Untangling the relationship between smoking and systemic sclerosis: an analysis of the EUSTAR cohort

Abstract

Objectives: To untangle the association between smoking and systemic sclerosis (SSc).

Methods: In the European Scleroderma Trials and Research cohort, the autoantibody status was compared between ever-smokers and never-smokers. Time until disease progression was assessed using Kaplan-Meier curves. Cox models were built to investigate the influence of smoking over 15 years of follow-up. All analyses were performed for the total cohort and stratified for sex and for positivity of anti-centromere (ACA) and anti-topoisomerase antibodies (ATA).

Results: Overall, 12 314 patients were included in the study. Of these, 10 393 were women (84%), 4637 were ACA-positive (38%), 3919 were ATA-positive (32%) and 4271 (35%) were ever-smokers. In men, but not in women, smoking was associated with mortality (HR 1.63, 95% CI 1.23 to 2.16, p=0.001). Ever-smoking women were at higher risk for skin progression (HR 1.10, 95% CI 1.00 to 1.22, p=0.046) and for 'any organ progression' (HR 1.07, 95% CI 1.00 to 1.13, p=0.036). In women, 34% of never-smokers were ATA-positive compared with 21% of ever-smokers (p<0.001). In the group of ever-smokers, higher exposure rates, reflected by the number of pack-years (OR 0.98, 95% CI 0.97 to 0.99, p<0.001) and by smoking duration (OR 0.96, 95% CI 0.95 to 0.97, p<0.001), were associated with lower frequency of ATA. In ACA-positive patients, the risk of mortality (HR 1.29, 95% CI 1.02 to 1.63, p=0.033), cardiac involvement (HR 1.25, 95% CI 1.03 to 1.43, p=0.001), skin progression (HR 1.21, 95% CI 1.03 to 1.42, p=0.018) and 'any organ progression' (HR 1.14, 95% CI 1.05 to 1.24, p=0.002) was increased among smokers. In ATA-positive smoking patients, mortality (HR 1.40, 95% CI 1.10 to 1.78, p=0.006), skin progression (HR 1.19, 95% CI 1.03 to 1.37, p=0.020) digital ulcers (HR 1.17, 95% CI 1.02 to 1.34, p=0.029) and 'any organ progression' (HR 1.11, 95% CI 1.00 to 1.22, p=0.048) occurred more frequently.

Conclusions: Our stratified analysis demonstrates that smoking is associated with an increased risk for mortality in male SSc patients but not in women. Strikingly, smoking is associated with lower prevalence of ATA positivity, in particular in women. In both ATA-positive and ACA-positive patients, smoking is a risk factor for mortality, skin progression and 'any organ progression'.

Keywords: Autoantibodies; Risk Factors; Smoking; Systemic Sclerosis.

Figure 1. Kaplan-Meier curves of ever-smokers and never-smokers showing mortality rate in the total cohort of EUSTAR patients (A) and after stratification based on sex (B). EUSTAR, European Scleroderma Trials and Research.

Figure 2. Kaplan-Meier curves of ever-smokers and never-smokers showing development of interstitial lung disease (ILD) (A), progression of ILD (B), development of cardiac involvement (C), progression of skin involvement (D), development of pulmonary hypertension (PH) (E), development of digital ulcers (DU) or digital ischaemia (F), development of gastrointestinal involvement (G) and development of renal involvement (H) in the total cohort of EUSTAR patients. EUSTAR, European Scleroderma Trials and Research.

Figure 3. Kaplan-Meier curves of ever-smokers and never-smokers showing ‘any organ progression’ in the total cohort of EUSTAR patients (A) and after stratification based on sex (B). EUSTAR, European Scleroderma Trials and Research.

Figure 4. Forest plot of HRs and 95% CIs based on multivariable Cox regression analysis of the effect of cigarette smoking on different systemic sclerosis progression outcomes in the total cohort of EUSTAR patients (A) and after stratification in female patients (B) and male patients (C). All models were adjusted for age. Forest plots were created using R statistical software, ‘ggplot2’ package (V.4.3.0; R Foundation for Statistical Computing, Vienna, Austria). EUSTAR, European Scleroderma Trials and Research; ILD, interstitial lung disease.

Figure 5. Kaplan-Meier curves of ever-smokers and never-smokers showing mortality rate (A), development of interstitial lung disease (ILD) (B), progression of ILD (C), development of cardiac involvement (D), progression of skin involvement (E), development of digital ulcers (DU) or digital ischaemia (F), development of pulmonary hypertension (PH) (G), development of gastrointestinal involvement (H), development of renal involvement (I) and ‘any organ progression’ (L) in the cohort of EUSTAR patients stratified by positivity of anti-centromere antibodies (ACA+), positivity of anti-topoisomerase I antibodies (ATA+) or negativity for both antibodies (ACA- ATA-). EUSTAR, European Scleroderma Trials and Research.

Figure 6. Forest plot of HRs and 95% CIs based on multivariable Cox regression analysis of the effect of cigarette smoking on different systemic sclerosis progression outcomes in the cohort of EUSTAR patients stratified by positivity of anti-centromere antibodies (ACA, A), positivity of anti-topoisomerase I antibodies (ATA, B) or negativity for both antibodies (C). All models were adjusted for age and sex. Forest plots were created using R statistical software, ‘ggplot2’ package (V.4.3.0; R Foundation for Statistical Computing, Vienna, Austria). EUSTAR, European Scleroderma Trials and Research; ILD, interstitial lung disease.