Female Systemic Lupus Erythematosus in Miyagi Prefecture, Japan : A Case-Control Study of Dietary and Reproductive Factors

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1 Tohoku J. Exp. Med., 1993, 169, Female Systemic Lupus Erythematosus in Miyagi Prefecture, Japan : A Case-Control Study of Dietary and Reproductive Factors YUKO MINAMI, TAKESHI SASAKI*, SHOKO KOMATSU, MITSUAKI NISHIKORI, AKIRA FUKAO, KAORU YOSHINAGA*'t and SHIGERU HISAMICHI Department of Public Health and * the Second Department of Internal Medicine, Tohoku University School of Medicine, Sendai 980 MINAMI, Y., SASAKI, T., KOMATSU, S., NISHIKORI, M., FUKAO, A., YOSHINAGA, K. and HISAMICHI, S. Female Systemic Lupus Erythematosus in Miyagi Prefecture, Japan : A Case-Control Study of Dietary and Reproductive Factors. Tohoku J. Exp. Med., 1993, 169 (3), To investigate risk factors of systemic lupus erythematosus (SLE) in relation to diet and reproduction, a populationbased case-control study was conducted during the period from October 1988 to October 1989 in Miyagi Prefecture in northeastern Japan. Included in the study were 52 female patients with the recent SLE onset. Two sex- and birth yearmatched (±2 years) controls for each patient were selected from the general population. The analysis on diet showed that the frequent intake of meat was associated with an increased risk (frequent vs. rare, relative risk (RR) 3.36; 95% confidence interval (CI) ) and that the patients preferred fatty meat such as beef or pork. The analysis on menstrual history revealed that menstrual irregularity was also associated with an increased risk (RR 3.79; 95% CI ). These results suggest that dietary and reproductive factors may be responsible for the onset and the progression of SLE. case-control study ; diet ; reproduction ; risk factor ; systemic lupus erythematosus The prevalence of systemic lupus erythematosus (SLE) is greater in female (Nived and Sturfelt 1987; Hochberg 1990), and exacerbations of the disease may be associated with menstration, pregnancy and the use of oral contraceptives (Jungers et al. 1982; Lahita 1985, 1986). Previous clinical studies have shown that patients with SLE may have an elevation of 16 a-hydroxyestrone, leading to increased entrogenic activity (Lahita et al. 1979, 1981). These suggest that sex hormone may play a role on the development of SLE. In the light of the role of nutrition on immune system, dietary factors may be associated with the course of SLE. This hypothesis has been supported by a number of studies (Dubois and Strain 1973; Beach et al. 1981; Levy et al ; Received January 29, 'Professor Emeritus. 1993; revision accepted for publication Feburary 10,

2 246 Y. Minami et al. Kelley and Izui 1983; Kubo et al. 1984; Corman 1985; Homsy et al. 1986) using an animal model, New Zealand Black/New Zealand White F 1 mice, which is characterized by the production of various kinds of autoantibodies and fatal immune complex glomerulonephritis (Helyer and Howie 1963). These studies have revealed that low fat diet delayed the onset of the autoimmune disease and improved the survival, and that high fat diet shortened the life span in mice (Levy et al ; Kelley and Izui 1983). Some other studies have also indicated that low calorie diet might be important in preventing the manifestation of autoimmune diseases in mice (Kubo et al. 1984; Ogura et al. 1989). In contrast to these reports on the effects of diet on the animal SLE model, reports relating to human subjects are sparse (Lom-Orta et al. 1980; Utermohlen et al. 1984). It has not yet been clarified whether diet may be associated with the onset of human SLE as well as the progression. Furthermore, although previous human studies have demonstrated the effects of sex hormone on the disease activity, risk factors in relation to reproduction are also unknown. We, therefore, conducted a population-based case-control study to inventigate dietary and reproductive factors which are suggested as risk factors by previous animal and human studies. MATERIALS AND METHODS SLE cases were selected based on the list of recipient-patients of national subsidy for "Specified Intractable Diseases". It has been regarded that the list could provide relatevely reliable numbers of patients treated for intractable diseases. SLE is one of the "Specified Intractable Diseases". National subsidy for each SLE patient is applied to Prefectural Government by a physician and the patient is registered as a recipient-patient. During the survey period, SLE patients under treatment at 28 hospitals in Miyagi Prefecture have been registered. Among these 28 hospitals, 17 hospitals, designated as referral clinics for SLE, were assigned for the selection of cases in the present study. At these hospitals, 61 female patients were newly diagnosed as SLE between January 1985 and October Of these, 52 patients between the ages of at the time of onset and with symptoms of recent onset ( ), were selected for cases in the present study. Between October 1988-October 1989, questionnaires on their daily life during the 3 years prior to the onset of the disease were handed to these 52 patients by physicians and collected a few days later by mail. All patients studied had satisfied four or more of eleven items in the 1982 revised criteria for the classification of systemic lupus erythematosus (Tan et al. 1982). The selection of controls was conducted by mail surveys in Miyagi Prefecture between Octeber 1988 and April Five hundred and twenty-three households were randomly selected from telephone directories throughout Miyagi Prefecture published by Nippon Telegraph and Telephone Corporation using the table of random numbers, and letters were sent asking only women in the households to complete questionnaires on their daily life during the last 3 years. After 1 week, one of the authors telephoned each household and asked them for their cooperation. In the mail surveys, 328 households agreed to cooperate. From these 328 households, 54 households were excluded, because all women in the family were aged 55 and over. After excluding them, possible controls, one women under the age of 55 from each household were selected from the remaining 274 households. From these possible controls, we selected two controls for each of the 52 patients, matched for birth year (+2 years). The questionnaire requested information about diet, menstrual and reproduc-

3 Female SLE Case-Control Study in Miyagi Prefecture, Japan 247 Live histories, medical history, and family hisory. Questions pertaining to diet were restricted to those regarding fatty foods. Of these fatty foods, the usual weekly consumption of meat including chicken and that of fish was estimated by taking only supper into consideration, since supper in Japan sufficiently represents individual dietary habit. For example, while only 20 percent of egg and milk per day are consumed at supper, more than 50 percent of meat including chicken and fish per day are consumed at supper (Sate and Sate 1976; Ito 1989). Besides the overall frequency of meat intake, a question about the type of meat most preferred was included in the questionnaires. Odds ratios as estimates of relative risk were computed for each variable with conditional logistic regression (Breslow and Day 1980). Food frequency categories were regrouped into three categories : rarely (twice or less per week), occasionally (three or four times per week), and frequently (five or more times per week). The relative risks for `occasionally' and `frequently' compared with `rarely' were computed. The relative risk for each facter on menstrual and reproductive histories was adjusted for all other factors examined. The analyses were performed with the PHGLM procedure available in the SAS statistical package (Harrell 1986). RESULTS The age distributions of the patients at the disease onset and at the time of the study, and the age distribution of the controls at the time of the study are shown in Table 1. The mean age of the patients at the disease onset and at the time of the study were 29.9 and 31.6 years, respectively. The mean age of the controls at the time of the study was 32.0 years. Neither the patients nor control subjects had relatives with histories of SLE. The relative risks for each food are shown in Table 2. Risk of SLE was associated with only the intake of meat. The relative risk for `frequently' compared with `rarely' was statistically significant (RR 3.36; 95% ). The test for trend across categories of the frequency of meat intake using logistic regression, however, was not statistically significant (p =0.07). Although not shown in the table, the patients preferred beef or pork to chicken (for patients ; beef or pork 96.0% and chicken 4.0%. for controls ; beef or pork 74.0% and chicken 26.0%). Table 3 presents the relative risks of SLE associated with various characteristics of menstrual and reproductive histories. The crude risk for menstrual irregularity was significantly increased. The risk for menstrual irregularity adjusted for TABLE 1. Age distribution of patients and controls

4 248 Y. Minami et al. TABLE 2. Relative risks of SLE associated with food TABLE 3. Relative risks of SLE associated with menstrual and reproductive histories all other menstrual and reproductive factors remained statistically significant (RR 3.79; 95% CI 1, ). All other factors except menstrual irregularity showed no significant association with SLE.

5 Female SLE Case-Control Study in Miyagi Prefecture, Japan 249 DISCUSSION In the present study, the cases were selected from the patients under treatment at 17 referral clinics for SLE. Since the new recipient-patients for SLE treated in these 17 hospitals accounted for 81% of all new recipient-patients in Miyagi Prefecture during , the cases were considered to represent the SLE patients with recent onset in Miyagi Prefecture. The selection of controls was carried out by using telephone directories. In Miyagi Prefecture, about 85% of household's phone numbers (Ms. Narita, oral communication) are listed in the directories, i.e. it could be said that our possible control group was a random sample of residents in this prefecture. The patients were asked to describe their daily life prior to the disease onset by physicians, and the birth year matched controls were asked to describe their daily life prior to the time of study by mail. The mean time interval between the disease onset and this study was 1.7 years. The discrepancy between the age of the patients at disease onset and the age of the controls at the time of the study was 2.1 years on average. Therefore, possible recell bias, especially related to diet, and bias due to the difference in the method of collecting data between patients and controls must be evaluated. Various studies have already explored the quality of questionnaire surveys on past dietary intake in different population subgroups and it has been reported that retrospective dietary assessment ranging from the past 6 months to 3 years could be useful in measuring dietary intake (Jamn et al. 1980; Rohan and Potter 1984; Willett et al. 1988). Taking these studies into consideration, it seems unlikely that the present results are seriously affected by the possible recall bias. Concerning the difference in the method of collecting data between patients and controls, information obtained from the patients is likely to be influenced by the communications with physicians. But, as both the patients and the controls were not privy to the study hypothesis, and information of the patients was obtained by self-administered questionnaires, not by physician's interview. Thus, the bias due to the method does not seem to be serious. A positive association with the frequent intake of meat was observed in this study. It was also indicated that the patients preferred fatty meat (Science and Technology Agency 1985) such as beef or pork to chiken. In animal models, the effects of diet on the course of autoimmune disease have been extensively researched (Dubois and Strain 1973; Beach et al. 1981; Levy et al. 1982; Kelley and Izui 1983; Kubo et al ; Corman 1985; Homsy et al ; Ogura et al. 1989) and it has been established that low fat diet and calorie restriction are able to have beneficial effects on animal SLE model. Recent animal studies also suggest that the type of fatty acids and amino acids could affects the course of autoimmune disease (Dubois and Strain 1973; Levy et al. 1982; Kelley and Izui 1983). On the other hand, the effects of diet in the course of human SLE have

6 250 Y. Minami et al. been poorly elucidated. The findings in the present study are comparable with the data in animal studies mentioned above and suggest that diet may affect the onset and the progression of human SLE, since both the frequent meat intake and the preference of fatty meats may influence total fat intake and total calorie intake. The analyses on menstrual history showed a high relative risk of SLE for menstrual irregularity. Previous epidemiologic studies of reproductive factors in SLE have shown that prior hysterectomy and tubal sterilization have protective effects, and that histories of endometriosis and miscarriage were associated with increased risk (Hochberg and Kaslow 1983 ; Grimes et al. 1985). The results of these previous studies suggest that some reproductive factors may be important for the onset of the disease. However, it has been difficult to explain the pathogenesis of SLE by hormone factors, since the relationships between the reproductive factors examined in previous studies and sex hormone are complex. Menstrual irregularity is usually due to a disturbance of the normal hormonal secretion (Gold 1975). The present results indicate that some sex hormones might be associated with the development of SLE. But there was a possibility that the onset of SLE might have induced menstrual irregurality. "A temporal sequence" (Schlesselman 1982), an important evidence showing that menstrual irregurality is causative, could not be established in this study. Furthermore, information on menstrual history may vary on the basis of whether the patients had menstrual irregurality or not at the time of the study (Schlesselman 1982). Although these unresolved problems on reproductive factors remain for further studies, our finding suggests that sex hormone could affect not only disease activity but also disease onset. This study indicates that dietary and reproductive factors may be associated with the onset and development of SLE. To date, epidemiologic studies of etiologic factors in SLE have not been extensively performed leaving many unanswered questions. Human studies including the evaluation of total fat or calorie intake and fat intake by type are required to more precisely clarify the roles of diet as well as sex hormone on the onset and the progression of SLE. In future studies, the association with socioeconomic status, which may affect diet and reproductive histories, should also be investigated. The clarification of temporal sequence for dietary and reproductive factors seems necessary for assessing causality. These studies may give important information to elucidate the etiology of SLE and make it possible to prevent the onset and progression of SLE. Acknowledgment We thank Drs. S. Ishida, F. Endo, T. Okazaki, Ta. Saito, Te. Saito, I. Sato, A. Suzuki, Y. Sekiguchi, K. Takahashi, Y. Taguma, E. Tamade, K. Tsuchikawa, K. Matsui, M. Mikami, Y. Michimata, N. Mitomo for their contributions in conducting questionnaire surveys for patients.

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