Risk factors for development of systemic lupus erythematosus

Journal of Clinical Epidemiology 55 (2002) 982–989

Risk factors for development of systemic lupus erythematosus: Allergies, infections, and family history Glinda S. Coopera,*, Mary Anne Dooleyb, Edward L. Treadwellc, E. William St. Claird, Gary S. Gilkesone a

Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC, USA b Division of Rheumatology, University of North Carolina, Chapel Hill, NC, USA c Division of Rheumatology, East Carolina University School of Medicine, Greenville, NC, USA d Division of Rheumatology, Allergy, and Clinical Immunology, Duke University Medical Center, Durham, NC, USA e Medical Research Service, Ralph H. Johnson Veterans Administration Medical Center and the Medical University of South Carolina, Charleston, SC, USA Received 22 May 2001; received in revised form 18 February 2002; accepted 7 March 2002

Abstract We examined risk factors for systemic lupus erythematosus (SLE) in 265 recently diagnosed patients in North Carolina and South Carolina and 355 control subjects identified through driver’s license records and frequency matched to patients by age, sex, and state. Analyses were limited to exposures before diagnosis (cases) or reference year (control subjects). SLE patients were more likely than control subjects to report a history of allergy to medications (odds ratio [OR] 3.1, 95% confidence interval [CI], 2.1–4.5), particularly to antibiotics. SLE risk increased with history of shingles (OR 2.5, 95% CI 1.1–5.9) and with frequent (more than once per year) cold sores in the 3 years before diagnosis (OR 2.8, 95% CI 1.4–5.4). There was little association with history of mononucleosis, a marker of late infection with Epstein-Barr virus, implanted medical devices, or hepatitis B vaccination. History of lupus in parents or siblings was associated with an increased risk (OR 3.3, 95% CI 1.2–8.6). Further research is needed to clarify whether medication allergies and specific infectious agents are involved in the etiology of SLE. Published by Elsevier Science Inc. Keywords: Systemic lupus erythematosus; Autoimmune disease; Sulfa drug; Herpes zoster; Infections

1. Introduction Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by the production of non-organ–specific autoantibodies including antinuclear, anti-double stranded DNA and antiphospholipid antibodies. Significant health consequences include renal failure, vasculitis, arthritis, seizures and other neurologic complications, and increased risk of infection [1]. Most (85%) SLE patients are female [2], and in the United States the incidence and prevalence of SLE are at least three times higher in African Americans compared with whites [3]. Autoimmune diseases, including SLE, are among the leading causes of death in women under age 65 years [4]. The role of genetics in SLE is suggested by patterns of disease susceptibility in murine models of SLE [5], familial

* Corresponding author. Epidemiology Branch A3-05, NIEHS, PO Box 12233, Durham, NC 27709. Tel.: 919-541-0799; fax: 919-541-2511. E-mail address: [email protected] (G.S. Cooper). 0895-4356/02/$ – Published by Elsevier Science Inc. PII: S0895-4356(02)00 4 2 9 - 8

association and linkage studies [6], and by concordance of disease in twins [7]. Little is known, however, about environmental (or nongenetic) risk factors. Few epidemiologic studies of SLE have been conducted, and size and design limitations (e.g., setting in tertiary care centers, control selection) have been noted in many of them [3]. Previous studies have reported associations with allergy to sulfa drugs and other medications [8,9], history of herpes zoster (shingles) [8], and Epstein-Barr virus infection [10]. Case reports of SLE diagnosis subsequent to hepatitis B vaccination have been reported [11], but this association has not been assessed in an epidemiologic study. We examined family history and medical-related risk factors, focusing on allergies and selected infectious agents, in a large, population-based, case-controlled study of recently diagnosed SLE. We also explored two issues that could affect the racial disparity seen in the incidence of SLE: (1) whether specific factors were associated with an increased risk of SLE among African Americans but not among whites and (2) whether specific risk factors were more prevalent in the African American population.

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2. Materials and Methods The Carolina Lupus Study is based in 60 contiguous counties in eastern North Carolina and eastern South Carolina. Cases were identified through community-based rheumatologists, university-based rheumatology practices (Duke University Medical Center, East Carolina University School of Medicine, University of North Carolina School of Medicine, and the Medical University of South Carolina), two public health clinics, and patient support groups. Thirty of the 40 community-based rheumatologists in the study area agreed to participate in the study by referring eligible patients to the study, seven other practices displayed a poster and brochures about the study, and three did not participate. At the university practices, the public health clinics, and 14 of the community-based practices, we reviewed the medical records of lupus patients seen during the study period to identify eligible patients. These 14 practices were the larger practices in the study area. We used a system of monthly phone calls to the physician and designated office staff, periodic letters, and other reminders to solicit eligible referrals at the 16 other community-based practices. The human subjects review boards at the National Institute of Environmental Health Sciences and other participating institutions reviewed and approved the study protocol. Patients were eligible for the study if they met the 1997 revised American College of Rheumatology classification criteria for SLE [12,13]; were diagnosed between January 1, 1995 and July 31, 1999; were 18 years or older at study enrollment; had lived within the study area during at least 6 months of the year before diagnosis; and could speak and understand English. We received 285 referrals of patients who were eligible for the study based on medical record data pertaining to the diagnostic criteria. Six patients refused screening to determine residential eligibility, and 14 declined to participate, for a total of 265 (93% of the referrals) case participants. Approximately half (n  130) of the patients were referred by university-based rheumatologists, and half (n  131) were referred by community-based rheumatologists. Four patients were referred from other types of physicians. The median time from diagnosis to enrollment in the study was 13 months, and 75% of patients were interviewed within 20 months of diagnosis. Information pertaining to diagnostic criteria and clinical and immunologic features was abstracted from medical records of the referring physician. Population-based control subjects were identified through driver’s license records and were frequency matched to the cases by age (5 year age groups), sex, and state. Eligibility criteria were the same as the nonmedical criteria used for cases with the added criterion of never having been diagnosed with any type of lupus. We deferred a randomly selected portion (one third) of the white control subjects so that the racial distribution of the control subjects would reflect the racial distribution of the source population, as estimated using census data for the counties in our study area

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(www.factfinder.census.gov). We selected 1873 potential control subjects from the driver’s license records of the study counties. Of these, 149 were determined to be ineligible (i.e., because of change of address or death) before telephone screening, 344 letters were returned from the post office with no change of address information (all tracing attempts were unsuccessful), a working phone number could not be found for 567, and 813 were contacted for telephone screening. In this group of 813, 163 refused screening, 46 were not eligible, 129 were eligible but deferred, 120 were eligible but declined to participate, and 355 (75% of the screened and eligible and not deferred) completed the study interview. Data collection included a structured 60-minute, in-person interview. The medical history section included questions on the presence and age at first occurrence of hay fever and hives; physician-diagnosed asthma, psoriasis, and eczema; allergic reaction to poison ivy, oak, or sumac, foods; bee or wasp sting, and animals. Questions about medication allergies included specific questions about allergy to sulfa drugs, penicillin, codeine, and an open-ended “other” category. The “other” responses were re-coded as sulfa drug, penicillin, codeine, or other as appropriate. Allergies were defined as a reaction causing a rash or breathing difficulties, not a reaction limited to stomach symptoms. The interview also included questions about diagnosis and age at occurrence of infectious diseases (hepatitis, infectious mononucleosis, tuberculosis, shingles, and urinary tract infections), frequency of colds, flu, and cold sores during the 3 years before diagnosis (with response categories of more than once a year, once a year, every few years, never, and don’t know), and vaccination for hepatitis B. History of blood transfusions (age and reason for each episode) was also ascertained. Because anemia and thrombocytopenia are clinical features of SLE [1] and may occur before a diagnosis is made, transfusions relating to anemia or platelet disorders were excluded from the analysis. The interview also asked about surgically implanted medical devices (including specific questions about pacemakers, heart valves, eye lens, dental implants, medication pumps, shunts, a urinary catheter for more than 1 month; artificial arteries, veins, or ligaments; and breast reconstruction or enhancement implants). Information on family history of specific diseases, including Sjogren syndrome, scleroderma, and lupus, was collected for mother, father, and each sibling. Control subjects were randomly assigned a reference month and year to correspond to the frequency distribution of the diagnosis month and year of cases. Analyses were limited to experiences that occurred before age at diagnosis for cases or reference age for control subjects. We used unconditional logistic regression to examine the association between specific factors (e.g., history of allergy to sulfa drugs) and risk of developing SLE. The associations were estimated as the odds ratio (OR) and 95% confidence interval (CI) and were adjusted for the matching variables (age as a continuous variable, sex, and state), race (two catego-

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ries: African-Americans and other minorities, whites), and education (did not complete high school, high school degree, some college or technical school, and college graduate). Additional stratified analyses were conducted for African Americans and whites to examine whether effect estimates differed between groups. Three participants who were adopted and did not have any information about their birth parents were excluded from the analysis of family history. The onset of SLE can be difficult to pinpoint, and symptoms may occur over a period of years before the diagnosis is made. In our study, most cases (60%) reported it had been less than 1 year between the occurrence of the first symptom and diagnosis, 13% reported it had been 1 to 2 years, 6% reported 3 to 4 years, and 20% reported 5 or more years. To examine the potential influence of the longer-onset cases on our results, we repeated the analyses excluding cases reporting 5 or more years between initial symptom and diagnosis. Results were similar using this more limited sample. Because control subjects were selected from the state driver’s license registries, we repeated the analyses excluding 27 (10%) cases who reported they did not have a state-issued driver’s license. This exclusion had little effect on any of the measures examined. We present the results from the full sample.

Table 1 Demographic characteristics of cases and control subjects in the Carolina Lupus Study Cases (n  265) Sex Female Male Ethnicity African-American White Other* Education Less than high school Completed high school Some college Completed college Age, y† 15–24 25–34 35–44 45–54 55–64 65–81

Control subjects (n  355)

n

%

n

%

240 25

90.6 9.4

321 34

90.4 9.6

160 89 16

60.4 33.6 6.0

99 230 26

27.9 64.8 7.3

59 66 80 60

22.3 24.9 30.2 22.6

32 77 130 116

9.0 21.7 36.6 32.7

43 86 49 46 24 17

16.2 32.5 18.5 17.4 9.1 6.4

44 103 76 72 35 25

12.4 29.0 21.4 20.3 9.9 7.0

*Includes Native Americans, Asians, and Hispanics. At diagnosis for cases or corresponding reference age for control subjects. †

3. Results Ninety percent of the 265 SLE cases in the Carolina Lupus Study were female, and 60% were African American (Table 1). The mean age at diagnosis was 39 years but was younger among African Americans (37 years) compared with whites (43 years) (P value for t test of racial difference in diagnosis age  0.001). Because of the age- and sexmatching procedure we used, these characteristics are similar in the control subjects. We did not match by race, and the racial distribution of control subjects is similar to the racial distribution of the population in the study area (Table 1). Common clinical features occurring up to 6 months postdiagnosis included arthritis (75%), photosensitivity (39%), malar rash (38%), pleuritis (37%), and proteinuria (25%), and 98% were positive for antinuclear antibodies. Allergy to medications was associated with an increased risk of developing SLE (OR 3.1) (Table 2). The association was strongest for sulfa drugs. The associations with history of any drug allergy and with specific drug allergies were seen in separate analyses for African Americans and whites (Table 2). The association with drug allergy was also seen in education-stratified analyses: OR 3.8 (95% CI 2.0–7.3) among people with a high school education or less and OR 2.9 (95% CI 1.8–4.6) among people with more than a high school education. A history of hives was associated with SLE risk (OR 1.8). Weak associations (ORs  2.0 that were not statistically significant) were seen with history of food allergy, psoriasis, and asthma. No association was seen with other allergic conditions or eczema (Table 2). SLE patients were more likely than control subjects to report a history of herpes zoster (5.7% compared with 3.1%

of control subjects, OR 2.5) (Table 3). An association was seen in African Americans (OR 5.4) and in whites (OR 2.2). None of the subjects were taking immunosuppressant drugs when shingles occurred. Frequent urinary tract infections were equally common in cases compared with controlsubjects (OR 1.0 for 11 or more compared with 0). There was no association between self-reported history of mononucleosis or hepatitis and SLE risk (Table 3). Further analysis provided little evidence of an increasing risk with older age at occurrence of mononucleosis (as a marker of late infection with Epstein Barr virus) compared with people who reported no history of mononucleosis: OR 1.0 (95% CI 0.2– 4.3) among people with infection at ages 15 years, OR 1.6 (95% CI 0.7–3.8) among people with infections between ages 15 and 19 years, and OR 1.0 (95% CI 0.3–4.1) among people with infections at or after age 20 years. SLE patients were more likely to report frequent cold sores and flu episodes in the 3 years before diagnosis, but this association was not seen with colds (Table 3). The association with cold sores was stronger among the 46 cases who had physician-documented oral or nasal ulcers (one of the classification criteria for SLE) (OR for cold sores more than once per year 5.9, 95% CI 2.1–16.4; OR for once per year 1.9, 95% CI (0.72–5.0); and OR for every few years 1.8, 95% CI 0.8–4.2) but was also seen in cases who did not exhibit this clinical feature of SLE (OR for cold sores more than once per year 2.3, 95% CI 1.1–5.0; OR for once per year 1.3, 95% CI 0.7–2.5; and OR for every few years 1.0, 95% CI 0.6–1.7). Our study showed little difference in the prevalence of vaccination for hepatitis B up to the diagnosis/reference age

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Table 2 Association between allergic conditions, asthma, psoriasis, eczema, and risk of SLE Total sample* Cases Medication allergy Sulfa drugs Penicillin Codeine Any Other allergy Poison ivy allergy Food allergy Insect allergy Animal allergy Hay fever Hives Asthma Psoriasis Eczema

Control Subjects

n

%

30 47 12 119

11.6 17.9 4.6 45.3

88 40 50 15 65 62 35 10 16

33.2 15.1 19.0 5.7 24.5 23.4 13.2 3.8 6.1

African Americans†

Whites‡

%

Adjusted OR§

95% CI

Adjusted OR

95% CI

Adjusted OR

95% CI

20 46 13 95

5.7 13.0 3.7 26.8

2.8 1.8 1.8 3.1

1.5–5.3 1.1–3.0 0.8–4.2 2.1–4.5

5.0 1.8 — 3.6

1.1–23.0 0.8–4.1 — 1.9–7.0

2.1 1.8 2.6 3.3

1.0–4.7 1.0–3.3 1.0–6.8 1.9–5.6

154 38 62 35 94 71 33 10 26

43.4 10.8 17.5 9.9 26.5 20.2 9.3 2.8 7.3

0.9 1.5 1.1 0.8 1.2 1.8 1.6 1.8 1.0

0.7–1.4 0.9–2.5 0.7–1.8 0.4–1.5 0.8–1.7 1.2–2.7 0.9–2.7 0.7–4.6 0.5–1.9

0.8 1.5 0.9 2.0 1.1 1.7 1.9 3.1 1.0

0.4–1.5 0.7–3.4 0.5–1.8 0.4–10.8 0.6–2.2 0.7–4.1 0.8–4.6 0.3–28.4 0.3–3.4

1.1 1.4 1.2 0.6 1.3 2.0 1.2 1.3 1.1

0.6–1.8 0.7–3.0 0.7–2.3 0.3–1.5 0.7–2.1 1.2–3.4 0.6–2.7 0.4–4.2 0.4–2.7

n

Abbreviations: SLE, systemic lupus erythematosis; OR, odds ratio; CI, confidence interval. *Total sample: 265 cases, 355 control subjects. Missing data (n cases, n control subjects): allergy to sulfa drugs (6 cases, 4 control subjects), allergy to penicillin (3 cases, 2 controls subjects), allergy to codeine (4 cases, 1 control subject), allergy to any medication (2 cases, 1 control subject), poison ivy (0 cases, 0 control subjects), food allergy (0 cases, 3 control subjects), insect allergy (2 cases, 0 control subjects), animal allergy (0 cases, 2 control subjects), hay fever (0 cases, 0 control subjects), hives (0 cases, 3 control subjects), asthma (0 cases, 0 control subjects), psoriasis (1 case, 1 control subject), eczema (3 cases, 0 control subjects). † African Americans: 160 cases, 99 control subjects. ‡ Whites: 89 cases, 230 control subjects. § Logistic regression adjusted for age (continuous), sex, race (2 groups: white; African American, and other minorities), state, and education (did not complete high school, high school degree, some college or technical school, and college graduate).  Not estimated because of zero cells.

among cases (18.7%) compared with control subjects (16.5%) (OR 1.3, 95% CI 0.8–2.1). An additional 12 cases and 11 control subjects reported vaccination at the same age as their diagnosis/reference age. Including these vaccinations did not appreciably change the association between vaccination history and SLE (OR 1.4, 95% CI 0.9–2.1). We were able to re-interview 10 of these 12 cases to obtain more detailed information about the timing of vaccination in relation to disease onset. One case reported vaccination was more than 2 years before diagnosis, five cases indicated that at least the first shot of the vaccination series occurred within the year before the diagnosis but could not provide more specific information, two were vaccinated subsequent to disease diagnosis, and two could not provide any information. There was no association with surgically implanted medical devices and risk of SLE: 7.2% of cases compared with 7.3% of control subjects reported this experience (OR 1.2, 95% CI 0.6–2.3). A history of transfusion (excluding transfusions relating to anemia or platelet disorders) was associated with an increased risk of SLE among African Americans (OR 3.8, 95% CI 1.0–14.0) but not among whites (OR 0.7, 95% CI 0.3, 1.5). This difference in effect (the race-transfusion interaction) was statistically significant (P  0.02). The association among African Americans was due to a low preva-

lence among control subjects rather than a high prevalence among cases: the prevalence of transfusions was 10.1% among African American cases and 11.4% among white cases, compared with 3.1% among African American control subjects and 15.7% among white control subjects. Fifteen cases (6%) and seven control subjects (2%) reported a history of lupus in a parent or sibling (OR 3.3, 95% CI 1.2–8.6). An additional four cases and five control subjects also reported a family history of Sjogren syndrome or scleroderma, resulting in an OR of 2.3 (95% CI, 1.1–5.2) for a family history of either of these three systemic autoimmune diseases. 4. Discussion A history of medication allergy was associated with an increased risk of developing SLE in our study. This association was strongest for sulfa medications but was seen to a lesser extent with penicillin and codeine. These results support observations from two previous case-controlled studies: Strom et al. [8] reported an association with medication allergy (OR 1.8, 95% CI 1.1–3.0), and Petri and Allbritton [9] reported an association with sulfonamide (OR 2.4, 95% CI 1.2–4.7) and penicillin/cephalosporin (OR 2.3, 95% CI 1.5–3.6) allergy. Using more detailed questions to define drug reaction (i.e., urticaria, angio-edema, or anaphylaxis),

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Table 3 Association between infections and SLE Total sample* Cases n Herpes zoster Mononucleosis Hepatitis Tuberculosis Urinary tract infections 11 4–10 1–3 Never Cold sores** once per year Once per year Every few years Never Colds** once per year Once per year Every few years or never

Control subjects %

n

%

African Americans†

Whites‡

Adjusted OR§

95% CI

Adjusted OR

95% CI

Adjusted OR

95% CI

15 15 6 2

5.7 5.7 2.3 0.8

11 31 9 2

3.1 8.8 2.5 0.6

2.5 1.3 1.1 2.4

1.1–5.9 0.7–2.6 0.4–3.5 0.3–19.0

5.4 — 0.4 —

0.6–46.8 — 0.1–2.7 —

2.2 1.2 2.7 1.4

0.8–6.4 0.5–2.6 0.7–10.8 0.1–16.0

13 35 64 121

5.6 15.0 27.5 51.9

24 53 106 171

6.8 15.0 30.0 48.4

1.1 1.3 0.9 1.0

0.5–2.4 0.7–2.2 0.6–1.4 referent

— 1.3 0.7 1.0

— 0.6–3.2 0.4–1.2 referent

0.6 1.2 1.2 1.0

0.2–2.1 0.6–2.7 0.6–2.3 referent

23 32 37 142

9.9 13.7 15.9 60.7

23 37 62 232

6.5 10.5 17.5 65.5

2.8 1.4 1.1 1.0

1.4–5.4 0.8–2.5 0.7–1.8 referent

2.8 1.0 1.1 1.0

0.5–4.2 0.5–2.5 0.5–2.3 referent

3.7 2.2 1.2 1.0

1.7–8.5 1.0–4.9 0.5–2.4 referent

88 123 54

33.2 46.4 20.4

90 189 76

25.4 53.4 21.4

1.3 0.9 1.0

0.8–2.1 0.6–1.3 referent

0.8 0.7 1.0

0.3–1.7 0.3–1.4 referent

2.1 1.0 1.0

1.0–4.3 0.5–1.8 referent

Abbreviations: SLE, systemic lupus erythematosis; OR, odds ratio; CI, confidence interval. *Total sample: 265 cases, 355 control subjects. Missing data (n cases, n control subjects): herpes zoster (0 cases, 0 control subjects), mononucleosis (1 case, 1 control subject), hepatitis (1 case, 1 control subject), urinary tract infections (32 cases, 2 control subjects), cold sores (0 cases, 1 control subject), colds (32 cases, 0 control subjects). The questions on urinary tract infections and colds during the 3 years before diagnosis/referent age were added after the initial 2 months of data collection. † African Americans: 160 cases, 99 control subjects. ‡ Whites: 89 cases, 230 control subjects. § Logistic regression adjusted for age (continuous), sex, race (2 groups: white; African American, and other minorities), state, and education (did not complete high school, high school degree, some college or technical school, and college graduate).  Not estimated because of zero cells. **In the 3 years before diagnosis/referent year.

another study (49 cases, 98 control subjects) reported a nonstatistically significant, but increased, association with SLE (OR 1.8, 95% CI 0.3–12.0) [14]. Sulfa drugs may cause disease flares in some patients [9], but we excluded events that occurred at the age of or after diagnosis, so it is unlikely that we mistakenly attributed a patient’s report of disease exacerbation in response to a sulfa medication as a drug allergy. If the observed associations are not caused by recall bias, the underlying mechanisms through which medication allergies affects disease risk are not known. None of the studies assessed the relationship of SLE risk to frequency of medication use or indications for their use. A role for infectious agents in the etiology of SLE has been postulated for many years [15]. SLE may result from an aberrant response or lack of immune control of a response to a relatively common pathogen. Several different types of studies provide support for this hypothesis. Disease expression and survival were prolonged in lupus-prone mice raised in a germ-free environment [16]. James et al. reported an increased prevalence of antibodies to EpsteinBarr virus among 117 young SLE patients (ages 4 to 19) compared with age-matched control subjects [10]. A peptide sequence in the Epstein-Barr nuclear antigen-1 is closely

related to a sequence in the Sm autoantigen, which is a target of autoantibodies seen in SLE patients [17]. Exposures to Epstein-Barr virus and other members of the herpes virus family (e.g., varicella-zoster, herpes simplex) are common [18–20]. One of the distinguishing characteristics of the herpes viruses is that they may persist in a latent state for many years, emerging again upon reactivation. Thus, other aspects of exposure (e.g., age at infection, host susceptibility, or experiences affecting their re-emergence) are likely to be involved if any of these viruses are causally linked to SLE. We observed an association between risk of developing SLE and history of herpes zoster. An association between SLE risk and herpes zoster was also reported by Strom et al. (OR 4.7, 95% CI 1.1–21.7), but no association was observed between risk of disease and history of chicken pox, measles, mumps, rubella, or herpes simplex (the herpes virus that can produce cold sores) [8]. In our study, the frequency of cold sores during the 3 years before diagnosis was higher in cases compared with control subjects and was higher still in cases who had documented evidence of oral or nasal ulcers. This association could result from a reporting or recall bias on the part of these patients. Other possible explanations for the observed associations with herpes

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zoster and with cold sores include an underlying immunologic deficiency or immune suppression before clinical presentation of SLE or common risk factors (e.g., stress) that result in more frequent viral re-emergence. We did not find an association between SLE risk and history of EpsteinBarr–related infectious mononucleosis. Later age at mononucleosis was associated with an increased risk of another autoimmune disease—multiple sclerosis—in the Nurses’ Health Study [21], but we did not see this association with SLE. Several case reports and a case series of SLE and other rheumatologic diseases following hepatitis B vaccination in children and in adults have been published [11]. However, in our study of adults, there was little evidence of an association between vaccination for hepatitis B and subsequent development of SLE. We observed an association between history of transfusions and subsequent risk of SLE among African Americans but not among whites. This was the only risk factor we examined for which a statistically significant interaction was seen with race. A study from Sweden reported an increased risk of another systemic autoimmune disease—rheumatoid arthritis—with a history of transfusions [22]. Transmission of an infectious agent is one potential mechanism through which transfusions could affect risk of SLE. Transfusions may also be a source of microchimerism, that is, the “engrafting” of cells from one individual into another individual. A role of microchimerism in the development of rheumatoid arthritis, scleroderma, SLE, and other autoimmune diseases has been recently proposed [23]. We observed an increased risk of SLE with a family history of lupus or other systemic autoimmune diseases in a parent or sibling. Similar results have been observed in previous studies [24,25]. It is difficult to conduct a population-based study of incident SLE in the United States because there are no central disease registries, the diagnosis is most often made as an out-patient visit, and there is no single test or pathology report that can be used to identify cases. Because our system for recruiting patients relied primarily on rheumatologists, we could have missed patients who were not seen by a rheumatologist. To assess the potential magnitude of this problem, we contacted 195 family practice physicians and internists in the North Carolina counties concerning their referral practices with respect to SLE. These physicians were selected from the 1995 listings of board-certified medical specialists [26]. Ninety-three percent reported that they routinely referred a lupus patient to a rheumatologist all or almost all of the time either for an initial consultation (55%) or for consultation and follow-up (38%), and only 7% reported that they did not refer a newly diagnosed SLE patient to a rheumatologist unless the patient was severely ill. The Carolina Lupus Study is the largest populationbased, case-controlled study of recently diagnosed patients with SLE that has been conducted in the United States. We believe that the completeness of case ascertainment was fairly high because we were able to use a systematic, active

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surveillance system (medical record review of all potentially eligible patients) at the universities, the larger community-based practices, and the practices known for SLE care. The clinical and immunologic features of cases in our study are similar to those reported in other large cohorts [27–29]. Data collection involved a standardized in-person interview. Recall error is possible, particularly for infections or conditions that may have occurred long ago. We did not systematically evaluate the accuracy of the self-reported medical history data in our study, but some data are available from other studies. Linet et al. reported 83% agreement for drug allergy comparing self-report to medical records in a case-controlled study of chronic lymphocytic leukemia [30]. However, studies among hospitalized patients have reported relatively low specificity for self-reported history of penicillin allergy when skin testing is used as the gold standard [31,32]. Schmader et al. reported a high level of accuracy comparing self-reported to physician-diagnosed herpes zoster in a longitudinal study of people over 65 years. Only 1 of 30 (3%) self-reported episodes was a false positive [33]. In a recent study of hepatitis B vaccination in relation to relapse in multiple sclerosis, 78% of reported vaccinations were confirmed by a copy of the vaccination report or by a written report from a physician [34]. Based on this information, and because of the possibility of differential recall bias, additional studies using more refined methods to determine history of medication allergies are warranted. The sex and racial disparity of our cases (i.e., 90% female and 60% African American) reflects the increased risk of SLE among these populations. We did not match on race in the selection of control subjects because we wanted the control group to reflect the source population. Although cases had a lower level of education than control subjects in our study, the education profile of cases is similar to what was expected based on census data for our study area (www. factfinder.census.gov). We included education in the logistic regression models and also examined education-stratified analyses to assure that our observed results were not confounded by education. The under-ascertainment of lowereducated control subjects in a population-based study is a common problem in epidemiologic research. In general, the increased risk experienced by African Americans could not be explained by an increased prevalence of the specific risk factors examined. For example, the prevalence of allergy to sulfa drugs was lower in African American (2%) compared with white (8%) control subjects. History of herpes zoster (1% and 4% in African American and white controls, respectively) and infectious mononucleosis (0% and 13% in African American and white control subjects, respectively) were also reported less often by African Americans. We do not know if the racial differences we observed are caused by differences in reporting or in the prevalence of these conditions. There is little published information on racial differences in prevalence of specific medication allergies, but Schmader et al. [35] also reported a lower incidence of herpes zoster in older (age over 65

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years) African Americans compared with whites in North Carolina. The associations between allergies and herpes zoster and risk of developing SLE were seen in our study for African Americans and whites despite the racial differences in the reported prevalence of these conditions This study demonstrates associations between the risk of developing SLE and allergies to medications and infectious conditions (particularly viruses in the herpes family). Although few epidemiologic studies of SLE have been conducted [8–10,14,21], epidemiology can provide insights and clues into the pathogenesis of this severe, chronic, autoimmune disease. Acknowledgments This study was supported by the Division of Intramural Research of the National Institute of Environmental Health Sciences. We thank the physicians who participated in the Carolina Lupus Study Group in North Carolina (H. Vann Austin, Faye Banks, Franc Barada, George Brothers, Walter Chmelewski, Duncan Fagundus, David Fraser, Stephen G. Gelfand, Helen Harmon, Robert A. Harrell, III, John Harshbarger, G. Wallace Kernodle, Jr, Elliot Kopp, Kara Martin, John L. McCain, Cathleen Melton, Gwenesta Melton, G. Radford Moeller, William Olds, David Puett, C. Michael Ramsdell, Byron Randolph A. Silvia Ross, Gregory Schimizzi, Evelyn Schmidt, T. Smith Claudia Svara, Anne Toohey, Randal White, Suzanne Zorn) and in South Carolina (Carlysle Barfield, John Brittis, Walter Bonner, William Edwards, Gary Fink, Mitchell Feinman, Frank Harper, Peter Hyman, Jr., Wendy Lee, Holly Mitchell, Alan Nussbaum, Georgia Roane, William Sheldon, Robert Turner).

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