Risk factors for developing systemic lupus erythematosus: a case–control study in southern Sweden

A. A. Bengtsson, L. Rylander1, L. Hagmar1, O. Nived and G. Sturfelt

Departments of Rheumatology and
1 Occupational and Environmental Medicine, University Hospital of Lund, S-221 85 Lund, Sweden


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To explore the risk factors that have been suggested to be associated with the development of SLE.

Methods. A case–control study was performed and a questionnaire was developed to obtain the data. Consecutive female incident cases diagnosed between 1981 and 1999 in a defined geographical area in southern Sweden were included. Controls, matched for calendar year of birth, were selected randomly from the same area. In total, 85 cases and 205 controls agreed to participate. The questionnaire included questions about formal education, body weight and height, medical history, family history of autoimmune diseases, exposure to ultraviolet radiation, animals, hair-colouring dyes, alfalfa (lucerne) sprouts, smoking and alcohol habits, history of physical traumata, blood transfusion, silicone breast implants, exogenous oestrogens, other medication, and significant negative life events.

Results. Using a multivariate model, a history of hypertension [odds ratio (OR)=3.7, 95% confidence interval (CI) 1.4–9.8], drug allergy (OR=3.6, 95% CI 1.4–9.5), a type I/II sun-reactive skin type (OR=2.3, 95% CI 1.1–4.8) and a family history of SLE (OR=6.8, 95% CI 1.4–32) were all significantly associated with an increased risk of developing SLE, whereas consumption of alcohol was inversely associated with the risk of SLE (use of alcohol very seldom, OR=1.0; 1–150 g/month, OR=0.4, 95% CI 0.2–1.0; >150 g/month, OR=0.2, 95% CI 0.1–0.5). A suggested association with increased SLE risk was seen for smoking (OR=1.8, 95% CI 0.9–3.6) and blood transfusions (OR=2.3, 95% CI 0.9–5.8). Neither exposure to exogenous oestrogen nor exposure to hair-colouring dyes was associated with SLE.

Conclusions. Risk factors of both exogenous and endogenous origin were identified in this population-based series of SLE patients.

KEY WORDS: SLE, Risk factors, Smoking, Alcohol, Drug allergy, Hypertension, Family history.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by typical involvement of many different organ systems and by immunological abnormalities, such as hyperactive B cells producing various autoantibodies. Although genetic and endogenous hormonal factors are clearly of great importance, other risk factors, including environmental exposure, might be equally important in the aetiology of SLE. Probably many different environmental factors act together to induce SLE in the genetically predisposed individual [1]. A number of drugs, especially those containing aromatic amines, have been suggested as aetiological factors in SLE [2]. Environmental agents containing these chemical components, such as tobacco smoke and hair-colouring products, have therefore been examined. The studies that have investigated the effects of hair-colouring products have shown conflicting results [36], while smoking seems to be associated with an increased risk of developing SLE [710], with few exceptions [11]. In contrast, recent findings demonstrate that alcohol consumption is associated with a decreased risk of SLE [79]. Hormonal treatment has also been studied, and the results indicate that hormone replacement therapy may be associated with increased risk of SLE [12, 13], whereas the use of oral contraceptives containing oestrogens seems to be associated with no risk or only a slightly increased risk of SLE [1416]. Infectious agents, especially those of viral origin, have also been discussed as triggers of SLE for many years [17]. In concordance with these theories are reports showing that anti-double-stranded DNA antibodies have been found in dogs owned by individuals with SLE [18], and the possibility of agents transmissible from animals to humans has therefore been discussed [19]. The role of stressful negative life events in the onset of autoimmune diseases is controversial. In Graves disease and insulin-dependent diabetes mellitus, it has been reported that such life events increase the risk of developing disease [20, 21], but this issue has been less investigated in SLE [22]. The fact that ultraviolet radiation (UVR) can induce exacerbation of established SLE disease has been known for a long time [23], but UVR has been less examined as a risk factor for the development of SLE. Additional potential aetiological factors are the ingestion of alfalfa (lucerne) sprouts [24] and the occurrence of disorders such as allergy and urticaria prior to the onset of SLE [16].

We undertook a population-based case–control study to investigate these potential risk factors in female SLE patients from a defined area in southern Sweden and in controls matched for sex and age.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Recruitment area
The population of 92 962 adult (>15 yr of age) female inhabitants in a specific region in southern Sweden (Lund-Orup Health Care District) was used to retrieve subjects for the study. A case–control study was performed within this recruitment area in 1999.

Cases
The cases were a series of female incident patients retrieved for the period 1981–1999 within a defined area in southern Sweden. Males were not included partly because they were too few and partly because some of the questions were restricted to females. We retrieved patients by the use of computerized diagnosis registers at the only hospital in the area (Lund University Hospital), where both out-patients and in-patients are registered [25]. Throughout the study period, the same principle for establishing the diagnosis of SLE had been employed: the presence of multisystemic disorder with concomitant immunological abnormalities, i.e. confirmed autoimmunity or complement deficiency, in the absence of any better alternative diagnosis explaining the patients’ symptoms [26]. After excluding 22 patients who had died, the total number of eligible cases was 91. Median age at clinical diagnosis was 45 yr (range 16–83) in this group of 91 patients, and median age at diagnosis in the deceased patients was 63 yr (45–88). The median time from diagnosis to participation in the present study was 9 yr (0–18). The median number of American College of Rheumatology (ACR) classification criteria was 5 (2–10) in the eligible cases and 6 (3–8) in the deceased patients. All eligible patients were sent a questionnaire by mail. Eighty-five (93%) of the patients agreed to participate in the study. Among the six non-responding patients, four did not want to participate, one was lost to follow-up and one had recently had a stroke and was not able to participate. The median number of ACR criteria fulfilled was 4 (4–5) in non-responding patients and 5 (2–10) in responding cases.

Controls
For each case, two female controls were selected randomly from the general population in the recruitment area using the computerized population register. Control subjects were matched to cases for calendar year of birth. The population in the study area is almost entirely Caucasian, and matching for race was therefore not done. A questionnaire was sent to all control subjects. If the questionnaire was not returned after a reminder telephone call, two new randomly selected controls were given a questionnaire. In total, 205 controls out of 383 agreed to participate, yielding a response rate of 53%. The lowest response rate was observed among the oldest (>75 yr) women. Because some patients declined to participate, 12 controls were reallocated according to the matching criteria. In addition, some questionnaires from controls were returned late, after two new controls had already been contacted. This procedure resulted in one matched set with one control, 55 sets with two controls, 23 sets with three controls, five sets with four controls and one set with five controls.

Questionnaire
The questionnaire included questions about formal education, body weight and height, exposure to UVR (sun and solarium), animals (ownership of dog and cat, and close contact with horse, sheep, goat and other), hair-colouring dyes (frequency and colour), diet (consumption of alfalfa sprouts), smoking (number of cigarettes per day, years of starting and stopping), alcohol consumption (quantity), history of serious accidents and blood transfusion, silicone breast implants, hormonal factors (postmenopausal hormone replacement therapy, use of oral contraceptives containing oestrogen, miscarriages, age at menarche and menopause), medication with specific drugs (sulphasalazine, penicillamine and gold salts). Sun-reactive skin types were classified according to the Fitzpatrick skin typing system: individuals reporting ‘always burn, never tan’ after exposure to the sun were classified as skin type I, those reporting ‘never burn, always tan’ as skin type IV, and intermediates as skin type II or III [27]. A history of diseases other than SLE, including drug allergy, and a family history of autoimmune diseases were also included in the questionnaire. In addition, questions about significant negative life events, such as divorce, loss of a close family member, unemployment etc., were asked.

Importantly, for all cases only exposures and histories preceding the time of clinical diagnosis were used in the statistical analyses. The exposures for the controls were also estimated for the period preceding the year of diagnosis of their corresponding case. In order to achieve this, the questions in the questionnaire were generally constructed in such a manner that the participants were first asked about the present exposure, and were then asked if this had been different previously. If no change in exposure was reported, the present exposure was used in the analyses as this would correspond to exposure before disease onset. If a different exposure was reported during any previous period, the participant was asked to specify this period (more than one period was possible) and the quantity of exposure. As described above, the year of diagnosis (i.e. disease onset) was taken into account, so that only the data from before disease onset were used. If more than one level of exposure was given for this period, the maximum level of exposure reported was used. An example showing the structure of one of the questions in the questionnaire is given in Fig. 1Go.



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FIG. 1.  An example showing the structure of one of the questions included in the questionnaire. The questions were generally constructed in such a manner that the participants were first asked about their present exposure, and were then asked if their exposure had been different previously. If no change in exposure was reported, the data were used in the analyses as the information would indicate exposure before disease onset. If a different exposure was reported during any previous period, the participant was asked to specify this period (more than one period was possible) and the quantity of exposure. The year of diagnosis (i.e. disease onset) was taken into account, so that that only the data relating to the period before disease onset were used. If more than one level of exposure was given in this period, the maximum level of exposure reported was used.

 
The Ethics Committee of Lund University approved the study.

Data analysis
The effect of the exposure variables on SLE were measured by means of the odds ratio (OR) and its 95% confidence interval (CI). Estimations were performed by conditional logistic regression [28]. In the multivariate analyses we also tested whether effect modification was present by including relevant interaction terms in the models.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
UVR
Data on UVR-related risk factors are summarized in Table 1Go. Women with the skin type ‘always burn, never/sometimes tan’ (sun-reactive skin type I/II) had an increased risk of developing SLE compared with women with other skin types. A similar finding was observed for subjects reporting marked burning after sun exposure during youth (i.e. when aged <20 yr).


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TABLE 1.  Distribution of cases and controls according to UVR-related risk factors, with corresponding OR and 95% CI

 

Smoking, alcohol and body mass index
A negative dose–response relationship between consumption of alcohol and the risk of SLE was observed (Table 2Go). The OR was 0.4 for those with an alcohol consumption >150 g/month, and in this group the median consumption was 307 g/month. Smokers tended to have a greater risk of SLE compared with non-smokers (OR=1.5, 95% CI 0.9–2.6). Women with a body mass index (BMI) greater than 21 kg/m2 tended to have a greater risk of SLE compared with women with lower BMI (OR=1.5, 95% CI 0.8–2.8). However, neither smoking habits nor BMI showed any dose–response relationship (Table 2Go).


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TABLE 2.  Distribution of cases and controls according to BMI and exposure to alcohol and smoking, with corresponding OR and 95% CI

 

Self-reported autoimmune diseases in relatives
The proportions of autoimmune diseases in first-degree relatives and the corresponding ORs are summarized in Table 3Go. A family history of any autoimmune disease was associated with increased risk of SLE. Especially a family history of SLE or multiple sclerosis was associated with a substantially increased risk of SLE.


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TABLE 3.  Distribution of cases and controls according to the existence of self-reported first-degree relatives with autoimmune diseases, with corresponding OR and 95% CI

 

Self-reported diseases and medication
The proportions of self-reported diseases and the corresponding ORs are summarized in Table 4Go. Hypertension was associated with increased risk of the development of SLE. Among the infectious diseases, only pneumonia was reported more often by cases than by controls. A history of blood transfusion was associated with a barely significantly increased risk of SLE. The reason for transfusion was almost exclusively surgery. Cases reported gastric ulcer more often than controls, whereas cancer was reported more often by controls, but these differences were not statistically significant. A history of drug allergy was significantly associated with increased risk of SLE (OR=2.6, 95% CI 1.2–2.9; data not shown in Table 4Go). Very few cases, and none of the controls, reported medication with drugs, such as sulphasalazine, penicillamine and gold salts (data not shown).


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TABLE 4.  Distribution of cases and controls according to presence of self-reported diseases, with corresponding OR and 95% CI

 

Hormonal factors
Age at menarche, age at menopause and numbers of pregnancies and miscarriages did not differ between cases and controls (data not shown). A relatively high proportion of cases (48%) had used oestrogen-containing oral contraceptives, but the proportion was even higher in controls (53%). The use of postmenopausal hormone replacement therapy was less frequent (16% of cases and 12% of controls). Only five women (two cases and three controls) reported hormonal treatment in association with in vitro fertilization, and only four (three cases and one control) had silicone breast implants.

Life events
The proportions of women with negative life events and the corresponding ORs are summarized in Table 5Go. For most life events included in the questionnaire, no increased risk of SLE was observed. However, death of a child and having been deeply offended were reported more frequently by cases than by controls, although the increased ORs were not statistically significant.


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TABLE 5.  Distribution of cases and controls according to reported life events with corresponding OR and 95% CI

 

Other items (hair colouring, animals and alfalfa sprouts)
The OR was 1.6 (95% CI 0.8–2.9) for hair colouring >=4 times/yr compared with less frequent hair colouring, but no tendency to a dose–response relationship was seen (data not shown). The proportion of women who reported consumption of alfalfa sprouts was similar among cases and controls (12% and 15% respectively). The proportions with close contact with dogs were 63% of the cases and 59% of the controls, with cats 47 and 43% respectively, with horses 31 and 28%, with sheep 16 and 7.3%, and with goats 7.1 and 4.4%. There was a significant difference between cases and controls only for contacts with sheep (OR=2.2, 95% CI 1.0–4.8).

Multivariate analyses
The associations between SLE and BMI, pneumonia, cancer, gastric ulcer, hair colouring, exposure to sheep, death of a child, having been deeply offended and a family history of autoimmune diseases except SLE, seen in univariate analyses, were not as obvious when simultaneous adjustment was made for alcohol consumption, smoking habits and hypertension in multivariate analyses. On the other hand, a family history of SLE, the sun-reactive skin type I/II and drug allergy remained significantly associated with SLE in the multivariate analyses. Moreover, blood transfusion tended to be associated with SLE. Thus, the final model included hypertension, drug allergy, a family history of SLE, sun-reactive skin type I/II, blood transfusion, smoking habits and alcohol consumption (Table 6Go). The first four of these independent variables were associated with a significantly increased risk of developing SLE, while smoking habits and blood transfusions were barely significantly associated with SLE. Alcohol consumption was inversely associated with the risk of SLE.


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TABLE 6.  Variables included in the final multivariate model, with corresponding adjusted OR and 95% CI

 


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The current view of the aetiology of SLE is that several environmental factors act on the genetically predisposed individual to either induce or protect from disease [1]. The results of the present study suggest roles for hypertension, drug allergy, skin type and family history of SLE as risk factors for developing SLE, and that alcohol is a potential protective factor. The study was based on a population-based consecutive case series of clinically well-characterized SLE patients, which improves the relevance and validity of the results. Furthermore, the response rate among cases was high (93%).

Our data suggest that smoking is associated with an increased risk of SLE, although this did not reach statistical significance. However, no dose–response relationship was observed. Our findings are in agreement with results published previously [7, 8]. Alcohol use has been suggested to be a protective factor. The present investigation demonstrated a dose-dependent inverse association between moderate alcohol use and SLE, which was even more pronounced in the multivariate model, further strengthening the observation. Our results are thus in agreement with the two previous studies that have addressed this issue specifically. However, in the study by Nagata et al. [7], the authors did not draw any firm conclusions because of the infrequent alcohol intake in Japan, and Hardy et al. [8] pointed out that their data were derived from exposure after diagnosis and therefore could be influenced by post-diagnosis changes in alcohol consumption. Our data could be influenced by recall bias, but the concordance of the results from all three studies taken together indicate strongly that the protective effect of alcohol is real and that smoking increases the risk of developing SLE.

The presence of aromatic amines in tobacco has been suggested as an explanation of the link between smoking and lupus, because drugs containing aromatic amines, such as hydralazine, are known inducers of SLE [29]. Aromatic amines are also present in hair-colouring products; one previous investigation suggested an association between the use of these products and connective tissue disease [3] but later, larger studies found less evidence of a link to SLE [46]. We could not find any indications of an association between hair colouring and SLE.

Among the self-reported diseases investigated in this study, hypertension was associated with the most pronounced increased risk of SLE. It is possible, though, that vascular damage and endothelial cell dysfunction contributing to hypertension in established SLE disease [30] could be an early event, preceding clinical SLE diagnosis, thus being a disease manifestation and not a risk factor. On the other hand, endothelial cell dysfunction has been shown to predispose to immune complex disease [31]. In addition, a history of hypertension is nearly always combined with the use of anti-hypertensive drugs, and among these are several that have been associated with SLE and SLE-like drug reactions [32]. The importance of drugs as possible SLE inducers [32, 33] is illustrated further by our finding that a history of drug allergy increased the risk of SLE markedly. This finding is in agreement with the results of a similar study, also investigating multiple risk factors, by Strom et al. [16]. These authors found that a history of allergic reactions or herpes zoster was associated with increased risk of SLE. In our study, most of the immunologically mediated diseases, including allergy, were not associated with increased risk of SLE. Regarding infectious diseases, a tendency to increased risk of SLE was seen with pneumonia, but in the multivariate model this increase in risk lost its significance. Blood transfusion, which could represent the transmission of infectious agents, was barely significantly associated with increased risk of developing SLE.

The deleterious effect of UVR in SLE patients is well known, and exacerbations of skin symptoms during spring and summer have been described [34], as have UVR-induced systemic flares [35]. UVR exposure as a risk factor for developing SLE has been less investigated. We found that individuals who constitutionally had a particular sun-reactive skin type had an increased risk of developing SLE. These individuals obviously tend to avoid extensive exposure to the sun and as a consequence the cases were less exposed to UVR compared with the controls in terms of frequency of sunbathing, the use of a solarium and going abroad to sunbathe (data not shown). Thus, our results indicate that host factors, such as a particular skin type, are the most important risk factors, and we did not find any indication of excessive UVR exposure prior to onset of SLE.

The results of the present study do not support several postulated aetiological factors in SLE, including exposure to hair-colouring products, dogs and exogenous oestrogen. This could be because too few subjects were investigated, which is the main drawback of this study. Furthermore, the recruitment rate was considerably higher in cases (93%) than in controls (53%), and there were some possible indications of selection bias in controls. The responders may have decided to participate because of a history of some kind of chronic disease or a family history of such a disease. For example, unexpectedly many of the controls (9.9%) reported that they had a first-degree relative with rheumatoid arthritis. Furthermore, cancer was reported more frequently in the control group than among the cases. This prompted us to compare responders with non-responders among the controls in the National Cancer Register, in which all incident cancer cases in Sweden are registered. In the responding control group, comprising 205 subjects, the observed number of cases with cancer was 19 and the expected number of cancers in this group was 19.5. In contrast, the observed number of individuals with cancer in the non-responding group was 13 and the expected number was 22.5.

Another source of error could be recall bias. Cases would probably be more likely to make an effort when filling in the questionnaire, but on the other hand a considerable fraction of SLE patients have cognitive dysfunction [36]. In addition, defining disease onset may be complicated in a disease such as SLE. We chose to use the year of diagnosis of SLE as this is the most reliable time-point, but we are aware of the possibility that this might have introduced a bias. Thus, the retrospective nature of the present and similar investigations clearly has disadvantages. Not much is known about the intervals between environmental exposure and the development of autoimmunity, the first clinical symptoms and full-blown disease. This leaves us uncertain regarding the time relationship between exposure and disease onset.

Notably, we did not find any indications that hormonal factors play any role as risk factors for SLE. Previously, only investigations on a larger number of subjects have demonstrated that exposure to exogenous oestrogen is associated with an approximately doubled risk of SLE [12, 1416].

The interesting issue of an infectious agent causing SLE being transmitted from animals, especially dogs, to humans has been reviewed recently [19]. However, we did not find any indications of a link between animal exposure and the risk of SLE, although a tendency was seen for exposure to sheep. Negative life events as risk factors were also investigated without finding any evidence of a connection.

As expected, the most obvious risk factor was a first-degree relative with SLE, which was associated with a more than six-fold increased risk of SLE. This illustrates the importance of genetic factors and suggests that environmental data and genetic data should, if possible, be combined in future studies. Thus, a specific environmental exposure might be a risk factor only for the genetically predisposed individual. In addition, when designing future studies of specific exposures, such as hormonal factors, it might be more informative to study certain age groups or other selected groups of patients. On the other hand, the methods used in the present investigation are well suited to the study of common exposures such as smoking habits and alcohol consumption. When using a population-based, consecutive case series of clinically well-characterized SLE patients, risk factors of both exogenous and endogenous origin can be identified, and further research in this area is merited.


    Acknowledgments
 
We gratefully acknowledge the help of Marita Lindgren for collecting the data, Agneta Svedberg, Cecilia Hemert and Zoli Mikoczy for designing the questionnaire, Ralph Rittner for the selection of controls and Palle Orbaek for advice on life event questions. This work was supported by grants from the Swedish Medical Research Council (Project No. 13489), the Medical Faculty of the University of Lund, the Swedish Rheumatism Association, the 80 Years Foundation of King Gustav V, the Greta and Johan Kock Foundation, the Anna-Greta Craaford Foundation, the Nanna Svartz Fund and the Österlund Foundation.


    Notes
 
Correspondence to: A. Bengtsson. Back


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 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 19 April 2001; Accepted 29 November 2001





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