematosus who smoke are less responsive to antimalarial treatment[END_REF][START_REF] Nanes | Predictors of clinical response in cutaneous lupus: A longitudinal study from the University of Texas Southwestern Cutaneous Lupus Registry[END_REF][START_REF] Leroux | Relationship between blood hydroxychloroquine and desethylchloroquine concentrations and cigarette smoking in treated patients with connective tissue diseases[END_REF][START_REF] Porta | Response to a combined hydroxychloroquine-quinacrine treatment in SLE with cutaneous and/or joint disease[END_REF][START_REF] Yokogawa | Response to hydroxychloroquine in Japanese patients with lupus-related skin disease using the cutaneous lupus erythematosus disease area and severity index (CLASI)[END_REF][START_REF] Parodis | Smoking and pre-existing organ damage reduce the efficacy of belimumab in systemic lupus erythematosus[END_REF][START_REF] Rahman | Smoking interferes with efficacy of antimalarial therapy in cutaneous lupus[END_REF] for detailed review regarding this topic.

Twelve studies investigated the effect of smoking on the efficacy of antimalarial drugs (primarily hydroxychloroquine) for treating cutaneous lesions in lupus patients. Characteristics of those studies are presented in Table 4. As dermatologic studies, Cutaneous Lupus Erythematosus (CLE) patients as well as SLE patients with dermatologic manifestations were included. Main endpoints and outcome evaluations varied among studies: five studies used qualitative clinical evaluation as their primary endpoint, 6 of them used the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) [START_REF] Albrecht | The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus[END_REF] and the last used study-specific criteria. In 4 studies, (near-)total healing of cutaneous lesions is also used as primary endpoint. Smoking status was mainly "current" vs "not-current" smokers (former-and never-smokers), except in two studies where smoking definition was ever vs never smokers. Figure 4 shows the meta-analysis of the 11 observational studies investigating the effect of tobacco smoking on antimalarial cutaneous effect. This meta-analysis further updates a previous meta-analysis from our group [START_REF] Chasset | Influence of smoking on the efficacy of antimalarials in cutaneous lupus: A meta-analysis of the literature[END_REF]. The pooled OR based on a random-effect model for cutaneous favorable outcome in smokers vs non-smokers was 0.53 (95%CI: 0.305-0.927) with significant heterogeneity (I²=66%, p<0.002). Visual inspection of the funnel plot did not reveal obvious asymmetry for all publications. The 2 additional studies were unfortunately not metanalyzable [START_REF] Nanes | Predictors of clinical response in cutaneous lupus: A longitudinal study from the University of Texas Southwestern Cutaneous Lupus Registry[END_REF][START_REF] Porta | Response to a combined hydroxychloroquine-quinacrine treatment in SLE with cutaneous and/or joint disease[END_REF].

Five studies investigated the relationship between hydroxychloroquine blood concentration and cigarette smoking in patients treated for SLE or others connective tissue diseases [START_REF] Jallouli | Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus: determinants of hcq blood concentration in SLE[END_REF][START_REF] Mok | Factors determining hydroxychloroquine serum levels in a cohort of chinese patients with systemic lupus erythematosus[END_REF][START_REF] Lee | Factors related to blood hydroxychloroquine concentration in patients with systemic lupus erythematosus: hcq concentration in SLE patients[END_REF][START_REF] Frances | Low blood concentration of Hydroxychloroquine is associated with failure of Hydroxychloroquine treatment in patients with cutaneous lupus: Results of a prospective study[END_REF][START_REF] Leroux | Relationship between blood hydroxychloroquine and desethylchloroquine concentrations and cigarette smoking in treated patients with connective tissue diseases[END_REF]. The rationale behind this is that resistance of cutaneous lupus to hydroxychloroquine might be explained by modification of the metabolism of this drug, as cigarette smoking is a potent inducer of cytochrome P450. Those studies, including a total of 1497 patients, did not show any significant relationship between cigarette smoking and hydroxychloroquine concentrations.

Finally, one study [START_REF] Parodis | Smoking and pre-existing organ damage reduce the efficacy of belimumab in systemic lupus erythematosus[END_REF] provides data on real-life effect of Belimumab in SLE with emphasis on predictors of treatment response. Fifty-height patients were enrolled and followed longitudinally.

Response to treatment was defined based on the SLE response index (SRI). After adjustment for baseline SLEDAI-2K scores and prednisone equivalent dosages, ever smokers had a decreased probability to attain SRI-4 response compared with never smokers (HR 0.46; 95% CI 0.22-0.95), as well as current smokers compared with former smokers (HR 0.10; 95% CI 0.02-0.43).

DISCUSSION

Regarding the risk of SLE, we have shown in our meta-analysis of 9 case-control studies that current smokers have an increased risk of developing SLE, compared to non-smokers (OR 1.49 [95%CI: 1.06-2.08]). Similar results were observed when comparing ever versus never-smokers (OR 1.54 [95%CI:

1.06-2.23]). The increased risk of developing SLE appears to be associated with current tobacco use but not former-smoking.

To date, we are aware of 2 others reviews with meta-analysis addressing the same clinical question [START_REF] Costenbader | Cigarette smoking and the risk of systemic lupus erythematosus: A meta-analysis[END_REF][START_REF] Jiang | Smoking and the risk of systemic lupus erythematosus: an updated systematic review and cumulative meta-analysis[END_REF]. In Costenbader et al., 9 studies (7 case-control and 2 cohort studies) were included. In Jiang et al., 13 studies (11 case-control studies and 2 cohort studies) were included.

Despite the fact that we meta-analyzed contingency data (and not ORs) and more drastically selected the included studies, similar results similar were found.

The mechanisms involved in the link between smoking and SLE development remain speculative.

According to current theories, tobacco smoking can promote the appearance of SLE by various mechanisms [START_REF] Harel-Meir | Tobacco smoking and autoimmune rheumatic diseases[END_REF]. Combustion byproducts of tobacco contain thousands of toxic components, including tars, nicotine, carbon monoxide, and polycyclic aromatic hydrocarbons among others.

These toxins and induced oxidative stress can react with DNA molecules and increase cell apoptosis. This increase of the apoptotic material containing modified DNA in individuals predisposed to a defective elimination of apoptotic blebs could theoretically induce systemic auto-immunity. This transitory effect linked to smoking could explain the disappearance of the risk in the smokers who have been weaned for over a year ("former-smokers").

Regarding ANA profiles, our meta-analysis of 9 case-control studies did not demonstrate an increased risk of anti-dsDNA, anti-Sm or Anti-SSA positivity according to smoking status. A link between smoking status and the presence of antinuclear antibodies (and especially anti-dsDNA) remains unclear in epidemiological studies. Results from Barbhaiya et al. [START_REF] Barbhaiya | Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts[END_REF], are often mentioned to highlight the increase in SLE dsDNA-positive in smokers. This study shows that this risk is linked to a consumption of more than 10 pack-years and disappears with smoking cessation. These results are used to support the hypothesis that active smoking, by modifying DNA and increasing its release via increased apoptosis, NETosis or necrosis, will induce a loss of tolerance and appearance of antibodies against double-stranded DNA in genetically susceptible individuals [START_REF] Perricone | Smoke and autoimmunity: The fire behind the disease[END_REF]. In addition, tobacco has been shown to be an environmental factor associated with survivin expression along with various autoimmune diseases. Survivin enhances antigen presentation, maintains persistence of autoreactive cells, and supports production of autoantibodies [START_REF] Gravina | Survivin in autoimmune diseases[END_REF].

No study about the impact of tobacco smoking upon the efficacy of hydroxychloroquine for the systemic manifestations of SLE was found. Following our previous meta-analysis [START_REF] Chasset | Influence of smoking on the efficacy of antimalarials in cutaneous lupus: A meta-analysis of the literature[END_REF], 2 new studies were published [START_REF] Kosi | Lupus Erythmetosus and smoking: the impact on clinical presentation and therapeutic response[END_REF][START_REF] Nanes | Predictors of clinical response in cutaneous lupus: A longitudinal study from the University of Texas Southwestern Cutaneous Lupus Registry[END_REF]. One of them had the design required to be included in the update of the previous meta-analysis [START_REF] Nanes | Predictors of clinical response in cutaneous lupus: A longitudinal study from the University of Texas Southwestern Cutaneous Lupus Registry[END_REF]. Unfortunately, this study was only published as a congress abstract and did not provide enough information to be pooled. However, their conclusion goes in the same direction as the meta-analyzed data. Interestingly, cutaneous lupus differs from systemic lupus in the very high prevalence of smoking and the sex ratio. The conclusions of this meta-analysis may therefore not be generalizable to all lupus patients. In the literature, 5 studies demonstrate that the pharmacokinetics of hydroxychloroquine is not influenced by cigarette smoking. Mechanisms by which tobacco smoking may interfere with hydroxychloroquine remain speculative. Others interactions such as modification of lysosomal accumulation of antimalarial drugs or increased disease activity must be investigated. Current data supports the hypothesis of a pharmacodynamic interaction between hydroxychloroquine and nicotine. Antimalarials accumulate in endosomes, bind nucleic acids and inhibit signaling via TLR-7 and TLR-9 [START_REF] Lamphier | Novel Small Molecule Inhibitors of TLR7 and TLR9: Mechanism of Action and Efficacy In Vivo[END_REF]. On the other hand, nicotine increases the reactivity of TLR-9 to nucleic acids [START_REF] Julian | Nicotine Treatment Improves Toll-Like Receptor 2 and Toll-Like Receptor 9 Responsiveness in Active Pulmonary Sarcoidosis[END_REF].

Finally, only one study [START_REF] Parodis | Smoking and pre-existing organ damage reduce the efficacy of belimumab in systemic lupus erythematosus[END_REF] investigated the impact of tobacco smoking on response to belimumab and the same authors [START_REF] Parodis | Smoking reduces the efficacy of belimumab in mucocutaneous lupus[END_REF] showed that the negative effect of tobacco on the efficacy of belimumab is consistent for muco-cutaneous manifestations (SLEDAI2K items and CLASI) Smoking cessation should therefore be advised prior to introduction of such costly treatment to maximize efficiency.

Case-control studies, by their retrospective design, may suffer from several biases. Prospective cohort studies are usually underpowered to highlight significant differences. Finally, as demonstrated in this review, the definition itself of active smoking may differ from study to study. Tobacco smoking is itself a heterogeneous phenomenon in time and place. The composition and quality of tobacco may vary from one period or region to another. Finally, smoking is not limited to controlled smoke inhalation as in a laboratory study. As a social phenomenon, tobacco smoking is linked to many confounding factors such as socio-economic level, stress, consumption of other stimulating substances, bad health habits or lack of therapeutic adherence. All these elements combined the heterogeneity observed across the different studies.

CONCLUSION

In addition to its usual adverse effects, cigarette smoking appears to be an important risk factor for SLE and negatively influences the course of the disease as well as treatment efficacy. Based on these findings, it seems that smoking cessation remains a highly cost-effective piece of advice that could improve the management of SLE patients from any point of view and lead to many other benefits. Therefore, we believe that smoking cessation should be one of the primary concerns of physicians treating SLE patients and must be a cornerstone of treatment. More in-depth studies regarding the impact of smoking on SLE are needed and require harmonization of definitions of smoking status and standardization of publication of available data for meta-analysis.

FIGURE 1

 1 FIGURE 1 Flowchart of the TABALUP study

FIGURE 4 .

 4 FIGURE 4. CLE response to Hydroxychloroquine -CURRENT vs NEVER

Table 4 : Tobacco smoking as a risk factor of SLE -Literature review results as shown in original articles Study

 4

				Study design and population					Improvement		(near)complete response
					Female	SLE	Endpoint	Outcome	NO	Smokers	Non-smokers	Smokers	Non-smokers
		Type	N	Mean Age	%	%	(months)	criteria	QAS	Event	Total	Event	Total	Event	Total Events	Total
										s		s		s
	Rahman and al. (1998)	retrospective	34	NA	NA	?	6	Clinical	NA	-	-	-	-	3	17	9	17
	Jewell and al. (2000)	retrospective	61	NA	70.5	?	≥ 2	Clinical	6	16	40	19	21	-	-	-	-
	Lardet and al. (2004)	prospective	28	35.5 (19-68)	75	17	2	Study	6	15	21	2	4	?	?	?	?
	Kreuter and al. (2009)	retrospective	36	47.4 (24-70)	58	0	3	CLASI	7	-	-	-	-	16	28	7	8
	Wahie and al. (2011)	retrospective	200	40 (16-81)	80	?	6	Clinical	6	77	125	43	75	-	-	-	-
	Frances and al. (2012)	prospective	300 46.6 (12-85)	84.3	39	18	Clinical	6	41	124	73	176	55	102	47	112
	Piette and al. (2012)	prospective	88	NA	NA	?	6	CLASI	6	21	48	16	40	-	-	-	-
	Yokogawa and al. (2012)	retrospective	27	40.7 (18-58)	85	63	4	CLASI-RC	6	6	7	17	20	?	7	?	20
	Kuhn and al. (2014)	retrospective	838	50.2	77	?	NA	Clinical	6	313	379	225	238	-	-	-	-
	Kosi and al. (2015)	retrospective	65	NA	78.5	35	NA	CLASI	4	18	48	9	17	-	-	-	-
	Porta and al. (2016)	prospective	37	NA	NA	100	3-6-12	CLASI	NA	Adding quinacrine. Rate of CR higher in smokers (OR 5, p=0.024)
	Nanes and al. (2017)	retrospective	63	NA	NA	?	NA	CLASI	6	-	-	-	-	-	-	-	-

NA= not available; NOQAS = Newcastle-Ottawa Quality Assessment Scale; CLASI = Cutaneous Lupus Erythematosus Disease Area and Severity Index; CLASI-RC = CLASI Response Criteria; CR = Clinical Response

  ("Lupus Erythematosus, Systemic"[Mesh] OR "Lupus Erythematosus, Cutaneous"[Mesh] OR "Lupus Vasculitis, Central Nervous System"*Mesh+ OR "Lupus Nephritis"*Mesh+ OR "Lupus"*tiab+ OR "Lupuslike"*tiab+)). EMBASE (('nicotine'/exp OR 'nicotine':ab,ti OR 'tobacco dependence'/exp OR 'tobacco dependence':ab,ti OR 'tobacco use'/exp OR 'tobacco use':ab,ti OR 'smoking'/exp OR 'smoking':ab,ti OR 'passive smoking'/exp OR 'passive smoking':ab,ti OR 'tobacco'/exp OR 'tobacco':ab,ti OR 'cigarette'/exp OR 'cigarette':ab,ti) AND ('systemic lupus erythematosus'/exp OR 'systemic lupus erythematosus':ab,ti OR 'skin lupus erythematosus'/exp OR 'skin lupus erythematosus':ab,ti OR 'cutaneous lupus erythematosus':ab,ti OR 'discoid lupus erythematosus'/exp OR 'discoid lupus erythematosus':ab,ti OR 'lupus':ab,ti))

NA= not available; NOQAS = Newcastle-Ottawa Quality Assessment Scale; ANA = antinuclear antibodies; dsDNA = double-strand DNA; Sm = anti-Smith antibody; SSa = anti-SSa/Ro antibody; NHS = Nurse Health Study Xa = raw data Xb = data shown as graph or odds ratio only, no extractable data for meta-analysis Xc = data shown as antibodies titers, no extractable data for meta-analysis