Eur J Epidemiol (2014) 29:63–71 DOI 10.1007/s10654-013-9869-9
IMMUNE DISEASES
Same-sex marriage, autoimmune thyroid gland dysfunction and other autoimmune diseases in Denmark 1989–2008 Morten Frisch • Nete Munk Nielsen Bo Vestergaard Pedersen
•
Received: 26 May 2013 / Accepted: 28 November 2013 / Published online: 5 December 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract Autoimmune diseases have been little studied in gay men and lesbians. We followed 4.4 million Danes, including 9,615 same-sex married (SSM) persons, for 47 autoimmune diseases in the National Patient Registry between 1989 and 2008. Poisson regression analyses provided first hospitalization rate ratios (RRs) comparing rates between SSM individuals and persons in other marital status categories. SSM individuals experienced no unusual overall risk of autoimmune diseases. However, the risk of autoimmune thyroid dysfunction was increased, notably Hashimoto’s thyroiditis (womenSSM, RR = 2.92; 95 % confidence interval (CI) 1.74–4.55) and Graves’ disease (menSSM, RR = 1.88; 95 % CI 1.08–3.01). There was also an excess of primary biliary cirrhosis (womenSSM, RR = 4.09; 95 % CI 1.01–10.7), and of psoriasis (menSSM, RR = 2.48; 95 % CI 1.77–3.36), rheumatic fever (menSSM, RR = 7.55; 95 % CI 1.87–19.8), myasthenia gravis (menSSM, RR = 5.51; 95 % CI 1.36–14.4), localized scleroderma (menSSM, RR = 7.16; 95 % CI 1.18–22.6) and pemphigoid (menSSM, RR = 6.56; 95 % CI 1.08–20.6), while Dupuytren’s contracture was reduced (menSSM, RR = 0.64; 95 % CI 0.39–0.99). The excess of psoriasis was restricted to same-sex married men with HIV/ AIDS (menSSM, RR = 10.5; 95 % CI 6.44–15.9), whereas Graves’ disease occurred in excess only among same-sex married men without HIV/AIDS (menSSM, RR = 1.99; 95 % CI 1.12–3.22). Lesbians and immunologically M. Frisch (&) N. M. Nielsen B. V. Pedersen Department of Epidemiology Research, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark e-mail: [email protected] M. Frisch Center for Sexology Research, Department of Clinical Medicine, Aalborg University, DK-9000 Aalborg, Denmark
competent gay men in same-sex marriage face no unusual overall risk of autoimmune diseases. However, the observed increased risk of thyroid dysfunction in these lesbians and gay men deserves further study. Keywords Autoimmune diseases Denmark Epidemiology Graves’ disease Hashimoto’s thyroiditis Homosexuality
Background Knowledge about health challenges in any population is a basic requirement for meaningful attempts to prevent disease and provide early intervention. For a number of reasons, there is an unfortunate paucity of studies addressing basic measures of health and morbidity in lesbians and gay men [1]. The absence of sexual orientation indicators in administrative data and routine health records [2], reluctance to incorporate questions about sexual orientation in survey questionnaires, and non-heterosexual persons’ hesitation to unveil their sexual orientation for fear of stigmatization are among the many obstacles that render population-based research in this field difficult. As a consequence, rigorous health investigations among large and well-characterized populations of lesbians and gay men are few [3–7]. Apart from well-documented excess morbidities associated with depression and suicidal behavior [5, 8, 9], overweight among lesbians [3, 10], and human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome (AIDS) and anal cancer among gay men [11, 12], little is known about the health profile in these groups. To our knowledge no previous study has systematically assessed the risk among lesbians and gay men of diseases
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referred to collectively as autoimmune diseases. These include common diseases like type 1 diabetes, psoriasis, thyroid diseases, rheumatoid arthritis, inflammatory bowel diseases and multiple sclerosis. We used favorable opportunities for register-based research in Denmark [13] to explore risk patterns for 47 diseases with an established or hypothesized autoimmune etiology in a nationally complete group of same-sex married lesbians and gay men.
Methods Study cohort The study cohort comprised 4.4 million Danes born between 1935 and 1990 who contributed between one day and 19.25 years of adult (C18 years) person-time at risk of autoimmune diseases between October 1, 1989 and December 31, 2008. Cohort members were identified in the Civil Registration System, a database that keeps continuously updated files on demographic variables (including marital status) for all Danish residents [14]. Since October 1, 1989, two adult persons of the same sex have been able in Denmark to engage in a registered partnership, whose legal implications are largely similar to those of heterosexual marriage [15]. Following a new law that came into operation on June 15, 2012, all previous same-sex registered partnerships and new same-sex marriages are now collectively referred to as same-sex marriages [16]. Marital status On a day-to-day basis cohort members contributed persontime at risk of autoimmune diseases in the relevant marital status category. For instance, a hypothetical man who entered his first opposite-sex marriage on February 1, 1992, divorced on June 30, 1995 and died on December 4, 2005 contributed person-time as unmarried (i.e., never married) between October 1, 1989 and January 31, 1992, as married between February 1, 1992 and June 29, 1995, and as divorced between June 30, 1995 and December 4, 2005. Another hypothetical person contributed person-time at risk as unmarried until a first heterosexual marriage, followed by a period as divorced and subsequently as samesex married. Autoimmune diseases The National Patient Register (NPR) has kept track of virtually all non-psychiatric inpatient hospital stays in Denmark since 1977 and all outpatient hospital contacts since 1995 [17]. While initiated for administrative purposes, the NPR has served as a valuable resource in
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epidemiological studies of a wide variety of outcomes, including autoimmune diseases [18–25]. In the present study, we identified all patients with hospital contacts between 1977 and 2008 for one or more of a list of 44 autoimmune diseases mentioned in Harrison’s Principles of Internal Medicine [26, 27], plus amyotrophic lateral sclerosis, Dupuytren’s contracture and induratio penis plastica (Peyronie’s disease) (Table 1). The latter diseases were included on the basis of literature suggesting an underlying autoimmune disease mechanism [28–30]. Persons with an autoimmune disease recorded in the NPR before October 1, 1989, were considered prevalent cases and were thus excluded from analyses of that particular autoimmune disease. In addition to disease-specific analyses, we combined the 47 autoimmune diseases to study the overall risk of autoimmune diseases in same-sex married lesbians and gay men. HIV/AIDS For those autoimmune diseases occurring in statistically significant excess among same-sex married men, we performed supplementary analyses of the possible impact of HIV/AIDS. To do so, we identified all men recorded in the NPR with a diagnosis of HIV or AIDS (ICD-8: 07983; ICD-10: B20-B24, Z21) until December 31, 2008. Socioeconomic variables From registers in Statistics Denmark we obtained annually updated data about each cohort member’s highest obtained educational level (basic school, high school, vocational education, short higher education, medium higher education, long higher education) and relative income level (expressed as percent of the average personal income for persons of the same sex and birth year: \50, 50–\75, 75–\125, 125–\150, C150 %) [31, 32]. Stratification of person-years and autoimmune diseases Incident cases of autoimmune diseases in the period from October 1, 1989 through December 31, 2008, were defined operationally as the first hospital record of a particular autoimmune disease in an individual, regardless of whether the diagnosis was established during inpatient hospitalization or outpatient hospital contact. For the analysis of overall risk, the first record for any of the 47 studied autoimmune diseases defined an incident case. Each cohort member contributed person-time at risk from age 18 years or October 1, 1989, whichever came later, to the date of first hospital contact for the autoimmune disease in question, death, emigration, disappearance, or December 31, 2008, whichever came first. Our
Autoimmune diseases in same-sex married Danes
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Table 1 Autoimmune diseases, corresponding ICD-8 and ICD-10 codes and their estimated female to male lifetime risk ratio in the general Danish population Disease
ICD-8
ICD-10
F:Ma
Induratio penis plastica (Peyronie’s disease)
60790
N486
0
Reiter’s disease (reactive arthritis)
13601
M023
Dupuytren’s contracture
73390
Bechterew’s disease
Table 1 continued Disease
ICD-8
ICD-10
F:Ma
Juvenile rheumatoid arthritis
71209
M080, M082, M083, M084, M088, M089
1.8
Multiple sclerosis
340
G35
1.8
0.2
Temporal arteritis/ polymyalgia rheumatica
44630, 44631,44639
M315, M316, M353
2.3
M720
0.3
Rheumatoid arthritis
M05, M06
2.4
71249
M45, M081
0.4
71219, 71229, 71239, 71259
Buerger’s disease
44319
I731, M311B
0.5
Erythema nodosum
69259
L52
2.7
Kawasaki’s disease
44692
M303
0.6
3.2
36602
H441B
0.7
70101, 70108, 70109
L940, L941, L943
Sympathetic ophthalmia
Localized scleroderma
M34
3.7
44619
M310
0.8
Systemic scleroderma
7340
Goodpasture’s syndrome Guillain Barre´’s syndrome
K743
3.9
G610
0.8
Primary biliary cirrhosis
57190
35400
L93
4.7
34809
G122G
0.8
Localized lupus erythematosus
69549
Amyotrophic lateral sclerosis Henoch–Scho¨nlein purpura
28709
D690
0.8
Wegener’s granulomatosus
44629
M313
Type 1 diabetes mellitus
249
Pemphigus foliaceus Sarcoidosis
Graves’ disease
2420
E050
5.1
73419
M32
5.2
0.9
Systemic lupus erythematosus Sjo¨gren’s disease
73490
M350
7.5
24503
E063
8.3
E10
0.9
Hashimoto’s thyroiditis Takayasu’s arteritis
44691
M314
9.3
69402
L102
0.9
135
D86
1.0
Raynaud’s syndrome
44300–44309
I730
1.1
Psoriasis
69609–69619
L40
1.1
Pemphigus vulgaris
69400
L100
1.1
Ulcerative colitis Dermatitis herpetiformis
56319, 56904 69309
K51 L130
1.1 1.2
Rheumatic fever
390, 391
I00, I01
1.2
Polyarteritis nodosa
44609
M300
1.3
Idiopathic thrombocytopenic purpura
28710
D693
1.3
Pemphigoid
69405
L12
1.3
Myasthenia gravis
73309
G700
1.4
Crohn’s disease
5630
K50
1.4
Hemolytic anemia
28390–28392
D590, D591
1.4
Behcet’s disease
13602
M352
1.5
Polymyositis/ dermatomyositis
716
M33
1.5
Addison’s disease
25510, 25511
E271, E272
1.6
Celiac disease
26900
K900
1.6
Vitiligo
70901
L80
1.6
Pernicious anemia
2810
D510
1.7
a
Female:Male (F:M) lifetime risk ratio obtained in study on autoimmune disease risk in Danish women with Turner’s syndrome [24]
study covered the entire age span from 18 through 73 years, although statistical power diminished gradually for successively older age groups (e.g. only persons born 1935–1938 reached age 70 during follow-up). Person-years and autoimmune diseases were stratified according to time-dependent values of the following potential confounders: age and calendar period (in 1-year intervals), annually updated values of educational level, and relative income 2 years before the actual year of observation; we used relative income 2 years before to reduce the risk of spurious associations due to possible disease-related changes in income level. Additionally, person-years and autoimmune diseases were stratified according to daily updated values of marital status (unmarried, opposite-sex married, opposite-sex divorced, opposite-sex widowed, or currently or formerly same-sex married), thus ensuring that all covariates and outcomes were allocated to the relevant marital status category. In supplementary analyses of the possible impact of HIV/AIDS in men, person-time and outcomes were stratified as HIVnegative until the date of first recorded diagnosis of HIV or AIDS, and as HIV-positive thereafter.
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Statistical analysis The statistical analysis of the resulting table of stratumspecific counts of person-years, autoimmune diseases and potential confounders was carried out as a log-linear Poisson regression analysis, yielding rate ratios (RRs) of first hospital contact for autoimmune diseases with 95 % confidence intervals (CIs), adjusted for educational level, relative income 2 years before the actual year, and age and calendar period using cubic splines restricted to be linear in the tails [33]. All analyses were conducted separately for women and men. In all analyses we compared rates of autoimmune diseases among cohort members who were currently or previously same-sex married (referred to hereafter simply as same-sex married) with corresponding rates in cohort members of the same sex in all other marital status categories. In supplementary analyses for men, we calculated separate RRs for same-sex married men with and without HIV/AIDS, again using men in all other marital status categories (regardless of HIV/AIDS status) as the reference category. Two-sided likelihood-ratio-based tests for homogeneity were applied, and p values\0.05 and 95 % CIs that excluded unity were considered indicators of statistical significance.
M. Frisch et al. Table 2 Rate ratios of autoimmune diseases in 4,264 currently or formerly same-sex married women compared with women in all other marital status categories
Autoimmune disease, overall
Cases
RR
95 % CI 0.97–1.34
152
1.15
Dupuytren’s contracture
4
0.88
0.27–2.06
Ankylosing spondylitis Type 1 diabetes mellitus
3 13
1.39 0.90
0.34–3.61 0.50–1.48
Sarcoidosis
4
0.82
0.26–1.92
Raynaud’s syndrome
3
1.16
0.29–3.01
Psoriasis
10
1.00
0.50–1.75
Ulcerative colitis
16
1.01
0.59–1.59
Crohn’s disease
5
0.70
0.25–1.51
Multiple sclerosis
14
1.29
0.73–2.10
3
0.79
0.20–2.06
Rheumatoid arthritis
20
1.02
0.64–1.54
Erythema nodosum
3
1.70
0.42–4.42
Localized scleroderma Primary biliary cirrhosis
2 3
3.64 4.09
0.60–11.3 1.01–10.7
Temporal arteritis/polymyalgia rheumatica
Graves’ disease Systemic lupus erythematosus Sjo¨gren’s syndrome Hashimoto’s thyroiditis
37
1.39
0.99–1.89
3
1.15
0.29–2.99
3
0.88
0.22–2.30
17
2.92
1.74–4.55
Denmark, October 1, 1989 through December 31, 2008
Results The cohort of 2,162,352 women and 2,252,751 men was followed for 67.6 million person-years between October 1, 1989, and December 31, 2008. During this period 107,496 women (5.0 %) and 91,987 men (4.1 %) developed one or more of the 47 studied autoimmune diseases. Among 4,264 women and 5,351 men who married a same-sex partner, 152 women (3.6 %) and 194 men (3.6 %) developed one or more autoimmune diseases. After controlling for age, calendar period, education and relative income, the overall risk of developing an autoimmune disease was slightly higher, though not significantly so, among same-sex married women (RR = 1.15; 95 % CI 0.97–1.34) and men (RR = 1.14; 95 % CI 0.98–1.31) than among women and men in other marital status categories (Tables 2, 3).
Autoimmune diseases listed include those occurring in at least two same-sex married women. Each of the following autoimmune diseases occurred in only one same-sex married woman: Buerger’s disease, Guillain–Barre´’s syndrome, Wegener’s granulomatosis, myasthenia gravis, Addison’s disease, celiac disease, juvenile rheumatoid arthritis and localized lupus erythematosus. None of the other diseases listed in Table 1 were observed in same-sex married women. Boldtype indicates that 95 % confidence interval excludes unity RR rate ratio, CI confidence interval
CI 1.74–4.55, 17 cases), but also Graves’ disease was marginally more common in same-sex married women (RR = 1.39; 95 % CI 0.99–1.89, 37 cases). The risk of primary biliary sclerosis was increased (RR = 4.09; 95 % CI 1.01–10.7, 3 cases), but this was based on small numbers. Men
Women During 37,926 person-years of observation same-sex married women experienced no unusual risk of most common autoimmune diseases, including rheumatoid arthritis (based on 20 cases), ulcerative colitis (16 cases), multiple sclerosis (14 cases), type 1 diabetes (13 cases), psoriasis (10 cases), and Crohn’s disease (5 cases) (Table 2). However, autoimmune thyroid gland dysfunction occurred in excess, most notably Hashimoto’s thyroiditis (RR = 2.92; 95 %
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Most autoimmune diseases did not occur in excess among same-sex married men, whom we followed for 55,150 person-years. Statistically inconspicuous risks were observed for common diseases like type 1 diabetes (based on 43 cases), ulcerative colitis (27 cases), rheumatoid arthritis (14 cases), Crohn’s disease (11 cases), induratio penis plastica (7 cases), ankylosing spondylitis (5 cases) and temporal arteritis/polymyalgia rheumatica (5 cases) (Table 3). Risks were elevated for two common diseases,
Autoimmune diseases in same-sex married Danes
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Table 3 Rate ratios of autoimmune diseases in 5,351 currently or formerly same-sex married men compared with men in all other marital status categories Cases Autoimmune disease, overall
RR
95 % CI
194
1.14
0.98–1.31
Induratio penis plastica
7
1.06
0.46–2.06
Reiter’s disease Dupuytren’s contracture
2 18
2.21 0.64
0.37–6.88 0.39–0.99
5
0.90
0.32–1.93
2
2.74
0.45–8.52
Type 1 diabetes mellitus
43
0.98
0.71–1.30
Psoriasis
38
2.48
1.77–3.36
Ulcerative colitis
27
1.41
0.94–2.01
Rheumatic fever
3
7.55
1.87–19.8
Ideopathic thrombocytopenic purpura
2
1.35
0.22–4.19
Pemphigoid
2
6.56
1.08–20.6
Ankylosing spondylitis Henoch-Scho¨nlein purpura
Myasthenia gravis Crohn’s disease
3
5.51
1.36–14.4
11
1.39
0.72–2.38
Addison’s disease
2
2.66
0.44–8.29
Celiac disease
3
1.75
0.43–4.55
Overall, 6,191 person-years (11 % of the observation period in same-sex married men) were accrued in 903 samesex married men with HIV/AIDS. The overall risk of autoimmune diseases was clearly elevated in same-sex married men with HIV/AIDS (RR = 2.36; 95 % CI 1.73–3.12, 44 cases), but not so in those without HIV/AIDS (RR = 0.99; 95 % CI 0.84–1.15, 150 cases). In particular, the risk of psoriasis was markedly elevated in same-sex married men with HIV/AIDS (RR = 10.5; 95 % CI 6.44–15.9, 19 cases), but not so in those without HIV/AIDS (RR = 1.41; 95 % CI 0.87–2.14, 19 cases). Point estimates for the RRs of rheumatic fever (RR = 25.3), pemphigoid (RR = 33.8) and myasthenia gravis (RR = 17.4) were also high for same-sex married men with HIV/AIDS, but these were based on only one case each. Only one of 15 cases of Graves’ disease in same-sex married men occurred in conjunction with HIV/AIDS (RR = 1.08), whereas, among those without HIV/AIDS, risk was doubled compared with men in all other marital status categories (RR = 1.99; 95 % CI 1.12–3.22, 14 cases).
Multiple sclerosis
7
0.98
0.42–1.90
Temporal arteritis/polymyalgia rheumatica
5
1.18
0.42–2.54
Discussion We studied a broad range of autoimmune diseases with a major impact on public health. During almost two decades of follow-up, around 5 % of Danes born 1935–1990 acquired at least one autoimmune disease. Our study is the first to systematically examine the risk of common diseases like type 1 diabetes, rheumatoid arthritis, thyroid diseases, psoriasis and inflammatory bowel diseases with a focus on relative risk in a nationally complete subset of lesbians and gay men. Overall, the risk of being diagnosed with any of the studied 47 autoimmune diseases was statistically inconspicuous, implying that lesbians and gay men—or at least those subsets who enter same-sex marriage—are generally not at any unusual risk of autoimmune diseases. However, a few novel and interesting exceptions to this general pattern emerged. In same-sex married women, the non-significant 15 % increase in overall risk was explained by an excess of autoimmune thyroid gland dysfunctions. Hypothyroidism caused by Hashimoto’s autoimmune thyroiditis was almost three-fold increased, and there was also a tendency towards an increased risk for the autoimmune hyperthyroidism known as Graves’ disease. No prior study has suggested an increased risk of these common thyroid diseases in lesbians, so our findings need replication and cautious interpretation. Recent case–control studies in Denmark suggest a beneficial influence of alcohol consumption on the risk of developing autoimmune thyroid diseases. Specifically, persons reporting moderate (B20 alcoholic units/week) or
Rheumatoid arthritis
14
1.10
0.62–1.79
Erythema nodosum
2
2.29
0.38–7.13
2
7.16
1.18–22.6
15
1.88
1.08–3.01
Localized scleroderma Graves’ disease
Denmark, October 1, 1989 through December 31, 2008 Autoimmune diseases listed include those occurring in at least two same-sex married men. Each of the following autoimmune diseases occurred in only one same-sex married man: Sympathetic ophtalmia, sarcoidosis, Raynaud’s syndrome, polyarteritis nodosa and hemolytic anemia. None of the other diseases listed in Table 1 were observed in same-sex married men. Boldtype indicates that 95 % confidence interval excludes unity RR rate ratio, CI confidence interval
namely psoriasis (RR = 2.48; 95 % CI 1.77–3.36, 38 cases) and Graves’ disease (RR = 1.88; 95 % CI 1.08–3.01, 15 cases), whereas hallmarks for markedly increased risks of rheumatic fever (RR = 7.55; 95 % CI 1.87–19.8), pemphigoid (RR = 6.56; 95 % CI 1.08–20.6), myasthenia gravis (RR = 5.51; 95 % CI 1.36–14.4), and localized scleroderma (RR = 7.16; 95 % CI 1.18–22.6) were statistically unstable and based on only two or three cases each. Same-sex married men were at reduced risk of Dupuytren’s contracture (RR = 0.64; 95 % CI 0.39–0.99, 18 cases). Impact of HIV/AIDS We explored whether the autoimmune diseases occurring in excess among same-sex married men were due to a higher prevalence of HIV/AIDS in this group (Table 4).
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Table 4 Rate ratios of selected autoimmune diseases in 5,351 currently or formerly same-sex married men by HIV/AIDS status compared with men in other marital status categories
Autoimmune disease, overall
Same-sex married men without HIV/ AIDS
Same-sex married men with HIV/ AIDS
Men in other marital status categoriesa
Cases
Cases
95 % CI
Cases
RR
95 % CI
RR
RR
150
0.99
0.84–1.15
44
2.36
1.73–3.12
91,793
1 (ref)
19
1.41
0.87–2.14
19
10.5
6.44–15.9
7,771
1 (ref)
Rheumatic fever
2
5.59
0.93–17.4
1
25.3
1.44–113
324
1 (ref)
Pemphigoid
1
3.64
0.21–16.2
1
33.8
1.92–151
157
1 (ref)
Myasthenia gravis
2
4.11
0.68–12.8
1
17.4
0.99–77.3
303
1 (ref)
14
1.99
1.12–3.22
1
1.08
0.06–4.78
4,001
1 (ref)
Psoriasis
Graves’ disease
Denmark, October 1, 1989 through December 31, 2008 Diseases listed include autoimmune disease, overall, and those autoimmune diseases occurring in statistically significant excess in Table 3 that were based on at least two cases with at least one case among same-sex married men with HIV/AIDS. Localized scleroderma occurred in two men without HIV/AIDS. Boldtype indicates that 95 % confidence interval excludes unity RR rate ratio, CI confidence interval a
The reference category comprised unmarried, heterosexually married, heterosexually divorced and heterosexually widowed men regardless of their HIV/AIDS status
high (C21 alcoholic units/week) levels of alcohol consumption had at least 49 % lower relative risk of autoimmune hypothyroidism and at least 42 % lower relative risk of Graves’ hyperthyroidism compared to persons reporting no weekly alcohol consumption [34, 35]. However, there is no evidence to suggest that lesbians and gay men in Denmark or elsewhere are more likely than others to be teetotalers. Indeed, in a 2009 survey Danish lesbians and gay men reported a higher weekly alcohol intake than heterosexual persons [36], thus rendering a low level of alcohol consumption an unlikely explanation for the increased risks of Hashimoto’s thyroiditis and Graves’ disease in our study. No prior study has suggested an excess among lesbians of primary biliary cirrhosis, a rare autoimmune disease of the small intrahepatic bile ducts. Among predisposing factors for primary biliary cirrhosis is the presence of autoimmune thyroid diseases or other autoimmune diseases in the individual or in first-degree relatives [37]. Interestingly, the observed excess of both primary biliary cirrhosis and autoimmune thyroid diseases in same-sex married Danish women is compatible with the idea that these autoimmune diseases might have overlapping etiologies. Additionally, recurrent urinary tract infections and tobacco smoking have been associated with increased risk of primary biliary cirrhosis, whereas use of oral contraceptives seems to be associated with lowered risk [37, 38]. The burden of urinary tract infections in lesbians has not been well studied, but tobacco smoking seems to be a common health hazard in this group [1, 39], and lesbians are likely to use oral contraceptives less frequently than heterosexual women [40]. Thus, lesbians might be a group at increased risk of primary biliary cirrhosis. However, in light of the
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large number of statistical tests performed and because the observed excess of primary biliary cirrhosis among lesbians in our study was based on only three cases, it might represent a chance finding. Confirmation in other settings is needed. Our study documents that same-sex married men face no unusual overall risk of being diagnosed with an autoimmune disease. Of note, however, these men experienced a reduced risk of Dupuytren’s contracture, a poorly understood male-predominant disease of the palmar fascia associated with manual work, notably exposure to vibration [41]. We are aware of no evidence to suggest a genuine protective effect of homosexuality in relation to Dupuytren’s contracture. Rather, this observation might reflect a higher average level of education among same-sex married Danish men, consistent with what has been reported for gay men in other studies [42, 43]. Interestingly, same-sex married men had a doubled risk of Graves’ disease confined to those who were not diagnosed with HIV or AIDS. We are aware of no previous large-scale study to suggest an increased risk of Graves’ disease in immunologically competent gay men. Studies have noted an excess of reactive hyperthyroidism associated with immune reconstitution from successful anti-retroviral therapy in patients with HIV [44, 45]. Our data on HIV/AIDS status were obtained in the NPR whose HIV/ AIDS diagnoses are considered accurate and 99 % complete [46], reflecting the fact that all treatments of HIVpositive individuals occur in Danish hospital settings to ensure qualified and free treatment to all. Thus, an impact of unrecorded HIV infections is unlikely. Additionally, the contrasting lack of an excess risk of Graves’ disease in same-sex married men who were diagnosed with HIV/
Autoimmune diseases in same-sex married Danes
AIDS supports the impression that the finding in men without HIV/AIDS was not a spurious result of misclassified anti-retroviral therapy-associated cases of reconstitution hyperthyroidism. It is worthy of notice that thyroid gland dysfunctions turned out to be the only autoimmune diseases occurring in numerically robust excess among both lesbians and immunologically competent gay men. While same-sex married lesbians had an almost three-fold increased risk of autoimmune hypothyroidism (Hashimoto’s thyroiditis), immunologically competent gay men had an almost doubled risk of autoimmune hyperthyroidism (Graves’ disease). If these opposite functionalities of the thyroid gland in lesbians and gay men are at all biologically linked, the explanation might somehow also be reflected in the previously reported contrasts in body composition. Several studies have reported an excess of overweight and obesity in lesbians [3, 10], while body measures of gay men are more often in the normal to low range [47, 48], and to some extent these body size patterns may be present already at birth [49]. Theoretically, therefore, our findings may suggest the existence of some underlying genetic or prenatal environmental factor that somehow links a small body size in males to homosexuality and an increased risk of hyperthyroidism, while simultaneously linking a large body size in females to homosexuality and an increased risk of hypothyroidism. Obviously, this hypothesis needs further scrutiny and substantiation. In the subgroup of same-sex married men with HIV/ AIDS, who represented 17 % of the men (but only 11 % of the person-years) in same-sex marriage, the overall risk of autoimmune diseases was more than doubled compared to the reference group of men in other marital status categories. This excess was explained to a large extent by a 10-fold increased risk of psoriasis. It has previously been established that Danish persons with HIV experience a 3–15 fold increased risk of hospital contacts for skin diseases over that of sex- and age-matched controls [50]. However, it is unclear if, and to what extent, the apparent excess risk of psoriasis is due to increased surveillance in patients with HIV/AIDS [51]. Theoretically, close follow-up of these individuals may result in hospital records of psoriasis and other skin lesions that would otherwise remain undiagnosed or be managed outside hospitals by general practitioners or practicing dermatologists. Additionally, while based on only one case of each disease, men with HIV/AIDS might be a group at increased risk of rheumatic fever, pemphigoid and myasthenia gravis. Again, however, the possible impact of multiple testing in our study plus the influence of increased clinical surveillance need consideration. Additional studies are clearly needed to address these anecdotal findings. Our study has several advantages. Its population-based nature ensured that findings were based on the entire
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Danish population, including all same-sex married persons in Denmark between 1989 and 2008. With a total of 9,615 same-sex married lesbians and gay men whom we observed for 93,074 person-years, our study had sufficient statistical power to identify unusual patterns for the most frequent autoimmune diseases. Thus, it seems fair to conclude that common autoimmune diseases like type 1 diabetes, rheumatoid arthritis, ulcerative colitis, Crohn’s disease and multiple sclerosis occur at approximately the same rate in heterosexual and homosexual individuals. Of note, however, the significant excesses of autoimmune thyroid gland dysfunctions were sufficiently robust to warrant scrutiny in other settings. Adding to the credibility of our findings was that we used data from the NPR, a valuable resource that has been used in several epidemiological studies of autoimmune diseases [18–25]. Also, in the present study we added individual information about education and income to the variable list, thus ensuring that findings were not materially confounded by socioeconomic factors. Some limitations need consideration. Formal validation of data in the NPR has only been undertaken for some of the common autoimmune diseases, including rheumatoid arthritis [18], type 1 diabetes [52], ulcerative colitis [53], Crohn’s disease [53] and multiple sclerosis [54], which all occurred at inconspicuous rates among same-sex married individuals in our study. Due to their documented validity, it is unlikely that our negative findings for these diseases emerged as a result of misclassification of these diagnoses in the NPR. To the extent present, any misclassification of other autoimmune diseases in the NPR would most likely be independent of marital status category and thus result in conservative RR estimates in our study. Therefore, among the many autoimmune diseases that did not differ materially between same-sex married and other persons in Denmark, we can not exclude the theoretical possibility that some differences were obscured by imprecisions in the underlying register data. However, the overall conclusion remains valid that with a few notable exceptions risks for most autoimmune diseases are similar among same-sex married and other persons in Denmark. Not all autoimmune diseases are routinely treated in hospital settings. This applies particularly to diseases of mild to moderate severity that are often treated by general practitioners or practicing specialists. We cannot exclude the possibility that some individuals may have been more likely to be recorded in the NPR with such mild to moderate autoimmune diseases due to coexisting morbidities requiring hospital contact. For instance, as discussed above, the observed 10-fold increased frequency of psoriasis among same-sex married men with HIV/AIDS might at least in part be a result of increased clinical detection and recording of skin lesions that usually do not lead to hospital contacts in immunologically competent individuals.
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The issue of multiple testing needs attention. We studied possible associations between different marital status categories and 47 different autoimmune disease outcomes. Moreover, for men, some analyses were divided according to HIV/AIDS status. Consequently, a large number of tests were performed, which may have rendered some of the observed associations statistically significant simply due to chance. While such chance findings may have occurred for any of the studied outcomes, it seems warranted to be particularly careful when evaluating findings based on small numbers that fell just below the 5 % significance level. It should be noted that our ability to study the risk of autoimmune diseases in Danish homosexuals was restricted to individuals in same-sex marriage. Thus, we cannot tell to what extent our findings will apply to other homosexuals, including those who are single, those living in unmarried same-sex cohabitation and those closeted gays and lesbians who live alone or with an opposite-sex partner. Future studies of health problems in homosexual persons are likely to benefit from the combined use of marital status information and novel address-based algorithms capturing broader segments of lesbians and gay men [55].
Conclusions Overall, Danish women and men in same-sex marriage seem to be no more likely than heterosexual peers to develop autoimmune diseases. However, the observed excess of autoimmune thyroid diseases, notably Hashimoto’s thyroiditis in lesbians and Graves’ disease in gay men, needs attention and confirmation in other settings. If confirmed, these findings might be a first clue to hitherto unrecognized links between genetic and/or intrauterine environmental factors and subsequent body composition, sexual orientation and adult thyroid gland function. Acknowledgments study.
No financial support was obtained for this
Conflict of interest: of interest.
All authors declare that they have no conflicts
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Autoimmune diseases in same-sex married Danes 25. Jørgensen KT, Nielsen NM, Pedersen BV, et al. Hyperemesis, gestational hypertensive disorders, pregnancy losses and risk of autoimmune diseases in a Danish population-based cohort. J Autoimmun. 2012;38(2–3): J120–J128. 26. Lipsky PE, Diamond B. Autoimmunity and autoimmune diseases. In: Braunwald E, Fauci AS, Kasper DL, et al., editors. Harrison’s principles of internal medicine. New York, NY: MacGraw-Hill; 2001. p. 1839–43. 27. Haynes BF, Fauci AS. Introduction to the immune system. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, et al., editors. Harrison’s principles of internal medicine. New York, NY: McGraw-Hill; 1998. p. 1753–76. 28. Baird KS, Alwan WH, Crossan JF, et al. T-cell-mediated response in Dupuytren’s disease. Lancet. 1993;341(8861):1622–3. 29. Staines DR. Are multiple sclerosis and amyotrophic lateral sclerosis autoimmune disorders of endogenous vasoactive neuropeptides? Med Hypotheses. 2008;70(2):413–8. 30. Ralph DJ, Mirakian R, Pryor JP, et al. The immunological features of Peyronie’s disease. J Urol. 1996;155(1):159–62. 31. Jensen VM, Rasmussen AW. Danish education registers. Scand J Public Health. 2011;39(7 Suppl):91–4. 32. Baadsgaard M, Quitzau J. Danish registers on personal income and transfer payments. Scand J Public Health. 2011;39(7 Suppl):103–5. 33. Harrell FE Jr. Regression modeling strategies: with applications to linear models, logistic regression, and survival analysis. New York, NY: Springer; 2001. 34. Carle A, Pedersen IB, Knudsen N, et al. Moderate alcohol consumption may protect against overt autoimmune hypothyroidism: a population-based case-control study. Eur J Endocrinol. 2012;167(4):483–90. 35. Carle A, Pedersen IB, Knudsen N, et al. Graves’ hyperthyroidism and moderate alcohol consumption: evidence for disease prevention. Clin Endocrinol (Oxf). doi:10.1111/cen.12106. 36. Gransell L, Larsen H. Lige og ulige? Homoseksuelle, biseksuelle og transkønnedes levevilka˚r [Survey report about living conditions among Danish LGBT individuals] (in Danish). Copenhagen, CASA; 1–128. 2009 http://www.dkr.dk/sites/default/files/lige_ og_ulige.pdf. Accessed 15 Nov 2013. 37. Corpechot C, Chretien Y, Chazouilleres O, et al. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol. 2010;53(1):162–9. 38. Smyk DS, Rigopoulou EI, Muratori L, et al. Smoking as a risk factor for autoimmune liver disease: what we can learn from primary biliary cirrhosis. Ann Hepatol. 2012;11(1):7–14. 39. Hyde Z, Comfort J, McManus A, et al. Alcohol, tobacco and illicit drug use amongst same-sex attracted women: results from the Western Australian Lesbian and Bisexual Women’s Health and Well-Being Survey. BMC Public Health. 2009;9:317. 40. Zaritsky E, Dibble SL. Risk factors for reproductive and breast cancers among older lesbians. J Womens Health (Larchmt). 2010;19(1):125–31.
71 41. Descatha A, Jauffret P, Chastang JF, et al. Should we consider Dupuytren’s contracture as work-related? A review and metaanalysis of an old debate. BMC Musculoskelet Disord. 2011;12:96. 42. Egan P, Edelman MS, Sherrill K. Findings from the Hunter College poll of lesbians, gays and bisexuals: new discoveries about identity, political attitudes, and civic engagement. New York, NY: City University of New York; 2008. p. 1–32. 43. Rothblum ED, Balsam KF, Solomon SE, et al. Lesbian, gay male, bisexual, and heterosexual siblings discrepancies in income and education in three US samples. In: Badgett L, Frank J, editors. Sexual orientation discrimination: an international perspective. New York, NY: Routledge; 2007. p. 62–75. 44. Weetman A. Immune reconstitution syndrome and the thyroid. Best Pract Res Clin Endocrinol Metab. 2009;23(6):693–702. 45. Gilquin J, Viard JP, Jubault V, et al. Delayed occurrence of Graves’ disease after immune restoration with HAART. Highly active antiretroviral therapy. Lancet. 1998;352(9144):1907–8. 46. Obel N, Reinholdt H, Omland LH, et al. Retrivability in The Danish National Hospital Registry of HIV and hepatitis B and C coinfection diagnoses of patients managed in HIV centers 1995–2004. BMC Med Res Methodol. 2008;8:25. 47. Blanchard R, Bogaert AF. Biodemographic comparisons of homosexual and heterosexual men in the Kinsey Interview Data. Arch Sex Behav. 1996;25(6):551–79. 48. Blanchard R, Dickey R, Jones CL. Comparison of height and weight in homosexual versus nonhomosexual male gender dysphorics. Arch Sex Behav. 1995;24(5):543–54. 49. Frisch M, Zdravkovic S. Body size at birth and same-sex marriage in young adulthood. Arch Sex Behav. 2010;39(1):117–23. 50. Engsig FN, Hansen AB, Gerstoft J, et al. Inpatient admissions and outpatient visits in persons with and without HIV infection in Denmark, 1995–2007. AIDS. 2010;24(3):457–61. 51. Morar N, Willis-Owen SA, Maurer T, et al. HIV-associated psoriasis: pathogenesis, clinical features, and management. Lancet Infect Dis. 2010;10(7):470–8. 52. Nielsen GL, Sørensen HT, Pedersen AB, et al. Analyses of data quality in registries concerning diabetes mellitus—a comparison between a population based hospital discharge and an insulin prescription registry. J Med Syst. 1996;20(1):1–10. 53. Fonager K, Sørensen HT, Rasmussen SN, et al. Assessment of the diagnoses of Crohn’s disease and ulcerative colitis in a Danish hospital information system. Scand J Gastroenterol. 1996;31(2):154–9. 54. Mason K, Thygesen LC, Stenager E, et al. Evaluating the use and limitations of the Danish National Patient Register in registerbased research using an example of multiple sclerosis. Acta Neurol Scand. 2012;125(3):213–7. 55. Frisch M, Simonsen J. Marriage, cohabitation and mortality in Denmark: national cohort study of 6.5 million persons followed for up to three decades (1982–2011). Int J Epidemiol. 2013;42(2):559–78.
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IMMUNE DISEASES
Same-sex marriage, autoimmune thyroid gland dysfunction and other autoimmune diseases in Denmark 1989–2008 Morten Frisch • Nete Munk Nielsen Bo Vestergaard Pedersen
•
Received: 26 May 2013 / Accepted: 28 November 2013 / Published online: 5 December 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract Autoimmune diseases have been little studied in gay men and lesbians. We followed 4.4 million Danes, including 9,615 same-sex married (SSM) persons, for 47 autoimmune diseases in the National Patient Registry between 1989 and 2008. Poisson regression analyses provided first hospitalization rate ratios (RRs) comparing rates between SSM individuals and persons in other marital status categories. SSM individuals experienced no unusual overall risk of autoimmune diseases. However, the risk of autoimmune thyroid dysfunction was increased, notably Hashimoto’s thyroiditis (womenSSM, RR = 2.92; 95 % confidence interval (CI) 1.74–4.55) and Graves’ disease (menSSM, RR = 1.88; 95 % CI 1.08–3.01). There was also an excess of primary biliary cirrhosis (womenSSM, RR = 4.09; 95 % CI 1.01–10.7), and of psoriasis (menSSM, RR = 2.48; 95 % CI 1.77–3.36), rheumatic fever (menSSM, RR = 7.55; 95 % CI 1.87–19.8), myasthenia gravis (menSSM, RR = 5.51; 95 % CI 1.36–14.4), localized scleroderma (menSSM, RR = 7.16; 95 % CI 1.18–22.6) and pemphigoid (menSSM, RR = 6.56; 95 % CI 1.08–20.6), while Dupuytren’s contracture was reduced (menSSM, RR = 0.64; 95 % CI 0.39–0.99). The excess of psoriasis was restricted to same-sex married men with HIV/ AIDS (menSSM, RR = 10.5; 95 % CI 6.44–15.9), whereas Graves’ disease occurred in excess only among same-sex married men without HIV/AIDS (menSSM, RR = 1.99; 95 % CI 1.12–3.22). Lesbians and immunologically M. Frisch (&) N. M. Nielsen B. V. Pedersen Department of Epidemiology Research, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark e-mail: [email protected] M. Frisch Center for Sexology Research, Department of Clinical Medicine, Aalborg University, DK-9000 Aalborg, Denmark
competent gay men in same-sex marriage face no unusual overall risk of autoimmune diseases. However, the observed increased risk of thyroid dysfunction in these lesbians and gay men deserves further study. Keywords Autoimmune diseases Denmark Epidemiology Graves’ disease Hashimoto’s thyroiditis Homosexuality
Background Knowledge about health challenges in any population is a basic requirement for meaningful attempts to prevent disease and provide early intervention. For a number of reasons, there is an unfortunate paucity of studies addressing basic measures of health and morbidity in lesbians and gay men [1]. The absence of sexual orientation indicators in administrative data and routine health records [2], reluctance to incorporate questions about sexual orientation in survey questionnaires, and non-heterosexual persons’ hesitation to unveil their sexual orientation for fear of stigmatization are among the many obstacles that render population-based research in this field difficult. As a consequence, rigorous health investigations among large and well-characterized populations of lesbians and gay men are few [3–7]. Apart from well-documented excess morbidities associated with depression and suicidal behavior [5, 8, 9], overweight among lesbians [3, 10], and human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome (AIDS) and anal cancer among gay men [11, 12], little is known about the health profile in these groups. To our knowledge no previous study has systematically assessed the risk among lesbians and gay men of diseases
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referred to collectively as autoimmune diseases. These include common diseases like type 1 diabetes, psoriasis, thyroid diseases, rheumatoid arthritis, inflammatory bowel diseases and multiple sclerosis. We used favorable opportunities for register-based research in Denmark [13] to explore risk patterns for 47 diseases with an established or hypothesized autoimmune etiology in a nationally complete group of same-sex married lesbians and gay men.
Methods Study cohort The study cohort comprised 4.4 million Danes born between 1935 and 1990 who contributed between one day and 19.25 years of adult (C18 years) person-time at risk of autoimmune diseases between October 1, 1989 and December 31, 2008. Cohort members were identified in the Civil Registration System, a database that keeps continuously updated files on demographic variables (including marital status) for all Danish residents [14]. Since October 1, 1989, two adult persons of the same sex have been able in Denmark to engage in a registered partnership, whose legal implications are largely similar to those of heterosexual marriage [15]. Following a new law that came into operation on June 15, 2012, all previous same-sex registered partnerships and new same-sex marriages are now collectively referred to as same-sex marriages [16]. Marital status On a day-to-day basis cohort members contributed persontime at risk of autoimmune diseases in the relevant marital status category. For instance, a hypothetical man who entered his first opposite-sex marriage on February 1, 1992, divorced on June 30, 1995 and died on December 4, 2005 contributed person-time as unmarried (i.e., never married) between October 1, 1989 and January 31, 1992, as married between February 1, 1992 and June 29, 1995, and as divorced between June 30, 1995 and December 4, 2005. Another hypothetical person contributed person-time at risk as unmarried until a first heterosexual marriage, followed by a period as divorced and subsequently as samesex married. Autoimmune diseases The National Patient Register (NPR) has kept track of virtually all non-psychiatric inpatient hospital stays in Denmark since 1977 and all outpatient hospital contacts since 1995 [17]. While initiated for administrative purposes, the NPR has served as a valuable resource in
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epidemiological studies of a wide variety of outcomes, including autoimmune diseases [18–25]. In the present study, we identified all patients with hospital contacts between 1977 and 2008 for one or more of a list of 44 autoimmune diseases mentioned in Harrison’s Principles of Internal Medicine [26, 27], plus amyotrophic lateral sclerosis, Dupuytren’s contracture and induratio penis plastica (Peyronie’s disease) (Table 1). The latter diseases were included on the basis of literature suggesting an underlying autoimmune disease mechanism [28–30]. Persons with an autoimmune disease recorded in the NPR before October 1, 1989, were considered prevalent cases and were thus excluded from analyses of that particular autoimmune disease. In addition to disease-specific analyses, we combined the 47 autoimmune diseases to study the overall risk of autoimmune diseases in same-sex married lesbians and gay men. HIV/AIDS For those autoimmune diseases occurring in statistically significant excess among same-sex married men, we performed supplementary analyses of the possible impact of HIV/AIDS. To do so, we identified all men recorded in the NPR with a diagnosis of HIV or AIDS (ICD-8: 07983; ICD-10: B20-B24, Z21) until December 31, 2008. Socioeconomic variables From registers in Statistics Denmark we obtained annually updated data about each cohort member’s highest obtained educational level (basic school, high school, vocational education, short higher education, medium higher education, long higher education) and relative income level (expressed as percent of the average personal income for persons of the same sex and birth year: \50, 50–\75, 75–\125, 125–\150, C150 %) [31, 32]. Stratification of person-years and autoimmune diseases Incident cases of autoimmune diseases in the period from October 1, 1989 through December 31, 2008, were defined operationally as the first hospital record of a particular autoimmune disease in an individual, regardless of whether the diagnosis was established during inpatient hospitalization or outpatient hospital contact. For the analysis of overall risk, the first record for any of the 47 studied autoimmune diseases defined an incident case. Each cohort member contributed person-time at risk from age 18 years or October 1, 1989, whichever came later, to the date of first hospital contact for the autoimmune disease in question, death, emigration, disappearance, or December 31, 2008, whichever came first. Our
Autoimmune diseases in same-sex married Danes
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Table 1 Autoimmune diseases, corresponding ICD-8 and ICD-10 codes and their estimated female to male lifetime risk ratio in the general Danish population Disease
ICD-8
ICD-10
F:Ma
Induratio penis plastica (Peyronie’s disease)
60790
N486
0
Reiter’s disease (reactive arthritis)
13601
M023
Dupuytren’s contracture
73390
Bechterew’s disease
Table 1 continued Disease
ICD-8
ICD-10
F:Ma
Juvenile rheumatoid arthritis
71209
M080, M082, M083, M084, M088, M089
1.8
Multiple sclerosis
340
G35
1.8
0.2
Temporal arteritis/ polymyalgia rheumatica
44630, 44631,44639
M315, M316, M353
2.3
M720
0.3
Rheumatoid arthritis
M05, M06
2.4
71249
M45, M081
0.4
71219, 71229, 71239, 71259
Buerger’s disease
44319
I731, M311B
0.5
Erythema nodosum
69259
L52
2.7
Kawasaki’s disease
44692
M303
0.6
3.2
36602
H441B
0.7
70101, 70108, 70109
L940, L941, L943
Sympathetic ophthalmia
Localized scleroderma
M34
3.7
44619
M310
0.8
Systemic scleroderma
7340
Goodpasture’s syndrome Guillain Barre´’s syndrome
K743
3.9
G610
0.8
Primary biliary cirrhosis
57190
35400
L93
4.7
34809
G122G
0.8
Localized lupus erythematosus
69549
Amyotrophic lateral sclerosis Henoch–Scho¨nlein purpura
28709
D690
0.8
Wegener’s granulomatosus
44629
M313
Type 1 diabetes mellitus
249
Pemphigus foliaceus Sarcoidosis
Graves’ disease
2420
E050
5.1
73419
M32
5.2
0.9
Systemic lupus erythematosus Sjo¨gren’s disease
73490
M350
7.5
24503
E063
8.3
E10
0.9
Hashimoto’s thyroiditis Takayasu’s arteritis
44691
M314
9.3
69402
L102
0.9
135
D86
1.0
Raynaud’s syndrome
44300–44309
I730
1.1
Psoriasis
69609–69619
L40
1.1
Pemphigus vulgaris
69400
L100
1.1
Ulcerative colitis Dermatitis herpetiformis
56319, 56904 69309
K51 L130
1.1 1.2
Rheumatic fever
390, 391
I00, I01
1.2
Polyarteritis nodosa
44609
M300
1.3
Idiopathic thrombocytopenic purpura
28710
D693
1.3
Pemphigoid
69405
L12
1.3
Myasthenia gravis
73309
G700
1.4
Crohn’s disease
5630
K50
1.4
Hemolytic anemia
28390–28392
D590, D591
1.4
Behcet’s disease
13602
M352
1.5
Polymyositis/ dermatomyositis
716
M33
1.5
Addison’s disease
25510, 25511
E271, E272
1.6
Celiac disease
26900
K900
1.6
Vitiligo
70901
L80
1.6
Pernicious anemia
2810
D510
1.7
a
Female:Male (F:M) lifetime risk ratio obtained in study on autoimmune disease risk in Danish women with Turner’s syndrome [24]
study covered the entire age span from 18 through 73 years, although statistical power diminished gradually for successively older age groups (e.g. only persons born 1935–1938 reached age 70 during follow-up). Person-years and autoimmune diseases were stratified according to time-dependent values of the following potential confounders: age and calendar period (in 1-year intervals), annually updated values of educational level, and relative income 2 years before the actual year of observation; we used relative income 2 years before to reduce the risk of spurious associations due to possible disease-related changes in income level. Additionally, person-years and autoimmune diseases were stratified according to daily updated values of marital status (unmarried, opposite-sex married, opposite-sex divorced, opposite-sex widowed, or currently or formerly same-sex married), thus ensuring that all covariates and outcomes were allocated to the relevant marital status category. In supplementary analyses of the possible impact of HIV/AIDS in men, person-time and outcomes were stratified as HIVnegative until the date of first recorded diagnosis of HIV or AIDS, and as HIV-positive thereafter.
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Statistical analysis The statistical analysis of the resulting table of stratumspecific counts of person-years, autoimmune diseases and potential confounders was carried out as a log-linear Poisson regression analysis, yielding rate ratios (RRs) of first hospital contact for autoimmune diseases with 95 % confidence intervals (CIs), adjusted for educational level, relative income 2 years before the actual year, and age and calendar period using cubic splines restricted to be linear in the tails [33]. All analyses were conducted separately for women and men. In all analyses we compared rates of autoimmune diseases among cohort members who were currently or previously same-sex married (referred to hereafter simply as same-sex married) with corresponding rates in cohort members of the same sex in all other marital status categories. In supplementary analyses for men, we calculated separate RRs for same-sex married men with and without HIV/AIDS, again using men in all other marital status categories (regardless of HIV/AIDS status) as the reference category. Two-sided likelihood-ratio-based tests for homogeneity were applied, and p values\0.05 and 95 % CIs that excluded unity were considered indicators of statistical significance.
M. Frisch et al. Table 2 Rate ratios of autoimmune diseases in 4,264 currently or formerly same-sex married women compared with women in all other marital status categories
Autoimmune disease, overall
Cases
RR
95 % CI 0.97–1.34
152
1.15
Dupuytren’s contracture
4
0.88
0.27–2.06
Ankylosing spondylitis Type 1 diabetes mellitus
3 13
1.39 0.90
0.34–3.61 0.50–1.48
Sarcoidosis
4
0.82
0.26–1.92
Raynaud’s syndrome
3
1.16
0.29–3.01
Psoriasis
10
1.00
0.50–1.75
Ulcerative colitis
16
1.01
0.59–1.59
Crohn’s disease
5
0.70
0.25–1.51
Multiple sclerosis
14
1.29
0.73–2.10
3
0.79
0.20–2.06
Rheumatoid arthritis
20
1.02
0.64–1.54
Erythema nodosum
3
1.70
0.42–4.42
Localized scleroderma Primary biliary cirrhosis
2 3
3.64 4.09
0.60–11.3 1.01–10.7
Temporal arteritis/polymyalgia rheumatica
Graves’ disease Systemic lupus erythematosus Sjo¨gren’s syndrome Hashimoto’s thyroiditis
37
1.39
0.99–1.89
3
1.15
0.29–2.99
3
0.88
0.22–2.30
17
2.92
1.74–4.55
Denmark, October 1, 1989 through December 31, 2008
Results The cohort of 2,162,352 women and 2,252,751 men was followed for 67.6 million person-years between October 1, 1989, and December 31, 2008. During this period 107,496 women (5.0 %) and 91,987 men (4.1 %) developed one or more of the 47 studied autoimmune diseases. Among 4,264 women and 5,351 men who married a same-sex partner, 152 women (3.6 %) and 194 men (3.6 %) developed one or more autoimmune diseases. After controlling for age, calendar period, education and relative income, the overall risk of developing an autoimmune disease was slightly higher, though not significantly so, among same-sex married women (RR = 1.15; 95 % CI 0.97–1.34) and men (RR = 1.14; 95 % CI 0.98–1.31) than among women and men in other marital status categories (Tables 2, 3).
Autoimmune diseases listed include those occurring in at least two same-sex married women. Each of the following autoimmune diseases occurred in only one same-sex married woman: Buerger’s disease, Guillain–Barre´’s syndrome, Wegener’s granulomatosis, myasthenia gravis, Addison’s disease, celiac disease, juvenile rheumatoid arthritis and localized lupus erythematosus. None of the other diseases listed in Table 1 were observed in same-sex married women. Boldtype indicates that 95 % confidence interval excludes unity RR rate ratio, CI confidence interval
CI 1.74–4.55, 17 cases), but also Graves’ disease was marginally more common in same-sex married women (RR = 1.39; 95 % CI 0.99–1.89, 37 cases). The risk of primary biliary sclerosis was increased (RR = 4.09; 95 % CI 1.01–10.7, 3 cases), but this was based on small numbers. Men
Women During 37,926 person-years of observation same-sex married women experienced no unusual risk of most common autoimmune diseases, including rheumatoid arthritis (based on 20 cases), ulcerative colitis (16 cases), multiple sclerosis (14 cases), type 1 diabetes (13 cases), psoriasis (10 cases), and Crohn’s disease (5 cases) (Table 2). However, autoimmune thyroid gland dysfunction occurred in excess, most notably Hashimoto’s thyroiditis (RR = 2.92; 95 %
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Most autoimmune diseases did not occur in excess among same-sex married men, whom we followed for 55,150 person-years. Statistically inconspicuous risks were observed for common diseases like type 1 diabetes (based on 43 cases), ulcerative colitis (27 cases), rheumatoid arthritis (14 cases), Crohn’s disease (11 cases), induratio penis plastica (7 cases), ankylosing spondylitis (5 cases) and temporal arteritis/polymyalgia rheumatica (5 cases) (Table 3). Risks were elevated for two common diseases,
Autoimmune diseases in same-sex married Danes
67
Table 3 Rate ratios of autoimmune diseases in 5,351 currently or formerly same-sex married men compared with men in all other marital status categories Cases Autoimmune disease, overall
RR
95 % CI
194
1.14
0.98–1.31
Induratio penis plastica
7
1.06
0.46–2.06
Reiter’s disease Dupuytren’s contracture
2 18
2.21 0.64
0.37–6.88 0.39–0.99
5
0.90
0.32–1.93
2
2.74
0.45–8.52
Type 1 diabetes mellitus
43
0.98
0.71–1.30
Psoriasis
38
2.48
1.77–3.36
Ulcerative colitis
27
1.41
0.94–2.01
Rheumatic fever
3
7.55
1.87–19.8
Ideopathic thrombocytopenic purpura
2
1.35
0.22–4.19
Pemphigoid
2
6.56
1.08–20.6
Ankylosing spondylitis Henoch-Scho¨nlein purpura
Myasthenia gravis Crohn’s disease
3
5.51
1.36–14.4
11
1.39
0.72–2.38
Addison’s disease
2
2.66
0.44–8.29
Celiac disease
3
1.75
0.43–4.55
Overall, 6,191 person-years (11 % of the observation period in same-sex married men) were accrued in 903 samesex married men with HIV/AIDS. The overall risk of autoimmune diseases was clearly elevated in same-sex married men with HIV/AIDS (RR = 2.36; 95 % CI 1.73–3.12, 44 cases), but not so in those without HIV/AIDS (RR = 0.99; 95 % CI 0.84–1.15, 150 cases). In particular, the risk of psoriasis was markedly elevated in same-sex married men with HIV/AIDS (RR = 10.5; 95 % CI 6.44–15.9, 19 cases), but not so in those without HIV/AIDS (RR = 1.41; 95 % CI 0.87–2.14, 19 cases). Point estimates for the RRs of rheumatic fever (RR = 25.3), pemphigoid (RR = 33.8) and myasthenia gravis (RR = 17.4) were also high for same-sex married men with HIV/AIDS, but these were based on only one case each. Only one of 15 cases of Graves’ disease in same-sex married men occurred in conjunction with HIV/AIDS (RR = 1.08), whereas, among those without HIV/AIDS, risk was doubled compared with men in all other marital status categories (RR = 1.99; 95 % CI 1.12–3.22, 14 cases).
Multiple sclerosis
7
0.98
0.42–1.90
Temporal arteritis/polymyalgia rheumatica
5
1.18
0.42–2.54
Discussion We studied a broad range of autoimmune diseases with a major impact on public health. During almost two decades of follow-up, around 5 % of Danes born 1935–1990 acquired at least one autoimmune disease. Our study is the first to systematically examine the risk of common diseases like type 1 diabetes, rheumatoid arthritis, thyroid diseases, psoriasis and inflammatory bowel diseases with a focus on relative risk in a nationally complete subset of lesbians and gay men. Overall, the risk of being diagnosed with any of the studied 47 autoimmune diseases was statistically inconspicuous, implying that lesbians and gay men—or at least those subsets who enter same-sex marriage—are generally not at any unusual risk of autoimmune diseases. However, a few novel and interesting exceptions to this general pattern emerged. In same-sex married women, the non-significant 15 % increase in overall risk was explained by an excess of autoimmune thyroid gland dysfunctions. Hypothyroidism caused by Hashimoto’s autoimmune thyroiditis was almost three-fold increased, and there was also a tendency towards an increased risk for the autoimmune hyperthyroidism known as Graves’ disease. No prior study has suggested an increased risk of these common thyroid diseases in lesbians, so our findings need replication and cautious interpretation. Recent case–control studies in Denmark suggest a beneficial influence of alcohol consumption on the risk of developing autoimmune thyroid diseases. Specifically, persons reporting moderate (B20 alcoholic units/week) or
Rheumatoid arthritis
14
1.10
0.62–1.79
Erythema nodosum
2
2.29
0.38–7.13
2
7.16
1.18–22.6
15
1.88
1.08–3.01
Localized scleroderma Graves’ disease
Denmark, October 1, 1989 through December 31, 2008 Autoimmune diseases listed include those occurring in at least two same-sex married men. Each of the following autoimmune diseases occurred in only one same-sex married man: Sympathetic ophtalmia, sarcoidosis, Raynaud’s syndrome, polyarteritis nodosa and hemolytic anemia. None of the other diseases listed in Table 1 were observed in same-sex married men. Boldtype indicates that 95 % confidence interval excludes unity RR rate ratio, CI confidence interval
namely psoriasis (RR = 2.48; 95 % CI 1.77–3.36, 38 cases) and Graves’ disease (RR = 1.88; 95 % CI 1.08–3.01, 15 cases), whereas hallmarks for markedly increased risks of rheumatic fever (RR = 7.55; 95 % CI 1.87–19.8), pemphigoid (RR = 6.56; 95 % CI 1.08–20.6), myasthenia gravis (RR = 5.51; 95 % CI 1.36–14.4), and localized scleroderma (RR = 7.16; 95 % CI 1.18–22.6) were statistically unstable and based on only two or three cases each. Same-sex married men were at reduced risk of Dupuytren’s contracture (RR = 0.64; 95 % CI 0.39–0.99, 18 cases). Impact of HIV/AIDS We explored whether the autoimmune diseases occurring in excess among same-sex married men were due to a higher prevalence of HIV/AIDS in this group (Table 4).
123
68
M. Frisch et al.
Table 4 Rate ratios of selected autoimmune diseases in 5,351 currently or formerly same-sex married men by HIV/AIDS status compared with men in other marital status categories
Autoimmune disease, overall
Same-sex married men without HIV/ AIDS
Same-sex married men with HIV/ AIDS
Men in other marital status categoriesa
Cases
Cases
95 % CI
Cases
RR
95 % CI
RR
RR
150
0.99
0.84–1.15
44
2.36
1.73–3.12
91,793
1 (ref)
19
1.41
0.87–2.14
19
10.5
6.44–15.9
7,771
1 (ref)
Rheumatic fever
2
5.59
0.93–17.4
1
25.3
1.44–113
324
1 (ref)
Pemphigoid
1
3.64
0.21–16.2
1
33.8
1.92–151
157
1 (ref)
Myasthenia gravis
2
4.11
0.68–12.8
1
17.4
0.99–77.3
303
1 (ref)
14
1.99
1.12–3.22
1
1.08
0.06–4.78
4,001
1 (ref)
Psoriasis
Graves’ disease
Denmark, October 1, 1989 through December 31, 2008 Diseases listed include autoimmune disease, overall, and those autoimmune diseases occurring in statistically significant excess in Table 3 that were based on at least two cases with at least one case among same-sex married men with HIV/AIDS. Localized scleroderma occurred in two men without HIV/AIDS. Boldtype indicates that 95 % confidence interval excludes unity RR rate ratio, CI confidence interval a
The reference category comprised unmarried, heterosexually married, heterosexually divorced and heterosexually widowed men regardless of their HIV/AIDS status
high (C21 alcoholic units/week) levels of alcohol consumption had at least 49 % lower relative risk of autoimmune hypothyroidism and at least 42 % lower relative risk of Graves’ hyperthyroidism compared to persons reporting no weekly alcohol consumption [34, 35]. However, there is no evidence to suggest that lesbians and gay men in Denmark or elsewhere are more likely than others to be teetotalers. Indeed, in a 2009 survey Danish lesbians and gay men reported a higher weekly alcohol intake than heterosexual persons [36], thus rendering a low level of alcohol consumption an unlikely explanation for the increased risks of Hashimoto’s thyroiditis and Graves’ disease in our study. No prior study has suggested an excess among lesbians of primary biliary cirrhosis, a rare autoimmune disease of the small intrahepatic bile ducts. Among predisposing factors for primary biliary cirrhosis is the presence of autoimmune thyroid diseases or other autoimmune diseases in the individual or in first-degree relatives [37]. Interestingly, the observed excess of both primary biliary cirrhosis and autoimmune thyroid diseases in same-sex married Danish women is compatible with the idea that these autoimmune diseases might have overlapping etiologies. Additionally, recurrent urinary tract infections and tobacco smoking have been associated with increased risk of primary biliary cirrhosis, whereas use of oral contraceptives seems to be associated with lowered risk [37, 38]. The burden of urinary tract infections in lesbians has not been well studied, but tobacco smoking seems to be a common health hazard in this group [1, 39], and lesbians are likely to use oral contraceptives less frequently than heterosexual women [40]. Thus, lesbians might be a group at increased risk of primary biliary cirrhosis. However, in light of the
123
large number of statistical tests performed and because the observed excess of primary biliary cirrhosis among lesbians in our study was based on only three cases, it might represent a chance finding. Confirmation in other settings is needed. Our study documents that same-sex married men face no unusual overall risk of being diagnosed with an autoimmune disease. Of note, however, these men experienced a reduced risk of Dupuytren’s contracture, a poorly understood male-predominant disease of the palmar fascia associated with manual work, notably exposure to vibration [41]. We are aware of no evidence to suggest a genuine protective effect of homosexuality in relation to Dupuytren’s contracture. Rather, this observation might reflect a higher average level of education among same-sex married Danish men, consistent with what has been reported for gay men in other studies [42, 43]. Interestingly, same-sex married men had a doubled risk of Graves’ disease confined to those who were not diagnosed with HIV or AIDS. We are aware of no previous large-scale study to suggest an increased risk of Graves’ disease in immunologically competent gay men. Studies have noted an excess of reactive hyperthyroidism associated with immune reconstitution from successful anti-retroviral therapy in patients with HIV [44, 45]. Our data on HIV/AIDS status were obtained in the NPR whose HIV/ AIDS diagnoses are considered accurate and 99 % complete [46], reflecting the fact that all treatments of HIVpositive individuals occur in Danish hospital settings to ensure qualified and free treatment to all. Thus, an impact of unrecorded HIV infections is unlikely. Additionally, the contrasting lack of an excess risk of Graves’ disease in same-sex married men who were diagnosed with HIV/
Autoimmune diseases in same-sex married Danes
AIDS supports the impression that the finding in men without HIV/AIDS was not a spurious result of misclassified anti-retroviral therapy-associated cases of reconstitution hyperthyroidism. It is worthy of notice that thyroid gland dysfunctions turned out to be the only autoimmune diseases occurring in numerically robust excess among both lesbians and immunologically competent gay men. While same-sex married lesbians had an almost three-fold increased risk of autoimmune hypothyroidism (Hashimoto’s thyroiditis), immunologically competent gay men had an almost doubled risk of autoimmune hyperthyroidism (Graves’ disease). If these opposite functionalities of the thyroid gland in lesbians and gay men are at all biologically linked, the explanation might somehow also be reflected in the previously reported contrasts in body composition. Several studies have reported an excess of overweight and obesity in lesbians [3, 10], while body measures of gay men are more often in the normal to low range [47, 48], and to some extent these body size patterns may be present already at birth [49]. Theoretically, therefore, our findings may suggest the existence of some underlying genetic or prenatal environmental factor that somehow links a small body size in males to homosexuality and an increased risk of hyperthyroidism, while simultaneously linking a large body size in females to homosexuality and an increased risk of hypothyroidism. Obviously, this hypothesis needs further scrutiny and substantiation. In the subgroup of same-sex married men with HIV/ AIDS, who represented 17 % of the men (but only 11 % of the person-years) in same-sex marriage, the overall risk of autoimmune diseases was more than doubled compared to the reference group of men in other marital status categories. This excess was explained to a large extent by a 10-fold increased risk of psoriasis. It has previously been established that Danish persons with HIV experience a 3–15 fold increased risk of hospital contacts for skin diseases over that of sex- and age-matched controls [50]. However, it is unclear if, and to what extent, the apparent excess risk of psoriasis is due to increased surveillance in patients with HIV/AIDS [51]. Theoretically, close follow-up of these individuals may result in hospital records of psoriasis and other skin lesions that would otherwise remain undiagnosed or be managed outside hospitals by general practitioners or practicing dermatologists. Additionally, while based on only one case of each disease, men with HIV/AIDS might be a group at increased risk of rheumatic fever, pemphigoid and myasthenia gravis. Again, however, the possible impact of multiple testing in our study plus the influence of increased clinical surveillance need consideration. Additional studies are clearly needed to address these anecdotal findings. Our study has several advantages. Its population-based nature ensured that findings were based on the entire
69
Danish population, including all same-sex married persons in Denmark between 1989 and 2008. With a total of 9,615 same-sex married lesbians and gay men whom we observed for 93,074 person-years, our study had sufficient statistical power to identify unusual patterns for the most frequent autoimmune diseases. Thus, it seems fair to conclude that common autoimmune diseases like type 1 diabetes, rheumatoid arthritis, ulcerative colitis, Crohn’s disease and multiple sclerosis occur at approximately the same rate in heterosexual and homosexual individuals. Of note, however, the significant excesses of autoimmune thyroid gland dysfunctions were sufficiently robust to warrant scrutiny in other settings. Adding to the credibility of our findings was that we used data from the NPR, a valuable resource that has been used in several epidemiological studies of autoimmune diseases [18–25]. Also, in the present study we added individual information about education and income to the variable list, thus ensuring that findings were not materially confounded by socioeconomic factors. Some limitations need consideration. Formal validation of data in the NPR has only been undertaken for some of the common autoimmune diseases, including rheumatoid arthritis [18], type 1 diabetes [52], ulcerative colitis [53], Crohn’s disease [53] and multiple sclerosis [54], which all occurred at inconspicuous rates among same-sex married individuals in our study. Due to their documented validity, it is unlikely that our negative findings for these diseases emerged as a result of misclassification of these diagnoses in the NPR. To the extent present, any misclassification of other autoimmune diseases in the NPR would most likely be independent of marital status category and thus result in conservative RR estimates in our study. Therefore, among the many autoimmune diseases that did not differ materially between same-sex married and other persons in Denmark, we can not exclude the theoretical possibility that some differences were obscured by imprecisions in the underlying register data. However, the overall conclusion remains valid that with a few notable exceptions risks for most autoimmune diseases are similar among same-sex married and other persons in Denmark. Not all autoimmune diseases are routinely treated in hospital settings. This applies particularly to diseases of mild to moderate severity that are often treated by general practitioners or practicing specialists. We cannot exclude the possibility that some individuals may have been more likely to be recorded in the NPR with such mild to moderate autoimmune diseases due to coexisting morbidities requiring hospital contact. For instance, as discussed above, the observed 10-fold increased frequency of psoriasis among same-sex married men with HIV/AIDS might at least in part be a result of increased clinical detection and recording of skin lesions that usually do not lead to hospital contacts in immunologically competent individuals.
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M. Frisch et al.
The issue of multiple testing needs attention. We studied possible associations between different marital status categories and 47 different autoimmune disease outcomes. Moreover, for men, some analyses were divided according to HIV/AIDS status. Consequently, a large number of tests were performed, which may have rendered some of the observed associations statistically significant simply due to chance. While such chance findings may have occurred for any of the studied outcomes, it seems warranted to be particularly careful when evaluating findings based on small numbers that fell just below the 5 % significance level. It should be noted that our ability to study the risk of autoimmune diseases in Danish homosexuals was restricted to individuals in same-sex marriage. Thus, we cannot tell to what extent our findings will apply to other homosexuals, including those who are single, those living in unmarried same-sex cohabitation and those closeted gays and lesbians who live alone or with an opposite-sex partner. Future studies of health problems in homosexual persons are likely to benefit from the combined use of marital status information and novel address-based algorithms capturing broader segments of lesbians and gay men [55].
Conclusions Overall, Danish women and men in same-sex marriage seem to be no more likely than heterosexual peers to develop autoimmune diseases. However, the observed excess of autoimmune thyroid diseases, notably Hashimoto’s thyroiditis in lesbians and Graves’ disease in gay men, needs attention and confirmation in other settings. If confirmed, these findings might be a first clue to hitherto unrecognized links between genetic and/or intrauterine environmental factors and subsequent body composition, sexual orientation and adult thyroid gland function. Acknowledgments study.
No financial support was obtained for this
Conflict of interest: of interest.
All authors declare that they have no conflicts
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