Smoking, Overweight, and the Likelihood of Developing RA
Smoking, Overweight, and the Likelihood of Developing RA
The results presented here show that modifiable lifestyle factors such as smoking and overweight may importantly contribute to the onset of clinically manifest arthritis in autoantibody-positive individuals at risk of developing RA.
The first important observation in this prospective study is the association between smoking and development of arthritis. Smoking has recently been suggested to be a risk factor for developing RA, but so far only association studies have been performed. Our study is the first analysing the impact of smoking on the development of arthritis by prospectively following individuals with RA-specific autoantibodies without signs of arthritis who are at risk of developing the disease.
Recent studies have suggested that the lung may be an early site of RA-related auto-immunity, supposedly by the effect of smoking on the citrullination of peptides. Interestingly, in a comparable cohort of individuals at risk for RA with elevated ACPA levels and greater than or equal to 2 RF isotypes without arthritis airway abnormalities were observed similar to those found in RA patients, and significantly more than in autoantibody-negative controls.
In contrast to what has been suggested previously, the high risk for smoking on arthritis development was not dependent on ACPA-status in our study. In addition, we were unable to define ACPA-status itself as risk factor, in contrast to what was observed in another cohort studying 147 autoantibody-positive individuals without clinically apparent arthritis. This is likely due to the relatively small number of study participants and differences in inclusion criteria between the current study and the previous. Second, overweight appeared to be a predicting factor for arthritis onset, independently of smoking. Thus far, the results of association studies of overweight/obesity and RA have been variable, with different results for ACPA positive and negative RA and males and females. More in general, an association between obesity and inflammation has been clearly demonstrated. Adiposity is characterised by adipocyte hypertrophy, leading to release of stress signals, such as endoplasmic reticulum stress, and production of reactive oxygen species. As a result, inflammatory pathways are activated and inflammatory cells, such as macrophages and CD8+ T-cells, recruited into the adipose tissue. Adiposity is associated with increased production of pro-inflammatory adipocytokines, including leptin, TNFα, interleukin 1 (IL-1), IL-6 and monocyte chemotactic protein 1 (MCP-1), and decreased production of the anti-inflammatory adiponectin. How this systemic proinflammatory state would lead to inflammation in the joint, needs to be elucidated. It is also possible that proinflammatory activity of adipose tissue in the synovial sublining of the joint might be involved. Previous work has shown that articular adipose tissue obtained from RA patients produced pro- and anti-inflammatory (adipo-) cytokines upon activation, with stimulating effects on fibroblast-like synoviocytes.
In our cohort the overall arthritis risk of 28% after a median of 27 months follow up increased to 60% in individuals with a smoking history combined with overweight. This observation was made in a relatively small cohort, suggesting that the effects of smoking and overweight are strong. In comparison, the risk for developing arthritis in never smokers with normal weight was only 2%, showing that life style modification might have important consequences for arthritis development in RA-prone individuals.
The importance of our findings is emphasised by the increased incidence of RA over the last decades, which cannot be explained by genetic factors, but is most likely influenced by environmental factors. Although this study does not demonstrate that smoking cessation and/or weight reduction are effective in reducing the risk of RA, it is obvious that smoking and increased body weight are inherently modifiable lifestyle factors which are also important in other diseases and that modification leads to decreased health risks in general. An intensive prevention programme in Finland aiming at dietary changes and smoking cessation has resulted in long-term prevention of cardiovascular diseases which was accompanied by a similar decline in the incidence of RA. Such programmes may contribute to the prevention of RA and related co-morbidities and to a decreased socio-economic burden.
The results of this study, if confirmed in larger, independent cohorts, may also help to better define a population at high risk of developing RA based on the presence of RA-specific autoantibodies, smoking history, and overweight. Improved prediction models may facilitate studies aimed at prevention of RA by targeted intervention during the preclinical phase.
A limitation of this study is the relatively small sample size. The effects observed in our cohort provide the rationale for larger studies in independent cohorts to validate the results presented here. Currently we are unable to determine whether smoking and obesity are crucial for development of autoantibody positive RA in most patients, or whether these factors merely advance the onset of arthritis. We will continue to follow these individuals to address this issue over time.
It should also be noted that we chose to define the presence of arthritis based on clinical assessment by two experienced investigators rather than by imaging, consistent with clinical practice and evaluation in most clinical trials. Of note, the implications of synovitis shown by ultrasound or MRI in the absence of clinical evidence of arthritis are currently still incompletely understood.
In conclusion, the results presented here suggest that preventable factors, such as smoking and overweight, may increase the risk of developing RA in RF and/or ACPA positive individuals.
Discussion
The results presented here show that modifiable lifestyle factors such as smoking and overweight may importantly contribute to the onset of clinically manifest arthritis in autoantibody-positive individuals at risk of developing RA.
The first important observation in this prospective study is the association between smoking and development of arthritis. Smoking has recently been suggested to be a risk factor for developing RA, but so far only association studies have been performed. Our study is the first analysing the impact of smoking on the development of arthritis by prospectively following individuals with RA-specific autoantibodies without signs of arthritis who are at risk of developing the disease.
Recent studies have suggested that the lung may be an early site of RA-related auto-immunity, supposedly by the effect of smoking on the citrullination of peptides. Interestingly, in a comparable cohort of individuals at risk for RA with elevated ACPA levels and greater than or equal to 2 RF isotypes without arthritis airway abnormalities were observed similar to those found in RA patients, and significantly more than in autoantibody-negative controls.
In contrast to what has been suggested previously, the high risk for smoking on arthritis development was not dependent on ACPA-status in our study. In addition, we were unable to define ACPA-status itself as risk factor, in contrast to what was observed in another cohort studying 147 autoantibody-positive individuals without clinically apparent arthritis. This is likely due to the relatively small number of study participants and differences in inclusion criteria between the current study and the previous. Second, overweight appeared to be a predicting factor for arthritis onset, independently of smoking. Thus far, the results of association studies of overweight/obesity and RA have been variable, with different results for ACPA positive and negative RA and males and females. More in general, an association between obesity and inflammation has been clearly demonstrated. Adiposity is characterised by adipocyte hypertrophy, leading to release of stress signals, such as endoplasmic reticulum stress, and production of reactive oxygen species. As a result, inflammatory pathways are activated and inflammatory cells, such as macrophages and CD8+ T-cells, recruited into the adipose tissue. Adiposity is associated with increased production of pro-inflammatory adipocytokines, including leptin, TNFα, interleukin 1 (IL-1), IL-6 and monocyte chemotactic protein 1 (MCP-1), and decreased production of the anti-inflammatory adiponectin. How this systemic proinflammatory state would lead to inflammation in the joint, needs to be elucidated. It is also possible that proinflammatory activity of adipose tissue in the synovial sublining of the joint might be involved. Previous work has shown that articular adipose tissue obtained from RA patients produced pro- and anti-inflammatory (adipo-) cytokines upon activation, with stimulating effects on fibroblast-like synoviocytes.
In our cohort the overall arthritis risk of 28% after a median of 27 months follow up increased to 60% in individuals with a smoking history combined with overweight. This observation was made in a relatively small cohort, suggesting that the effects of smoking and overweight are strong. In comparison, the risk for developing arthritis in never smokers with normal weight was only 2%, showing that life style modification might have important consequences for arthritis development in RA-prone individuals.
The importance of our findings is emphasised by the increased incidence of RA over the last decades, which cannot be explained by genetic factors, but is most likely influenced by environmental factors. Although this study does not demonstrate that smoking cessation and/or weight reduction are effective in reducing the risk of RA, it is obvious that smoking and increased body weight are inherently modifiable lifestyle factors which are also important in other diseases and that modification leads to decreased health risks in general. An intensive prevention programme in Finland aiming at dietary changes and smoking cessation has resulted in long-term prevention of cardiovascular diseases which was accompanied by a similar decline in the incidence of RA. Such programmes may contribute to the prevention of RA and related co-morbidities and to a decreased socio-economic burden.
The results of this study, if confirmed in larger, independent cohorts, may also help to better define a population at high risk of developing RA based on the presence of RA-specific autoantibodies, smoking history, and overweight. Improved prediction models may facilitate studies aimed at prevention of RA by targeted intervention during the preclinical phase.
A limitation of this study is the relatively small sample size. The effects observed in our cohort provide the rationale for larger studies in independent cohorts to validate the results presented here. Currently we are unable to determine whether smoking and obesity are crucial for development of autoantibody positive RA in most patients, or whether these factors merely advance the onset of arthritis. We will continue to follow these individuals to address this issue over time.
It should also be noted that we chose to define the presence of arthritis based on clinical assessment by two experienced investigators rather than by imaging, consistent with clinical practice and evaluation in most clinical trials. Of note, the implications of synovitis shown by ultrasound or MRI in the absence of clinical evidence of arthritis are currently still incompletely understood.
In conclusion, the results presented here suggest that preventable factors, such as smoking and overweight, may increase the risk of developing RA in RF and/or ACPA positive individuals.
