The risk of developing rheumatoid arthritis: epidemiological studies on associations with socioeconomic status, psychosocial work stress and smoking


Abstract. Author Camilla Bengtsson


Rheumatoid arthritis (RA) is a chronic, inflammatory disease. Knowledge about the contribution of genetics is rapidly increasing, but data on environmental factors that may cause RA is scarce. The aim of this thesis was to contribute to better knowledge about the etiology of the disease by investigating the association between RA and socioeconomic status, psychosocial work stress and smoking. A further aim was to evaluate participation/non-participation and late response in a large population-based case-control sstudy (1913 cases, 2214 controls) on incident cases of RA, called EIRA.


The thesis is based on data from EIRA, comprising the population, aged 18-70 years, in parts of Sweden. A case was defined as a person in the study base with newly diagnosed RA, in accordance with the American College of Rheumatology criteria. Controls were randomly selected from the study base, taking age, gender and residential area into consideration. Cases and controls answered a questionnaire regarding e.g. socioeconomic status, psychosocial work stress and smoking. The response proportion was 96 % among cases and 82 % among controls. A blood sample was taken in order to analyse rheumatoid factor (RF) and HLA-DRB1 shared epitope (SE) alleles. In order to evaluate possible selection bias in EIRA, socio-demographic data were collected from registers as Statistics Sweden, for all identified study subjects.


According to the results, low socioeconomic status (low formal education and low occupational class, respectively) was associated with increased risk of RA. This increased risk was more pronounced for RF positive RA as compared to RF negative RA. Low decision latitude, a marker of psychosocial work stress, was associated with an increased risk of developing RA. No major differences were observed according to RF status. Cigarette smokers had an increased risk of developing RF positive RA, but not RF negative RA. This increased risk occurred after a long duration, but of merely moderate intensity of smoking, and remained for several years after smoking cessation. A striking gene-environment interaction between smoking and HLA-DRB1 SE alleles was seen for RF positive RA but not for RF negative RA.


In a methodological study, the decreasing participation in epidemiological studies seen in recent years was not observed in EIRA. According to both the high participation and results from a non-participation analysis, selection bias due to non-participation is probably of minor magnitude in EIRA and the results in the thesis are likely to be only marginally biased by this source of systematic error. In a late response analysis, inclusion of smoking and occupational class data from late respondents did not alter the results compared with those of the early respondents only. Thus, several reminders to include reluctant or difficult-to-find study subjects in epidemiological studies might not be worthwhile if the costs and efforts to include these subjects are high.


In conclusion, the results in this thesis add to the likelihood that socioeconomic status and psychosocial factors in the work environment influence the risk of developing RA. With regards to smoking the results indicate that the effect of smoking is complex, slow, or delayed. The striking gene-environment interaction between smoking and HLA-DRB1 genotype for RF positive but not RF negative RA, emphasizes that we are only at the beginning of an era where it will be possible to disentangle the complex interactions between different environmental and genetic risk factors and to understand what different biological mechanisms may be triggered in the context of various combinations of genes and environmental factors.


Articles included in the thesis


Socioeconomic status and the risk of developing rheumatoid arthritis: results from the Swedish EIRA study.

Bengtsson C, Nordmark B, Klareskog L, Lundberg I, Alfredsson L; EIRA Study Group. Ann Rheum Dis. 2005 Nov;64(11):1588-94. Epub 2005 Apr 20.


Psychosocial Stress at Work and the Risk of Developing Rheumatoid Arthritis: Results from the Swedish EIRA Study.

Bengtsson C, Theorell T, Klareskog L, Alfredsson L. Psychother Psychosom. 2009 Mar 24;78(3):193-194. [Epub ahead of print]


Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases.
Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L, Alfredsson L; EIRA study group. Ann Rheum Dis. 2003 Sep;62(9):835-41. Review.


A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis.

Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. Arthritis Rheum. 2004 Oct;50(10):3085-92.


Evaluation of participation and nonparticipation in a population-based case-control study of rheumatoid arthritis.

Bengtsson C, Berglund A, Serra M-L, Nise L, Nordmark B, Klareskog L, Alfredsson L, The EIRA study group. Submitted.




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