The authors have declared that no competing interests exist.
Conceived and designed the experiments: DX XY ZGW XFZ. Performed the experiments: DX XY ZGW QYZ JHX LDJ LG FQW JRG YT JWC JLZ MTL YZ XFZ. Analyzed the data: JLZ MTL. Contributed reagents/materials/analysis tools: DX XY ZGW QYZ JHX LDJ LG FQW JRG YT JWC JLZ MTL YZ XFZ. Wrote the paper: DX XY ZGW QYZ.
¶ The complete membership of the author group can be found in the Acknowledgments.
Our study aimed to investigate the effect of cigarette smoking on the clinical phenotype of patients registered in the Chinese Systemic Lupus Erythematosus (SLE) Treatment and Research (CSTAR) group registry database, the first online registry of Chinese patients with SLE.
A prospective cross-sectional study of Chinese SLE patients was conducted using the CSTAR. Our case-control analysis was performed on age- and gender-matched subjects to explore the potential effect of cigarette smoking on the clinical manifestation of SLE.
Smokers comprised 8.9% (65/730) of patients, and the ratio of females/males was 19/46. Thirty-nine patients were current smokers, and 26 were ex-smokers. Data showed significant differences between smokers and nonsmokers in the following areas: nephropathy (58.5% vs. 39.2%; p = 0.003), microscopic hematuria (30.8% vs. 19.1%; p = 0.025), proteinuria (53.8% vs. 34.4%; p = 0.002), and SLE Disease Activity Index(DAI) scores (12.38±8.95 vs. 9.83±6.81; p = 0.028). After adjusting for age and gender, significant differences between smokers and nonsmokers were found with photosensitivity (35.9% vs. 18%; p = 0.006), nephropathy (59.4% vs. 39.8%; p = 0.011), and proteinuria (54.7% vs. 35.2%). Although smokers tended to have greater disease severity compared with nonsmokers (SLEDAI scores: 12.58±8.89 vs.10.5±7.09), the difference was not significant (p = 0.081).
Cigarette smoking triggers the development and exacerbation of SLE, especially with respect to renal involvement. Chinese smokers with SLE should be advised to discontinue cigarette use.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multisystem involvement and generation of multiple autoantibodies. Although the etiology and pathogenesis of SLE are still unclear, exposure to environmental factors, such as infectious agents, drugs, occupational pollutants, and smoking, may play an important and complex role. Of these, smoking is one of the few potential causative factors that can be controlled by patient behavior. Cigarette smoke is known to affect the development and prognosis of many autoimmune diseases, especially rheumatoid arthritis. To date, the association between smoking and SLE has been controversial [
This prospective cross-sectional analysis was based on the online CSTAR registry, which includes patients from 104 high-ranking rheumatology centers, covering 30 provinces in China. This study was approved by the Medical Ethics Committee of Peking Union Medical College Hospital (PUMCH), which was the lead research site; most centers accepted Ethics Committees(EC) from PUMCH as the leading site, some approved by their own EC, included Beijing Tongren Hospital, the General Hospital of TianJing Medical University, and the Second Affiliated Hospital of Guangzhou Medical College. Patients were registered only if they provided written informed consent. Patients with SLE were included only if they met the 1997 revised American College of Rheumatology criteria. Furthermore, patients were excluded if they presented with overlapping systemic sclerosis, rheumatoid arthritis, polymyositis, or other undifferentiated connective tissue diseases. This ongoing registry was launched in April 2009, and the cut-off for this study was February 2010.
All CSTAR centers used the same protocol-directed methods to provide uniform evaluations and patient data. All investigators received training on diagnostic confirmation of disease, evaluation of disease activity, as well as data input and quality control. Demographic data were also collected. Systemic manifestations (nervous system, vasculitis, arthritis, myositis, nephritis, rash, oral ulceration, pleuritis, pericarditis, and fever) were assessed using the SLE Disease Activity Index (SLEDAI), and all occurrences were classified according to SLEDAI definitions. Laboratory findings were also recorded, including leukocytopenia, thrombocytopenia, hypocomplementemia, and autoantibodies. Autoantibody levels were measured at local laboratories and included anti-double-stranded (ds) DNA, anti-Smith, anti-SSA/Ro, anti-SSB/La, anti-ribonucleoprotein (RNP) and anti-ribosomal RNP antibodies. SLE disease activity was evaluated in all patients by SLEDAI.
Patients who smoked at least one cigarette per day for three consecutive months were classified as smokers. Patients, who fulfilled the smoker criteria, but had given up smoking for at least 1 year prior to enrollment, were classified as ex-smokers. Patients who did not fulfill the criteria of smokers, were classified as nonsmokers[
For all subjects belonging to the smokers group, further analyses were performed to eliminate the confounding factors of gender and age. Gender and age were matched according to a 1:2 ratio for the recruitment of controls in CSTAR.
The Statistical Package for the Social Sciences (SPSS) version 13.0 software (SPSS Inc, Chicago, IL, USA) was used for data processing and analysis. Variables were described using counts and/or percentages or medians and ranges. Gender and age were matched according to a 1:2 ratio, and smokers were compared to nonsmokers in a case-control study. Chi-squared and Fisher’s exact tests were used to compare categorical data, and independent sample Student’s
Out of 730 patients, 65 (8.9%) were either current or past smokers. Among these 65 patients, 19 were female, including 13 current and six ex-smokers, and 46 were male, including 26 current and 20 ex-smokers. Although SLE is a predominantly female disease, males are much more likely to smoke than females in the Chinese population. Thus, the ratio of female: male smokers in our SLE cohort was near 1:2.
Compared to nonsmokers, there were more male smokers (46/65 vs.27/665), as well as more smokers patients with nephropathy (58.5% vs. 34.4%), microscopic hematuria (30.8% vs. 19.1%), proteinuria (53.8% vs. 34.4%), and highly active disease (SLEDAI scores: 12.38 ± 8.95 vs. 9.83 ± 6.81) (p<0.05). There was not a significant difference in autoantibodies between smokers and nonsmokers; however, anti-dsDNA positivity was slightly higher in smokers (p = 0.655; Tables
smokers(N = 65) | Nonsmokers(N = 665) | P value | |
---|---|---|---|
Gender(F/M) | 19/46 | 638/27 | |
Fever | 21.5 | 20.5 | 0.836 |
Rash | 43.1 | 36.8 | 0.321 |
Alopecia | 26.2 | 25.3 | 0.875 |
Photosensitivity | 35.4 | 26.6 | 0.130 |
Oral ulcers | 18.5 | 11.1 | 0.080 |
Arthritis | 47.7 | 53.5 | 0.368 |
Myositis | 6.2 | 2.4 | 0.094 |
Pleuritis | 16.9 | 9.6 | 0.064 |
Pericarditis | 12.3 | 12.2 | 0.976 |
Vasculitis | 12.3 | 6.6 | 0.089 |
Nephropathy | 58.5 | 39.2 | 0.003 |
Renal cast | 3.1 | 3.3 | 1.000 |
Microscopic hematuria | 30.8 | 19.1 | 0.025 |
Proteinuria | 53.8 | 34.4 | 0.002 |
Sterile pyuria | 3.1 | 4.1 | 1.000 |
Nervous system | 7.7 | 5.1 | 0.381 |
Hematological abnormalities | 58.5 | 58.6 | 0.977 |
F, female; M, male
smokers(N = 65) | Nonsmokers(N = 665) | P value | |
---|---|---|---|
Hypocomplementemia | 60.0 | 69.6 | 0.110 |
ANA positivity | 95.4 | 91.4 | 0.348 |
Anti dsDNA antibody positivity | 55.4 | 52.5 | 0.655 |
Anti Sm antibody positivity | 10.8 | 7.8 | 0.405 |
Anti RNP antibody positivity | 16.9 | 11 | 0.152 |
Anti SSA antibody positivity | 23.1 | 19.4 | 0.477 |
Anti SSB antibody positivity | 16.9 | 11.7 | 0.222 |
Anti rRNP antibody positivity | 26.9 | 17.9 | 0.257 |
APL antibody positivity | 40.7 | 46.2 | 0.584 |
SLEDAI score | 12.38±8.95 | 9.83±6.81 | 0. |
SLE: systemic lupus erythematosus; SLEDAI: SLE disease activity index; ANA: antinuclear antibody; Sm: Smith; RNP: ribonucleoprotein; rRNP: ribosomal RNP; APL: antiphospholipid.
Because one male smoker was 78-years-old and no matching patients could be found, this patient was excluded from the case-control study. In total, 64 SLE smokers and 128 SLE nonsmokers were included in the case-control analysis. Compared to nonsmokers, there was more nephropathy (59.4% vs.39.8%), proteinuria (54.7% vs. 35.2%), and photosensitivity (35.9% vs. 18%) found in smokers (p<0.05). There was no significant difference in autoantibody production between smokers and nonsmokers, although smokers tended to show more anti-dsDNA positivity (p = 0.358). Smokers also tended to have more active disease (SLEDAI scores: 12.58 ± 8.89 vs.10.5 ± 7.09), but these differences were not significant (p = 0.081; Tables
smokers(N = 64) | Nonsmokers(N = 128) | P value | |
---|---|---|---|
Fever | 21.9 | 24.2 | 0.718 |
Rash | 43.8 | 32.8 | 0.138 |
Alopecia | 26.6 | 24.2 | 0.724 |
Photosensitivity | 35.9 | 18.0 | 0.006 |
Oral ulcers | 18.8 | 14.1 | 0.399 |
Arthritis | 46.9 | 56.3 | 0.226 |
Myositis | 6.3 | 3.1 | 0.444 |
Pleuritis | 17.2 | 10.9 | 0.225 |
Pericarditis | 12.5 | 10.9 | 0.749 |
Vasculitis | 12.5 | 9.4 | 0.504 |
Nephropathy | 59.4 | 39.8 | |
Renal cast | 3.1 | 4.7 | 0.721 |
Microscopic hematuria | 31.3 | 20.3 | |
Proteinuria | 54.7 | 35.2 | |
Sterile pyuria | 3.1 | 3.1 | 1.000 |
Nervous system | 7.8 | 3.9 | 0.305 |
Hematological abnormalities | 59.4 | 57.8 | 0.836 |
smokers(N = 64) | nonsmokers(N = 128) | P value | |
---|---|---|---|
Hypocomplementemia | 60.9 | 70.3 | 0.192 |
ANA positivity | 85.3 | 88.3 | 0.115 |
Anti dsDNA antibody positivity | 56.3 | 49.2 | 0.358 |
Anti Sm antibody positivity | 10.9 | 12.5 | 0.753 |
Anti RNP antibody positivity | 17.2 | 11.7 | 0.296 |
Anti SSA antibody positivity | 23.4 | 21.1 | 0.711 |
Anti SSB antibody positivity | 17.2 | 10.9 | 0.225 |
Anti rRNP antibody positivity | 26.9 | 23.3 | 0.722 |
APL antibody positivity | 42.3 | 40.7 | 0.894 |
SLEDAI score | 12.58±8.89 | 10.5±7.09 |
SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; ANA, antinuclear antibody; Sm, Smith; RNP, ribonucleoprotein; rRNP, ribosomal RNP; APL antiphospholipid.
It is well-known that cigarette smoking is harmful to human health and increases the risk of pulmonary carcinoma. However, the relationship between smoking and SLE is still controversial. Previous studies have mostly focused on the risk of developing SLE. Ghaussy
Following adjustments for age and gender, our study showed that photosensitivity was more frequent in smokers. This finding is consistent with a study by Bourré-Tessier
Lupus nephritis is a common and severe complication that worsens the prognosis in SLE patients, especially if proteinuria is present. We observed that SLE patients who smoke had more nephropathy and proteinuria. However, in a separate study, the incidence of lupus nephritis itself was not associated with smoke exposure [
Other clinical manifestations have been reported to be associated with smoking in SLE patients. Rubin
Autoantibodies are one of the characteristic features of SLE. In the present study, we did not find any association between smoking status and all autoantibodies examined in our cohort. Previous studies have mostly focused on anti-dsDNA, an antibody known to correlate with disease activity in SLE. Different results have been reported in previous studies. In a retrospective case-control analysis, Freemer
Similar to anti-dsDNA results, the association between smoking and SLEDAI scores has been controversial in previous studies. In our study, we observed higher SLEDAI scores in smokers. Although adjusting for age and gender showed that this difference was not significant (p = 0.081), smokers still had higher SLEDAI scores than nonsmokers (12.58 ± 8.89 versus 10.5 ± 7.09, respectively). Likewise, Ghaussy
In summary, cigarette smoking may be a trigger for the development and worsening of SLE, especially with respect to renal damage. Our findings suggest that smoking cessation should be particularly encouraged in Chinese patients with SLE.
Demographic data and clinical manifestations are included. Systemic involvement was measuredby SLE classification criteria, which includedmalar rash, discoid lesion, photosensitivity, oralulcers, arthritis, serositis, hematologic involvement,nephropathy, and neurologic involvement.
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We would like to thank CSTAR co-authors as following for assistance with the collections of cases.
¶ CSTAR Co-authors:
1. Peking Union Medical College Hospital: Hongmei Song, Xuejun Zeng, Wen Zhang, Xiaomei Leng, Qingjun Wu, Jinmei Su, Qun Shi, Wenjie Zheng, Ying Jiang, Yong Hou, Min Shen, Hua Chen, Xiaodan Gan, Chaojun Hu, Suxian Liu.
2. The Affiliated Drum Tower Hospital of Nanjing University Medical School: Lingyun Sun.
3. Anhui Provincial Hospital: Xiangpei Li, Xiaomei Li.
4. The Affiliated Hospital of Bengbu Medical College: Zhijun Li, Changhao Xie.
5. The First Affiliated Hospital of Sun Yat-sen University: Xiuyan Yang.
6. The Second Hospital of Shanxi Medical University: Xiaofeng Li, Jinli Ru.
7. Beijing Hospital Affiliated to the Ministry of Health of PRC: Cibo Huang, Bei Lai.
8. China-Japan Friendship Hospital Affiliated to the Ministry of Health of PRC: Donghai Wu, Li Ma.
9. Beijing Chao-Yang Hospital, Capital Medical University: Yi Zheng, Xiaohong Wen.
10. Xuanwu Hospital Affiliated to Capital Medical University: Xiaoxia Li.
11. Beijing Friendship Hospital Affiliated to Capital Medical University: Ting Duan.
12. Beijing Children Hospital Affiliated to Capital Medical University: Caifeng Li.
13. Capital Institute of Pediatrics: Fengqi Wu.
14. Chinese People's Liberation Army General Hospital: Feng Huang, Jian Zhu.
15. Changhai Hospital Affiliated to the Second Military Medical University: Dongbao Zhao.
16. Changzheng Hospital Affiliated to the Second Military Medical University: Huji Xu.
17. Huashan Hospital Affiliated to Fudan University: Hejian Zou, Haomin Qiu.
18. The First Affiliated Hospital of Anhui Medical University: Jianhua Xu, Li Mu.
19. Qilu Hospital of Shandong University: Xingfu Li.
20. The Second Affiliated Hospital of Zhejiang University School of Medicine: Huaxiang Wu.
21. The Third Affiliated Hospital of Sun Yat-sen University: Jieruo Gu, Ou Jin.
22. The Second Affiliated Hospital of Guangzhou Medical College: Yi Tao.
23. Guangdong Provincial People's Hospital: Xiao Zhang, Guangfu Dong.
24. Xiangya Hospital, Central South University: Xiaoxia Zuo, Yisha Li.
25. The First Affiliated Hospital of Harbin Medical University: Zhiyi Zhang, Yifang Mei.
26. The First Hospital of China Medical University: Weiguo Xiao, Hongfeng Zhang.
27. Xijing Hospital affiliated to the Fourth Military Medical University: Ping Zhu, Zhenbiao Wu.
28. The Second Hospital of Lanzhou University: Yi Wang.
29. West China Hospital Affiliated to Sichuan University: Yi Liu.
30. The Affiliated Hospital of North Sichuan Medical College: Guohua Yuan.
31. Sichun Provincial People’s Hospital: Bin Zhou.
32. The People's Hospital of Xinjiang Autonomous Region: Lijun Wu.
33. Jiangsu Provincial People's Hospital: Miaojia Zhang.
34. The First Affiliated Hospital of Zhengzhou University: Shengyun Liu.
35. Shengjing Hospital Affiliated to China Medical University: Ning Zhang.
36. The First Affiliated Hospital of Shantou University Medical College: Qingyu Zeng.
37. Tianjin First Central Hospital: Wencheng Qi, Feng Han.
38. Peking University First Hospital: Zhuoli Zhang, Yu Wang.
39. Peking University Shougang Hospital: Shuling Han.
40. Beijing Jishuitan Hospital: Hui Song, Shumin Yan.
41. Fuxing Hospital Affiliated to Capital Medical University: Wen Luo.
42. Beijing Shunyi Hospital: Xiaomin Liu.
43. Peking University Third Hospital: Xiangyuan Liu, Xiaoli Deng.
44. South-West Hospital Affiliated to Third military Medical University: Yongfei Fang.
45. The First People's Hospital of Foshan: Guoqiang Chen.
46. Fujian Provincial Hospital: He Lin.
47. The Second Affiliated hospital of Fujian Medical University: Ling Lin.
48. Fuzhou General Hospital of Nanjing Military Region: Yinong Li.
49. Zhongshan Hospital Affiliated to Fudan University: Lindi Jiang, Lili Ma.
50. The First Affiliated Hospital of Guangxi Medical University: Cheng Zhao, Zhanrui Chen.
51. The People’s Hospital of Guangxi Autonomous Region: Jinying Lin.
52. The Affiliated Hospital of Guiyang Medical College: Long Li.
53. The Second Affiliated Hospital of Harbin Medical University: Yinhuan Zhao.
54. Hainan Provincial People’s Hospital: Feng Zhan, Shudian Lin.
55. Hebei Provincial People’s Hospital: Fengxiao Zhang, Yonglong Yan.
56. Bethune International Peace Hospital: Zhenbin Li.
57. Henan Provincial People’s Hospital: Fengmin Shao, Wei Liu.
58. The First Hospital of Qiqihar: Xiaowei Gong.
59. Tongji Hospital Affiliated to Tongji Medical School of Huazhong University of Science and Technology: Shaoxian Hu.
60. Jiangxi Provincial People’s Hospital: Youlian Wang.
61. No.202 Hospital of People’s Liberation Army: Yiping Lin, Lin Guo.
62. The Affiliated Hospital of Inner Mongolia Medical College: Hongbin Li.
63. Nanfang Hospital Affiliated to Southern Medical University: Min Yang.
64. The General Hospital of Ningxia Medical University: Yi Gong, Hong Zhu.
65. The Affiliated Hospital of QingdaoUniversityMedicalCollege: Jibo Wang.
66. The Fourth People’s Hospital of Shenzhen Affiliated to Guangdong Medical College: Zhizhong Ye, Zhihua Yin.
67. The General Hospital of TianJin Medical University: Lu Gong.
68. Beijing Tongren Hospital Affiliated to Capital Medical University: Zhengang Wang, Li Cui.
69. The Second People’s Hospital of Wuxi: Tianli Ren.
70. The People’s Hospital of Wuxi: Yaohong Zou.
71. The Second Xiangya Hospital of Central South University: Jinwei Chen, Ni Mao.
72. The First People’s Hospital of Yunnan Province: Qin Li.
73. The First Affiliated Hospital of Zhejiang University School of Medicine: Jin Lin.
74. SunYat-sen Memorial Hospital, SunYat-sen University: Lie Dai, Baiyu Zhang.
75. The First People’s Hospital of Changzhou: Min Wu, Wen Xie.
76. The Affiliated Orthopaedic Hospital of Shandong Linyi People’s Hospital: Zhenchun Zhang.
77. Zhejiang Provincial People’s Hospital: Zhenhua Ying.
78. The First Affiliated Hospital of Baotou Medical College: Yongfu Wang.
79. The Affiliated Hospital of Nantong University: Zhanyun Da, Genkai Guo.
80. The First Affiliated Hospital of Suzhou University: Zhiwei Chen.
81. Beijing Shijitan Hospital: Miansong Zhao.
82. Shandong Yantai Yuhuangding Hospital: Weiling Yuan.
83. The General Hospital of Daqing Oilfield: Xiangjie Bi.
84. First Affiliated Hospital of Medical College of Xi’an Jiaotong University: Lan He, Dan Pu.
85. Provincial Hospital affiliated to Shandong University, Jinan, China: Yuanchao Zhang, Limin Zhang.
86. Ji’nan University 2nd Cinical Medicine College, Shenzhen People’s Hospital: Dongzhou Liu, Xiaoping Hong.
87. No.285 Hospital of People’s Liberation Army: Zhu Chen.
88. The First Hospital of Shanxi Medical University: Xiumei Liu, Yiqun Hao.
89. Kailuan Hospital Affiliated to North China Coal Medical College: Liufu Cui.
90. Peking University Shenzhen Hospital: Qingwen Wang, Yi-Sheng Zhu.
91. The First Affiliated hospital of Fujian Medical University: Junmin Chen.
92. The First Hospital of Ningbo: Xiafei Xi.
93. Shanxi Provincial People's Hospital: Lihua Fang.
94. The Second Hospital of Hebei Medical University: Hongtao Jin, Huifang Guo.
95. The First Affiliated Hospital of Wenzhou Medical College: Xiaochun Zhu.
96. The Third Affiliated Hospital of Hebei Medical University: Ping Wei.
97. The First Affiliated Hospital of Xinjiang Medical University: Li Wei.
98. Qingdao Municipal Hospital: Houheng Su.
99. Wuhan Union Hospital affiliated to Tongji Medical School of Huazhong University of Science and Technology: Lingxun Shen.
100. No. 264 Hospital of People's Liberation Army: Jinli Ru, Xiaoxiang Xie.
101. Zhongda Hospital Affiliated to Southeast University: Meimei Wang.
102. The Central Hospital of Sichuan Mianyang: Jing Yang, Yu Zhang.
103. The Seventh People’s Hospital of Shenyang: Zhen Wang, Tienan Li.