Association of Smoking With Cutaneous Manifestations in Systemic Lupus Erythematosus

Authors


Abstract

Objective

To examine the association between smoking and cutaneous involvement in systemic lupus erythematosus (SLE).

Methods

We analyzed data from a multicenter Canadian SLE cohort. Mucocutaneous involvement was recorded at the most recent visit using the Systemic Lupus Erythematosus Disease Activity Index 2000 Update (rash, alopecia, and oral ulcers), Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (alopecia, extensive scarring, and skin ulceration), and the ACR revised criteria for SLE (malar rash, discoid rash, photosensitivity, and mucosal involvement). Multivariate logistic regression models were used to estimate the independent association between mucocutaneous involvement and cigarette smoking, age, sex, ethnicity, lupus duration, medications, and laboratory data.

Results

In our cohort of 1,346 patients (91.0% women), the mean ± SD age was 47.1 ± 14.3 years and the mean ± SD disease duration was 13.2 ± 10.0 years. In total, 41.2% of patients were ever smokers, 14.0% current smokers, and 27.1% past smokers. Active mucocutaneous manifestations occurred in 28.4% of patients; cutaneous damage occurred in 15.4%. Regarding the ACR criteria, malar rash was noted in 59.5%, discoid rash in 16.9%, and photosensitivity in 55.7% of patients. In the multivariate analysis, current smoking was associated with active SLE rash (odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.07, 2.48]). Having ever smoked was associated with ACR discoid rash (OR 2.36 [95% CI 1.69, 3.29]) and photosensitivity (OR 1.47 [95% CI 1.11, 1.95]), and with the ACR total cutaneous score (OR 1.50 [95% CI 1.22, 1.85]). We did not detect any associations between previous smoking and active cutaneous manifestations. No association was found between smoking and cutaneous damage or mucosal ulcers. No interaction was seen between smoking and antimalarials.

Conclusion

Current smoking is associated with active SLE rash, and ever smoking with the ACR total cutaneous score. This provides additional motivation for smoking cessation in SLE.

INTRODUCTION

In patients with systemic lupus erythematosus (SLE), cutaneous activity and damage are common and can produce considerable morbidity. Recent studies have found an association between smoking and the prevalence or the activity of various autoimmune conditions ([1-3]). Moreover, because smoking may decrease the effectiveness of antimalarial agents, tobacco use may be associated with increased skin manifestations in SLE ([4, 5]). We evaluated the possible association between current, past, and lifetime smoking status and cutaneous activity and damage in a multicenter Canadian SLE cohort.

Box 1. Significance & Innovations

  • Tobacco smoking is a serious and preventable health hazard that can cause and exacerbate a number of diseases including cutaneous disease in systemic lupus erythematosus (SLE) patients. Current smoking is associated with active SLE rash and ever smoking with the American College of Rheumatology total cutaneous score.
  • The association between smoking and cutaneous manifestations seems independent of treatment with antimalarials.
  • These findings certainly provide additional motivation for smoking cessation in SLE.

PATIENTS AND METHODS

Study population.

The 1000 Canadian Faces of Lupus cohort is a large prospective multicenter cohort of adult and pediatric patients with SLE. Recruitment started in July 2005 and included both incident and prevalent cases presenting at one of the 14 participating centers across Canada. Only patients ages ≥16 years were included in the current study. The annual study visits consisted of a history, a physical examination, completion of standardized forms (Systemic Lupus Erythematosus Disease Activity Index 2000 Update [SLEDAI-2K] and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology [ACR] Damage Index [SDI]) ([6, 7]), and laboratory tests.

Study variables.

Combined and individual cutaneous elements, as recorded at the most recent visit to the respective lupus clinic by the SLEDAI-2K (rash and alopecia) ([6]), the SDI (alopecia, extensive scarring, and skin ulceration) ([7]), and the ACR revised criteria for SLE (discoid rash, malar rash, and photosensitivity) ([8]), were used as primary outcomes. Mucosal ulcers as recorded by the SLEDAI-2K and the ACR criteria were also studied. For scoring the SLEDAI-2K, cutaneous activity must be present at the time of the annual visit or in the preceding 10 days (2 points given for each cutaneous element present, with possible scoring totals of 0, 2, or 4). For the SDI, each cutaneous damage item is scored as 1 point, and items must be present for >6 months. Data on age, sex, race/ethnicity, and lupus duration were available; data on smoking status were obtained. Ever smokers were defined as having smoked regularly (at least 1 cigarette per day) for ≥3 months over their lifetime; never smokers were defined as those who did not smoke regularly for ≥3 months over their lifetime. Current smokers were defined as patients answering “yes” to the question “Are you presently a smoker?” Past smokers were defined as patients that fulfilled the definition for ever smokers, but answering “no” to the above question. For each outcome studied, 3 methods of modeling smoking were used: 1) smoking as a single factor comparing ever smoking to never smoking, 2) comparing current with noncurrent (past plus never) smoking, and 3) comparing current smoking to never smoking and past smoking to never smoking. Among smokers, a dose-response relationship for the amount smoked was tested. The following factors were included in the laboratory analyses: antinuclear antibodies (ANAs), anti–double-stranded DNA antibodies, extractable nuclear antigen (ENA) profile (anti-Ro/SSA, anti-La/SSB, anti-Sm, and anti-RNP), anticardiolipin antibodies (aCL), and lupus anticoagulant (LAC). Medications presently being taken were recorded, including antimalarials, prednisone, immunosuppressants (azathioprine, methotrexate, mycophenolate mofetil, leflunomide, cyclophosphamide, cyclosporine, and biologic agents), nonsteroidal antiinflammatory drugs, oral contraceptive pills, medroxyprogesterone, hormone replacement therapy, and warfarin. The noncutaneous elements of the SLEDAI-2K and the SDI were also used as potential predictors.

Statistical analysis.

Descriptive statistics are shown using means, medians, SD, interquartile range, and proportions, as appropriate. We first estimated the effects of smoking on the presence of cutaneous manifestations using univariate logistic regression analysis. A cross-sectional analysis with multivariate regression models was used to assess the effect of smoking on each individual cutaneous item and on the combined cutaneous SLEDAI-2K, SDI, or ACR scores. For the combined outcomes, we used multivariate ordered logit regression, which allows the outcome to be categorical. All multivariate models examined the effect of smoking on each outcome of interest and included age, sex, race/ethnic origin, SLE disease duration, noncutaneous elements of the SLEDAI-2K and the SDI, anti-DNA, ENA, antiphospholipids (aPL; aCL and/or LAC), and drug exposure. We investigated confounding by comparing odds ratios (ORs) for each main variable of interest as possible confounders exited or entered the model. Also, to evaluate if smoking interacted with the efficacy of antimalarials, interaction terms were introduced in the multivariate analyses. The effects of the number of cigarettes smoked per day (smoking intensity), total smoking duration, and the combination of both (pack-years) were assessed. Analyses were performed using SAS software, version 9.2. The study was approved by the Institutional Ethics Board of each participating site and written consent was obtained according to the Declaration of Helsinki.

RESULTS

Characteristics of the patients.

From a total of 1,724 patients identified between July 2005 and January 2009, we excluded patients ages <16 years (n = 299) and patients who did not meet the ACR criteria (n = 79). Therefore, 1,346 SLE patients were studied. The baseline characteristics of the patients for the total cohort and divided according to smoking status are shown in Table 1. The majority of patients (91.0%) were women and 62.6% were white. The mean ± SD age at the time of the most recent visit to the patients' respective lupus clinic was 47.1 ± 14.3 years and the mean ± SD lupus disease duration was 13.2 ± 10.0 years. The mean ± SD SLEDAI-2K score was 4.3 ± 4.5 and the mean ± SD SDI score was 1.6 ± 1.9. A total of 554 patients (41.2% of the entire cohort) reported ever smoking, 34.1% of whom (14.0% of the entire cohort) were current smokers and 65.9% of whom (27.1% of the entire cohort) were past smokers. The mean ± SD number of cigarettes smoked per day was 12.2 ± 8.4 for current smokers and 17.7 ± 14.0 for past smokers. The mean ± SD total duration of smoking was 22.3 ± 10.4 years for current smokers and 19.5 ± 13.4 years for past smokers. The majority of patients (69.9%) were presently receiving antimalarials (63.5% receiving hydroxychloroquine and 6.4% receiving chloroquine), while 34.8% were taking immunosuppressant drugs. At the baseline study visit, 96.9% of patients had laboratory results positive for ANAs. The prevalence rate of laboratory results positive for anti-Ro/SSA was 22.7% and the prevalence rate of those positive for aPL was 14.6%. In total, 28.4% of patients had some mucocutaneous activity, 14.7% had rash, 13.4% had alopecia, and 7.9% had mucosal ulcers; 7.6% of patients had at least 2 manifestations. Cutaneous damage according to the SDI occurred in 15.4% of patients, including 12.3% with alopecia, 4.0% with scarring, and 0.2% with skin ulceration; 1.1% of patients had at least 2 damage items. Concerning ACR criteria ever achieved, malar rash occurred in 59.5% of patients, discoid rash in 16.9%, photosensitivity in 55.5%, and ulcers in 56.0%.

Table 1. Clinical and laboratory data of the study participants*
VariablesTotal (n = 1,346)Current smoker (n = 189)Past smoker (n = 365)Never smoker (n = 792)
  1. Values are the percentage unless otherwise indicated. SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000 Update; SDI = Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index; ANA = antinuclear antibodies.
Age, mean ± SD years47.1 ± 14.345.7 ± 12.351.1 ± 13.145.7 ± 14.9
Female sex91.087.389.092.7
Disease duration, mean ± SD years13.2 ± 10.011.8 ± 8.514.7 ± 10.412.8 ± 10.0
Ethnicity    
White62.669.375.954.2
African Caribbean9.55.83.613.0
Asian14.75.85.820.7
Arboriginal5.011.16.32.9
Other8.26.98.08.4
SLEDAI-2K score, mean ± SD4.3 ± 4.54.9 ± 4.74.3 ± 4.44.2 ± 4.5
SDI score, mean ± SD1.6 ± 1.91.5 ± 1.81.7 ± 2.01.5 ± 1.8
Antibodies    
ANAs68.570.469.668.5
Anti-DNA33.641.026.635.0
Anti-Ro/SSA22.724.922.223.4
Anti-La/SSB14.317.411.814.6
Anti-RNP18.216.912.921
Anti-Sm20.417.514.023.7
Anticardiolipin antibodies10.911.114.59.1
Lupus anticoagulant8.010.111.06.1
Medications    
Antimalarials69.969.472.468.8
Immunosuppressants34.833.331.236.8
Prednisone40.338.135.643.0
SLEDAI-2K items    
Rash14.720.214.813.3
Alopecia13.412.213.513.8
Mucosal ulcers7.99.08.87.3
SDI items    
Skin ulcers0.20.50.00.3
Alopecia12.313.211.812.0
Extensive scarring4.05.83.33.9
ACR criteria    
Malar rash59.553.060.460.5
Discoid rash16.924.321.212.9
Photosensitivity55.564.359.351.8
Mucosal ulcers56.053.157.956.0

Effect of smoking on cutaneous disease activity (SLEDAI-2K) (Tables 2 and 3).

In the multivariate analysis, being a current smoker was associated with the presence of active rash, as recorded by the SLEDAI-2K (OR 1.63 [95% confidence interval (95% CI) 1.07, 2.48] for current versus noncurrent smokers and OR 1.68 [95% CI 1.08, 2.60] for current versus never smokers). Being an ex-smoker was not clearly associated with active cutaneous manifestations. No clear association was seen between mucosal ulcers and smoking across the various smoking groups (Table 3).

Table 2. The effect of smoking on cutaneous manifestations of systemic lupus erythematosus*
 Ever smoked versus neverCurrent smoker versus noncurrentCurrent smoker versus neverPast smoker versus never
  1. Values are the odds ratio (95% confidence interval) from multivariate analysis using different methods of modeling smoking. SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000 Update; SDI = Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index.
  2. aSignificant.
  3. bBecause only 3 patients had skin ulceration (SDI), no multivariate analysis was performed for this specific item; however, skin ulceration was included in the SDI total cutaneous score. Other variables in the multivariate models included age, sex, race/ethnic origin, systemic lupus erythematosus disease duration, and antimalarials.
SLEDAI-2K    
Alopecia1.16 (0.81, 1.67)0.92 (0.56, 1.50)1.05 (0.63, 1.76)1.23 (0.82, 1.83)
Rash1.29 (0.92, 1.80)1.63 (1.07, 2.48)a1.68 (1.08, 2.60)a1.09 (0.74, 1.61)
Total cutaneous1.16 (0.88, 1.54)1.29 (0.89, 1.88)1.25 (0.85, 1.84)1.08 (0.78, 1.5)
SDI    
Alopecia1.09 (0.76, 1.56)1.17 (0.73, 1.88)1.19 (0.72, 1.95)1.04 (0.69, 1.57)
Extensive scarring1.02 (0.59, 1.78)1.66 (0.83, 3.29)1.54 (0.75, 3.13)0.78 (0.39, 1.54)
Total cutaneousb1.12 (0.81, 1.54)1.47 (0.97, 2.22)1.54 (1.00, 2.36)0.95 (0.65, 1.39)
ACR criteria    
Discoid rash2.36 (1.69, 3.29)a1.96 (1.31, 2.92)a2.70 (1.74, 4.18)a2.19 (1.51, 3.17)a
Malar rash0.94 (0.74, 1.20)0.79 (0.57, 1.10)0.80 (0.57, 1.12)1.03 (0.78, 1.37)
Photosensitivity1.47 (1.11, 1.95)a1.39 (0.94, 2.07)1.56 (1.04, 2.35)a1.42 (1.03, 1.96)a
Total cutaneous1.50 (1.22, 1.85)a1.46 (1.09, 1.95)a1.66 (1.23, 2.24)a1.44 (1.13, 1.82)a
Table 3. The effect of smoking on mucosal ulcers*
 SLEDAI-2K mucosal ulcersACR criteria mucosal ulcers
  1. Values are the odds ratio (95% confidence interval) from multivariate analysis using different methods of modeling smoking. Other variables in the multivariate models included age, sex, race/ethnic origin, systemic lupus erythematosus disease duration, and antimalarials. SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000 Update; ACR = American College of Rheumatology.
Ever smoked versus never1.11 (0.71, 1.7)1.01 (0.80, 1.27)
Current smoker versus noncurrent0.99 (0.56, 1.77)0.90 (0.65, 1.24)
Current smoker versus never1.04 (0.57, 1.91)0.91 (0.66, 1.28)
Past smoker versus never1.14 (0.70, 1.88)1.06 (0.82, 1.38)

Effect of smoking on ACR criteria (Tables 2 and 3).

Having ever smoked was associated with the presence of ACR total cutaneous criteria (OR 1.50 [95% CI 1.22, 1.85]). This association was driven by the specific items of discoid rash (OR 2.36 [95% CI 1.69, 3.29]) and photosensitivity (OR 1.47 [95% CI 1.11, 1.95]). For these 2 specific items, the association was seen among both current and past smokers. No clear association was seen between smoking and the presence of the ACR criteria of malar rash or mucosal ulcers (Table 3).

Effect of smoking on cutaneous damage (SDI) (Table 2).

No association was seen between smoking and cutaneous damage, either for the individual SDI cutaneous items or the SDI total cutaneous grouping.

Effect of intensity and duration of smoking.

The number of cigarettes smoked per day was not clearly associated with any mucocutaneous outcome in the various multivariate models. However, the product of smoking intensity per day and smoking duration as the number of years (pack-years) was associated with the presence of active rash among current smokers (relative risk [RR] per 5 pack-years 1.17 [95% CI 1.06, 1.29]). In addition, for both current and past smokers, the number of pack-years was associated with the presence of discoid rash according to the ACR criteria (RR per 5 pack-years 1.25 [95% CI 1.13, 1.37]). This effect was mainly driven by the number of years of smoking, with each year of smoking increasing the risk of discoid rash (RR per year of smoking 1.05 [95% CI 1.03, 1.07]). In summary, although our conclusions regarding the potential association between smoking intensity and cutaneous outcomes are limited, it seems that the risk of having an active skin rash or a discoid rash increases with smoking intensity. Smoking duration has a more important effect than the number of cigarettes smoked per day.

Other variables.

Several other variables were associated with cutaneous manifestations in the multivariate analyses. Among them, male sex was associated with a decreased risk of total cutaneous manifestations by either the SLEDAI-2K (OR 0.53 [95% CI 0.30, 0.93]) or by the ACR criteria (OR 0.55 [95% CI 0.38, 0.78]). African Caribbean ethnicity was associated with the specific items alopecia on both the SLEDAI-2K (OR 3.07 [95% CI 1.92, 4.90]) and the SDI (OR 3.22 [95% CI 2.00, 5.17]), extensive scarring on the SDI (OR 3.03 [95% CI 1.52, 6.03]), total cutaneous damage score (OR 3.17 [95% CI 2.06, 4.86]), and the ACR criterion discoid rash (OR 3.50 [95% CI 2.19, 5.58]). The presence of anti-Ro/SSA antibodies was not associated with cutaneous manifestations.

Multivariate analyses were performed to examine the association between smoking and global disease activity, as measured by the total SLEDAI-2K. Being a current smoker increased the total SLEDAI-2K score (increases of 2.00 points [95% CI 0.97, 3.03] for current versus noncurrent smokers and 2.17 points [95% CI 1.03, 3.32] for current versus never smokers), but being an ex-smoker did not significantly increase the total SLEDAI-2K score (increase of 0.47 points [95% CI −0.88, 1.81]).

Interaction between smoking and antimalarial efficacy.

Interaction terms linking antimalarials (hydroxychloroquine or chloroquine) and the various smoking groups were introduced in every multivariate analysis. The CIs were large and no important interaction could be ascertained.

DISCUSSION

To our knowledge, this is the largest study to date investigating the effect of smoking on cutaneous outcomes in SLE patients. We used 3 methods of modeling smoking in our analysis and assessed the effect of intensity and duration of smoking. Previous studies on the effect of smoking in SLE patients were limited by small sample sizes ([3, 9]) or by the use of simplified analyses that focused on a single aspect of smoking (for example, ever versus never smoked), thus ignoring the multidimensional aspect of smoking history ([9-11]). The importance of proper modeling of smoking and its potential impact has recently been emphasized, for example, in the scleroderma population ([12, 13]).

We showed that being a current smoker, but not an ex-smoker, is a risk factor for active skin manifestations as recorded by the SLEDAI-2K. The number of pack-years among current smokers is also an important predictor. These observations confirm a previous study reporting a greater prevalence of cutaneous manifestations among active smokers ([9]) and are also in accordance with another study showing that active smoking promotes disease activity in various autoimmune conditions ([3]). This is not surprising, given that cigarettes contain multiple chemical factors that may generate free radicals and alter inflammatory cell function and extracellular matrix turnover ([14]). These chemical factors may also interact with DNA and promote the production of autoantibodies directed against altered DNA ([3, 15]). The fact that past smoking was not associated with active skin rash on the SLEDAI-2K raises the potential of a reversible effect, such that smoking cessation may decrease active skin disease.

It is also interesting that, in addition to current smoking, past smoking was associated with the ACR criteria of discoid rash and photosensitivity. Because the ACR criteria are cumulative, this association suggests that past smoking may have triggered the prior emergence of cutaneous criteria, although this could not be established with any certainty in the current study. Still, this reinforces the association between smoking and cutaneous manifestations in SLE.

Although there was an association between current smoking and active rash, we did not find an association between current smoking and cutaneous damage. This may be due to the small number of patients with cutaneous damage in our cohort, or may suggest that longer periods of observation are required to demonstrate this possible relationship. A recent analysis from a US SLE cohort (in which 41% of those studied were African American) suggested more skin damage among current smokers compared with never smokers, but a recent report from Canada did not demonstrate such an association ([10, 11]). These contradictory results may be related to study power, design issues, or different ethnic composition of the populations.

In a previous small study examining 17 smokers and 19 nonsmokers, smoking appeared to interact with antimalarials, possibly decreasing the efficacy of this therapy ([5]). Our study including 189 current smokers, 365 past smokers, and 792 never smokers used multivariate analyses and did not demonstrate such an interaction, which is in agreement with other publications in which the response to antimalarials was not significantly decreased by cigarette smoking ([16, 17]).

The present study was limited because some potential confounders such as medication nonadherence and sun exposure were not considered in our analyses. The estimates of cigarette smoking were based on self-report and were not validated with biochemical tests; however, self-reported smoking status has demonstrated validity when compared with measured serum cotinine levels ([18]). If self-reported smoking had been inaccurate in our cohort, it is likely that participants would have underreported their cigarette consumption, therefore leading to an underestimation of the real association between smoking and cutaneous manifestations. Additionally, because of a lack of information on the time since smoking cessation in our cohort, we were unable to use the Comprehensive Smoking Index, an integrated index that has many statistical advantages ([19]).

In conclusion, tobacco smoking is a serious and preventable health hazard that can cause and exacerbate a number of diseases including cutaneous disease in SLE patients. The association between smoking and cutaneous manifestations seems independent of the use of antimalarials. The prevalence rate of active smoking, 14% in our cohort, remains too high and the need to counsel patients on smoking cessation should be emphasized.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Pineau had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Bourré-Tessier, Peschken, Bernatsky, Hitchon, Tucker, Arbillaga, Pineau.

Acquisition of data. Bourré-Tessier, Peschken, Bernatsky, Clarke, Fortin, Hitchon, Mittoo, Smith, Zummer, Pope, Tucker, Hudson, Arbillaga, Silverman, Chédeville, Huber, Pineau.

Analysis and interpretation of data. Bourré-Tessier, Bernatsky, Joseph, Clarke, Esdaile, Belisle, Pineau.

ACKNOWLEDGMENT

We thank the Canadian Network for Improved Outcomes in Systemic Lupus Erythematosus coordinators and research assistants for their dedicated work in recruiting the patients.

APPENDIX: A: THE CANADIAN NETWORK FOR IMPROVED OUTCOMES IN SYSTEMIC LUPUS ERYTHEMATOSUS (CaNIOS)

The Canadian Network for Improved Outcomes in Systemic Lupus Erythematosus (CaNIOS) 1000 Canadian Faces of Lupus investigators are as follows: Murray B. Urowitz, Dafna D. Gladman, Carolina Landolt-Marticorena (Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada); Sai Yan Yuen (Hopital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada); Deborah M. Levy (Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada); Suzanne Ramsey (IWK Grace Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada); Jean-Luc Senécal (Centre hospitalier de l'Université de Montréal, Montreal, Quebec, Canada).

Ancillary