Skip to main content Accessibility help
×
Home

Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study

Published online by Cambridge University Press:  02 January 2018

Shaw-Ji Chen
Affiliation:
Yuli Mental Research Center, Department of Psychiatry, Yuli Veteran Hospital, Hualien, and Institute of Medical Science, Tzu Chi University, Hualien, Taiwan
Yu-Lin Chao
Affiliation:
Institute of Medical Science, Tzu Chi University, Hualien, Taiwan
Chuan-Yu Chen
Affiliation:
Institute of Public Health, School of Medicine, National Yang-Ming University, Taipei, and Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
Chia-Ming Chang
Affiliation:
Department of Psychiatry, Chang Gung Memorial Hospital, Lin-Kou & Chang Gung University, Taoyuan, Taiwan
Erin Chia-Hsuan Wu
Affiliation:
Graduate Institute of Humanity in Medicine, Taipei Medical University, Taipei, Taiwan
Chi-Shin Wu
Affiliation:
Department of Psychiatry, Far Eastern Memorial Hospital, Taipei, Taiwan
Hsueh-Han Yeh
Affiliation:
Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
Chia-Hsiang Chen
Affiliation:
Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
Hui-Ju Tsai
Affiliation:
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA, and Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
Corresponding
E-mail address:
Rights & Permissions[Opens in a new window]

Abstract

Background

The association between autoimmune diseases and schizophrenia has rarely been systematically investigated.

Aims

To investigate the association between schizophrenia and a variety of autoimmune diseases and to explore possible gender variation in any such association.

Method

Taiwan's National Health Insurance Research Database was used to identify 10 811 hospital in-patients with schizophrenia and 108 110 age-matched controls. Univariate and multiple logistic regression analyses were performed, separately, to evaluate the association between autoimmune diseases and schizophrenia. We applied the false discovery rate to correct for multiple testing.

Results

When compared with the control group, the in-patients with schizophrenia had an increased risk of Graves' disease (odds ratio (OR) = 1.32, 95% CI 1.04–1.67), psoriasis (OR = 1.48, 95% CI 1.07–2.04), pernicious anaemia (OR = 1.71, 95% CI 1.04–2.80), celiac disease (OR = 2.43, 95% CI 1.12–5.27) and hypersensitivity vasculitis (OR = 5.00, 95% CI 1.64–15.26), whereas a reverse association with rheumatoid arthritis (OR = 0.52, 95% CI 0.35–0.76) was also observed. Gender-specific variation was found for Sjögren syndrome, hereditary haemolytic anaemia, myasthenia gravis, polymyalgia rheumatica and dermatomyositis.

Conclusions

Schizophrenia was associated with a greater variety of autoimmune diseases than was anticipated. Further investigation is needed to gain a better understanding of the aetiology of schizophrenia and autoimmune diseases.

Type
Papers
Copyright
Copyright © Royal College of Psychiatrists, 2012 

Schizophrenia is a devastating neuropsychiatric illness and a complex disease, and both genetic components and environmental factors play a role in its development. Reference van Os and Kapur1Reference Leucht, Burkard, Henderson, Maj and Sartorius3 In general, around 1% of the total population is affected by schizophrenia. Reference Jones, Mowry, Pender and Greer4 However, despite a considerable number of studies, the aetiology of schizophrenia remains unclear. In addition, people with schizophrenia often develop somatic symptoms, particularly autoimmune disorders. Reference Jones, Mowry, Pender and Greer4 Previous studies have reported that, compared with the general population, individuals with schizophrenia have a different prevalence of some autoimmune diseases and experience different immunological responses, Reference Jones, Mowry, Pender and Greer4,Reference Strous and Shoenfeld5 which suggests that aberrant autoimmune responses may play a role in the aetiology of schizophrenia. Autoimmune involvement may account for the high rate of perinatal obstetric complications observed in people with schizophrenia and may have potential influence on central nervous system infection, which generates antibodies against the brain tissue in those with schizophrenia. Reference Kirch6,Reference Chengappa, Nimgaonkar, Bachert, Yang, Rabin and Ganguli7 In addition, a number of genetic studies have found that human leukocyte antigens were associated with schizophrenia; however, the results were inconsistent across different studies. Reference Li, Underhill, Liu, Sham, Donaldson and Murray8Reference Palmer, Hsieh, Reed, Lonnqvist, Peltonen and Woodward10 Therefore, investigating the association between autoimmune diseases and schizophrenia is particularly important to facilitate a dissection of the aetiology of schizophrenia.

To our knowledge, to date only Eaton et al has simultaneously examined a number of autoimmune diseases in relation to schizophrenia in a Danish population. Reference Eaton, Byrne, Ewald, Mors, Chen and Agerbo11 They used data from the Danish national registries from 1981 to 1988 to evaluate the association between schizophrenia and 29 autoimmune diseases. They found that a positive association existed between schizophrenia and a variety of autoimmune diseases, Reference Eaton, Byrne, Ewald, Mors, Chen and Agerbo11 and concluded that schizophrenia was associated with a larger variety of autoimmune diseases than was expected. Since then, no study has applied a similar approach to examine the association between autoimmune diseases and schizophrenia, mainly due to the limited sample size in a single study. Few efforts have been directed to study this connection in Asian populations; only Chang et al has reported a connection between autoimmune diseases and schizophrenia. Reference Chang, Chiang, Chiu, Tsai, Tsai and Huang12 In particular, they measured the messenger ribonucleic acid expression levels of a number of cytokines in the monocytes of people with schizophrenia. Although their findings demonstrated a suggestive increased autoimmunological response in participants with schizophrenia, the association between schizophrenia and autoimmune diseases has not yet been systematically investigated. To address this issue, we turned to the 2005 National Health Insurance data in Taiwan. First, we compared the prevalence of 34 autoimmune diseases in in-patients with schizophrenia with that of a control group of individuals without schizophrenia from the general population. Next, we examined the association between autoimmune diseases and schizophrenia, and further explored possible gender variation in such connections.

Method

Study population

The data used in this study were obtained from Taiwan's National Health Insurance Research Database (NHIRD) for 2005. The NHIRD is derived from the National Health Insurance Program (NHIP), which was launched in 1995. In detail, the NHIP provides mandatory comprehensive medical care services to residents of Taiwan. Since 1995, the NHIRD has collected the data of all ambulatory care and in-patient claims from NHIP enrolees, which represent over 98% of the total population in Taiwan. Reference Chen, Liu, Su, Huang and Lin13 Therefore, the NHIRD provides a valuable data source and a unique opportunity to undertake the objectives addressed in this study.

In-patients with schizophrenia were identified from the Psychiatric Inpatient Medical Claim Dataset (PIMCD) of the NHIRD from 2005. Specifically, participants with a primary diagnosis of schizophrenia (ICD-9-CM 14 code: 295) Reference Chien, Hsu, Lin, Bih, Chou and Chou15 and having at least one claim for using the in-patient service for schizophrenia treatment in 2005 were included in the study. A total of 10 811 in-patients with schizophrenia (schizophrenia group) were identified in this data-set.

The comparison participants (control group) were identified from the Longitudinal Health Insurance Database 2005 (LHID2005) of the NHIRD; they had no reports of any diagnosis of schizophrenia in 2005. In detail, the LHID2005 contains all the registration and claim data for 1 000 000 individuals, which were collected by the NHIP and randomly sampled from the 2005 Registry for Beneficiaries of the NHIRD. Detailed information on the sampling method representative of the LHID2005 is provided at: http://w3.nhri.org.tw/nhird/date_cohort.htm#1. In addition, participants in the control group were matched with participants in the schizophrenia group by age group (by 10-year interval) with a ratio of 1:10 and were randomly drawn from the LIHD2005. A total of 108 110 age-matched comparison participants were identified in this data-set.

Definition of autoimmune diseases

We determined the autoimmune diseases to be included in our analysis on the basis of ‘the list of catastrophic illnesses of rheumatology’ and those with autoimmune properties provided by the NHIP. Of note, this list represents the most serious auto-immune diseases with a heavy economic burden in Taiwan. As a result, a total of 34 autoimmune diseases were considered and identified based on their ICD-9-CM codes (see Appendix). For both the schizophrenia and control groups, medical records for any of the 34 autoimmune diseases were retrieved from the in-patient and ambulatory services in the NHIRD in 2005.

Statistical analyses

We first computed and compared the distribution of demographic characteristics between the schizophrenia group and the control group using the χ2 test, including age (<29, 30–39, 40–49, 50–59 and 60 years); gender; region (northern, central, southern and eastern); urbanicity (urban, suburban and rural); enrolee category (a proxy measure of socioeconomic status); and information regarding health system utilisation such as number of hospital admissions in 2005 and length of hospital stay in 2005. Detailed information regarding enrolee category has been provided elsewhere. Reference Chen, Liu, Su, Huang and Lin16 Briefly, the insurance fee was determined based on enrolees’ wages as indicated in the NHIP. Participants were put into four enrolee categories, with wages of those in the first group (I) higher than those in subsequent categories (II–IV).

Next, we computed the prevalence rates for all examined autoimmune diseases among both the schizophrenia and control groups. Univariate and multiple logistic regression analyses were performed, separately, to evaluate the association between selected autoimmune diseases and schizophrenia. The covariates adjusted in the multiple conditional logistic regression models were gender, enrolee category and region. In addition, to examine the gender effect between autoimmune diseases and schizophrenia, gender-stratified analysis was carried out, which included the covariates enrolee category and region. All of the analyses were performed using SAS version 8.2 for Windows. Furthermore, to control for potential false positive results due to multiple testing, we applied the false discovery rate (FDR) to correct for multiple testing. Reference Benjamini, Drai, Elmer, Kafkafi and Golani17 The FDR procedure was performed using statistical packages R 2.10.0 (www.r-project.org/) and Bioconductor 2.7 (www.bioconductor.org/), both run on Windows.

Results

Study sample characteristics

A total of 118 921 participants (10 811 in the schizophrenia group and 108 110 in the control group) were included in this study. Table 1 shows the distribution of demographic characteristics in both groups. In general, the distribution of gender, enrolee categories (a proxy measure of socioeconomic status), region, urbanicity, average number of hospital admissions in 2005 and length of hospital stay in 2005 are significantly different between the schizophrenia group and the control group. Compared with the control group there were a higher percentage of males among the schizophrenia group (54.9% v. 49.5%), a higher number of hospital admissions in 2005 (1.15 v. 0.10 times) and a longer hospital stay in 2005 (28.38 v. 0.44 days). The percentage of those in enrolee category IV was greater in the schizophrenia group than that in the control group (57.2% v. 15.4%). In other words, those in the schizophrenia group tended to have a lower socioeconomic status than those in the control group. Additionally, when we grouped the study sample by age, we found that the highest number of participants in the schizophrenia group were aged 30–39 years for both males and females (Fig. 1).

TABLE 1 Demographic characteristics of schizophrenia and control groups

Variable Schizophrenia
group (n = 10 811)
Control group
(n = 108 110)
P
Age, years: % 1.00
   <29 28.0 27.9
   30–39 27.3 27.3
   40–49 23.8 23.8
   50–59 13.7 13.7
   >60 7.3 7.3
Gender, % <0.0001
   Male 54.9 49.5
   Female 45.1 50.5
   Unknown 0.1 0
Enrolee category, % <0.0001
   I 3.2 8.5
   II 14.0 43.5
   III 24.4 32.6
   IV 57.2 15.4
   Unknown 1.2 0.1
Region, % <0.0001
   Northern 44.6 51.3
   Central 19.1 18.0
   Southern 30.5 28.5
   Eastern 4.6 2.2
   Unknown 1.2 0.1
Urbanicity, % <0.0001
   Urban 23.1 31.9
   Suburban 61.4 57.9
   Rural 12.2 7.8
   Unknown 3.2 2.4
Health system
utilisation, mean (s.d.)
   Hospital admissions in 2005, n 1.15 (1.24) 0.10 (0.48) <0.0001
   Hospital stay in 2005, days 28.38 (39.12) 0.44 (3.03) <0.0001

FIG. 1 Number of in-patients with schizophrenia across different age groups, stratified by gender.

Prevalence of autoimmune diseases

Next, we calculated and compared the annual prevalence of 34 autoimmune diseases among both groups in 2005 (Table 2 and online Table DS1). In the schizophrenia group, 14 out of 34 autoimmune diseases had a higher prevalence than that found in the control group (Table 2 and online Table DS1). When stratifying by gender, in the schizophrenia group the prevalence of 16 autoimmune diseases was higher in females than in males. Conversely, among the control group the prevalence of 21 autoimmune diseases was higher in females than in males (Table 2 and online Table DS1).

TABLE 2 Prevalence (per 1000) of autoimmune diseases (where total n ⩾ 5 in the schizophrenia group) among schizophrenia and control groups (stratified by gender)

Schizophrenia group Control group
Autoimmune
diseaseFootnote a
Total
(n = 10 811)
Males
(n = 5936)
Females
(n = 4875)
Total
(n = 108 110)
Males
(n = 52 513)
Females
(n = 55 597)
n Prevalence n Prevalence n Prevalence n Prevalence n Prevalence n Prevalence
Graves’ disease 92 8.510 31 5.222 61 12.513 787 7.280 174 3.313 613 11.026
Psoriasis 56 5.180 37 6.233 19 3.897 311 2.877 184 3.504 127 2.284
Type 1 diabetes 31 2.867 12 2.022 19 3.897 175 1.619 92 1.752 83 1.493
Rheumatoid arthritis 30 2.775 12 2.022 18 3.692 507 4.690 164 3.123 343 6.169
Ankylosing spondylitis 29 2.682 17 2.864 12 2.462 400 3.700 219 4.170 181 3.256
Sjögren syndrome 24 2.220 11 1.853 13 2.667 312 2.886 81 1.542 231 4.155
Pernicious anaemia 22 2.035 9 1.516 13 2.667 107 0.990 26 0.495 81 1.457
Hereditary haemolytic anaemia 17 1.572 6 1.011 11 2.256 119 1.101 52 0.990 67 1.205
Myasthenia gravis 16 1.480 11 1.853 5 1.026 116 1.073 53 1.009 63 1.133
Systemic lupus erythematosus 12 1.110 3 0.505 9 1.846 128 1.184 16 0.305 112 2.014
Polyarteritis nodosa 10 0.925 4 0.674 6 1.231 48 0.444 17 0.324 31 0.558
Celiac disease 9 0.832 4 0.674 5 1.026 41 0.379 23 0.438 18 0.324
Hypersensitivity vasculitis 8 0.740 2 0.337 6 1.231 15 0.139 3 0.057 12 0.216
Alopecia areata 5 0.462 2 0.337 3 0.615 93 0.860 37 0.705 56 1.007
Polymyalgia rheumatica 5 0.462 1 0.168 4 0.821 70 0.647 23 0.438 47 0.845
Dermatomyositis 5 0.462 4 0.674 1 0.205 21 0.194 7 0.133 14 0.252

a. See Appendix for ICD-9-CM codes.

Association of autoimmune diseases with schizophrenia

For the 16 autoimmune diseases where the number of individuals with these conditions was ⩾5 in the schizophrenia group, we further examined the association between autoimmune diseases and schizophrenia. In particular, when compared with the comparison group, participants in the schizophrenia group had a significantly higher risk of Graves’ disease (odds ratio (OR) = 1.32, 95% CI 1.04–1.67), psoriasis (OR = 1.48, 95% CI 1.07–2.04), pernicious anaemia (OR = 1.71, 95% CI 1.04–2.80), celiac disease (OR = 2.43, 95% CI 1.12–5.27) and hypersensitivity vasculitis (OR = 5.00, 95% CI 1.64–15.26); whereas a reverse association with rheumatoid arthritis (OR = 0.52, 95% CI 0.35–0.76) was observed (Table 3). Of note, the positive association between hypersensitivity vasculitis and schizophrenia remained significant after correcting for multiple testing. Likewise, the reverse association of rheumatoid arthritis with schizophrenia also remained significant after accounting for multiple corrections.

Gender effect of autoimmune diseases on schizophrenia

In addition, we performed a gender-stratified analysis to examine the gender effect (Table 3). We observed a gender-specific effect for Sjögren syndrome, hereditary haemolytic anaemia, myasthenia gravis, polymyalgia rheumatica and dermatomyositis, although none of these observed associations were statistically significant (Table 3).

Furthermore, Graves’ disease, psoriasis and dermatomyositis were significantly associated only with males in the schizophrenia group. Whereas, type 1 diabetes, hereditary haemolytic anaemia, celiac disease and hypersensitivity vasculitis were significantly associated only with females in the schizophrenia group, and in addition there was a significant inverse association of rheumatoid arthritis with females in this group. Among those autoimmune diseases found to be significantly associated with the schizophrenia group, only Graves’ disease in males and rheumatoid arthritis in females remained statistically significant after correction for multiple testing (Table 3).

TABLE 3 Association between autoimmune diseases (where total n ⩾5 in the schizophrenia group) and schizophrenia among the schizophrenia and control groups (stratified by gender)

Total Males Female
Autoimmune diseasesFootnote a Adjusted ORFootnote b (95% CI) Crude OR (95% CI) Adjusted ORFootnote c (95% CI) Crude OR (95% CI) Adjusted ORFootnote c (95% CI)
Graves’ disease 1.32 Footnote d (1.04–1.67) 1.59 Footnote d (1.08–2.34) 1.86 Footnote e (1.22–2.84) 1.12 (0.86–1.47) 1.16 (0.87–1.54)
Psoriasis 1.48 Footnote d (1.07–2.04) 1.81 Footnote e (1.26–2.59) 1.60 Footnote d (1.08–2.36) 1.15 (0.86–2.44) 1.26 (0.70–2.26)
Type 1 diabetes 1.54 (0.99–2.37) 1.46 (0.80–2.70) 1.18 (0.62–2.25) 2.39 Footnote e (1.39–4.11) 1.98 Footnote d (1.11–3.54)
Rheumatoid arthritis 0.52 Footnote e (0.35–0.76) 0.66 (0.37–1.19) 0.59 (0.32–1.08) 0.59 Footnote d (0.36–0.94) 0.48 Footnote e (0.30–0.79)
Ankylosing spondylitis 0.71 (0.47–1.06) 0.70 (0.43–1.15) 0.71 (0.42–1.21) 0.74 (0.41–1.33) 0.71 (0.38–1.34)
Sjögren syndrome 0.92 (0.59–1.41) 1.23 (0.65–2.30) 1.30 (0.82–3.14) 0.63 (0.36–1.10) 0.68 (0.38–1.20)
Pernicious anaemia 1.71 Footnote d (1.04–2.80) 3.13 Footnote e (1.46–6.67) 1.91 (0.84–4.35) 1.80 Footnote d (1.00–3.23) 1.57 (0.84–2.93)
Hereditary haemolytic anaemia 1.45 (0.84–2.50) 1.04 (0.45–2.43) 0.95 (0.39–2.35) 1.84 (0.97–3.48) 1.99 Footnote d (1.00–3.93)
Myasthenia gravis 1.18 (0.67–2.09) 1.87 (0.98–3.59) 1.42 (0.69–2.92) 0.89 (0.36–2.21) 0.86 (0.34–2.23)
Systemic lupus erythematosus 1.22 (0.66–2.27) 1.69 (0.49–5.81) 2.78 (0.76–10.12) 0.90 (0.46–1.78) 1.02 (0.50–2.07)
Polyarteritis nodosa 2.04 (0.95–4.39) 2.12 (0.72–6.31) 1.91 (0.50–7.22) 2.17 (0.90–5.20) 2.19 (0.86–5.58)
Celiac disease 2.43 Footnote d (1.12–5.27) 1.57 (0.54–4.54) 1.51 (0.49–4.66) 3.12 Footnote d (1.16–8.39) 4.10 Footnote d (1.42–11.78)
Hypersensitivity vasculitis 5.00 Footnote e (1.64–15.26) 4.51 (0.41–49.75) 5.65 (0.51–62.41) 4.48 Footnote d (1.41–14.29) 4.69 Footnote d (1.34–16.45)
Alopecia areata 0.72 (0.29–1.83) 0.49 (0.12–2.02) 0.65 (0.15–2.82) 0.60 (0.19–1.92) 0.78 (0.24–2.57)
Polymyalgia rheumatica 0.77 (0.30–1.98) 0.39 (0.05–2.90) 0.39 (0.05–3.03) 0.95 (0.34–2.65) 1.02 (0.35–2.95)
Dermatomyositis 2.55 (0.88–7.39) 5.16 Footnote d (1.51–17.62) 5.11 Footnote d (1.25–20.93) 0.80 (0.11–6.08) 0.93 (0.11–7.62)

a. See Appendix for ICD-9-CM codes.

b. Adjusted for gender, enrolee category and region.

c. Adjusted for enrolee category and region.

d. Significant results. P: 0.007<P raw<0.05.

e. P: significant after false discovery rate (FDR) correction (P raw = 0.007 is equal to P FDR = 0.05 in this study).

Discussion

In general, schizophrenia and autoimmune diseases share many common clinical features. First, the diagnostic procedures are largely dependent on clinical criteria such as lacking a specific aetiological diagnosis. Second, the treatments are usually palliative, not curative. Third, schizophrenia and most autoimmune diseases have unequal distributions of incidence for age, gender, cultures and across different ethnic groups. Reference Messias, Chen and Eaton18,Reference Youinou, Pers, Gershwin and Shoenfeld19 However, schizophrenia is more prevalent among males, whereas most of the autoimmune diseases disproportionally affect females. Finally, both are complex disorders; that is, disorders that are caused by multiple genetic, environmental and lifestyle factors and the interaction between these factors, and they do not follow a clear Mendelian pattern of inheritance. Furthermore, due to limited knowledge of pathophysiology, individuals with schizophrenia and/or certain autoimmune diseases might be similar in clinical presentation, but their underlying aetiologies are very heterogeneous. Therefore, using large medical databases to identify whether certain autoimmune diseases co-occur with schizophrenia more or less commonly than expected by chance should provide an insight into the possible shared genetic, immunological and environmental mechanisms of both disorders. To our knowledge, this is the first study using a national database to address the association between schizophrenia and autoimmune diseases in an Asian population. More importantly, our data indicated that a certain number of auto-immune diseases were significantly associated (either positively or negatively) with in-patients with schizophrenia.

Significant association between autoimmune diseases and schizophrenia

Overall, a significant increased risk for Graves’ disease, psoriasis, pernicious anaemia, celiac disease and hypersensitivity vasculitis were found in the schizophrenia group, whereas a significant reverse association was observed between rheumatoid arthritis and this group. Several studies have reported the association of Graves’ disease and rheumatoid arthritis with schizophrenia, respectively, which we discuss below.

Graves’ disease, also known as thyrotoxicosis, is an auto-immune disease that affects up to 2% of the female population, and has a female-to-male incidence ratio ranging from 5:1 to 10:1. Reference Manji, Carr-Smith, Boelaert, Allahabadia, Armitage and Chatterjee20,Reference Weetman21 In agreement with previous studies, Reference Eaton, Byrne, Ewald, Mors, Chen and Agerbo11,Reference Othman, Abdul Kadir, Hassan, Hong, Singh and Raman22,Reference Wright, Sham, Gilvarry, Jones, Cannon and Sharma23 our present study revealed that participants with schizophrenia had a higher prevalence of Graves’ disease than did those in the comparison group. In addition, thyroid hormone dysfunction per se can result in cognitive function impairment, and emotional and behavioural disturbance. Therefore, further investigation of the autoimmune process of Graves’ disease in individuals with schizophrenia is warranted.

The inverse relationship between rheumatoid arthritis and schizophrenia observed in our study is generally consistent with previous findings in the area of autoimmune diseases. Reference Leucht, Burkard, Henderson, Maj and Sartorius3,Reference Eaton, Hayward and Ram24Reference Oken and Schulzer26 It has been proposed that this relationship may be attributed to the interplay of genetic influence (hitch-hiking of major histocompatibility complex genes), environmental factors (institutionalisation and sedentary lifestyle due to negative symptoms), immunological aspects (common infectious aetiology and immunity) and pharmacological effects (anti-inflammatory and analgesic effects of antipsychotics). Reference Torrey and Yolken27 Specifically, rheumatoid arthritis is a progressive, systemic inflammatory disorder that may affect many tissues and organs, but mainly attacks synovial joints. The peak onset of rheumatoid arthritis occurs between the fourth to sixth decade of life, and women are two to five times more likely than men to develop this disease. Reference Scott, Wolfe and Huizinga28 Of interest, as shown in Table 3, we observed a significant inverse association of rheumatoid arthritis with females in the schizophrenia group. It will be of importance in future studies to dissect the relationship between rheumatoid arthritis and schizophrenia to gain a better understanding of the interplay of the four components listed above.

TABLE 4 Comparison of the prevalence (per 1000) of autoimmune diseases in the general population in Taiwan and that in Asian populations

Autoimmune disease Country of study
population
Prevalence in general
population in our study
Prevalence in the
compared study
Source
Graves’ disease China 7.3 12 Shapira et al Reference Shapira, Agmon-Levin and Shoenfeld 29
Rheumatoid arthritis China 4.7 2–9.3 Zeng et al Reference Zeng, Chen, Darmawan, Xiao, Chen and Wigley 30
Psoriasis Japan 2.9 2.4–11.8 Raychaudhuri et al Reference Raychaudhuri and Farber 31
Pernicious anaemia China 1.0 1.3 Chan et al Reference Chan, Liu, Kho, Lau, Li and Chan 32
Celiac disease India 0.4 0.2–2 Cummins & Roberts-ThomsonReference Cummins and Roberts-Thomson 33
Hypersensitivity vasculitis India 0.1 0.03–0.1 WattsReference Watts 34

Comparison of autoimmune disease prevalence found in the present study and Asian populations

We compared the prevalence of the 34 autoimmune diseases we had investigated in the general population in Taiwan to that reported in Asian populations. The data in Table 4 show the comparisons between the prevalence of the six significant auto-immune diseases observed in Table 3 and the prevalence of these reported in Asian populations. We found that the prevalence of these six conditions was comparable with that reported by other groups (Table 4).

Genetic influences on schizophrenia and autoimmune diseases

Recent genome-wide association studies have identified a growing number of disease-associated loci and provided enormous insight into the aetiology of complex genetic disorders, including schizophrenia and autoimmune diseases. For example, using molecular pathway-based analysis, genome-wide association studies of schizophrenia revealed a number of genes involved in neuronal cell adhesion, membrane scaffolding, apoptosis, glutamate metabolism or synaptogenesis. Reference Jia, Wang, Meltzer and Zhao35,Reference O'Dushlaine, Kenny, Heron, Donohoe, Gill and Morris36 Meanwhile, genome-wide association studies of autoimmune diseases have highlighted immune-associated genes involved in lymphocyte activation (receptor signalling and co-stimulation pathways), microbial recognition and cytokines or cytokine receptors. Reference Gregersen and Olsson37 Strikingly, consistent with the results from previous linkage and case–control association studies, genome-wide association study results confirmed a shared genetic association in the major histocompatibility complex (also known as human leukocyte antigen) region between schizophrenia and most autoimmune diseases. Reference Shi, Levinson, Duan, Sanders, Zheng and Pe'er38,Reference Zenewicz, Abraham, Flavell and Cho39 The unique coding and non-coding genetic variation of human leukocyte antigen alleles are involved in shaping the nature of antigen responses to self- or non-self-antigens. Moreover, extensive allelic variation and linkage disequilibrium (non-random or correlated association of alleles due to physical closeness) have been observed throughout the major histocompatibility complex region. Reference Trowsdale40 Therefore, this shared gene region of association may influence direct involvement of certain human leukocyte antigens, or it may be through linkage disequilibrium between the loci related to schizophrenia and those related to autoimmune diseases in human leukocyte antigen regions. Genotyping more dense single-nucleotide polymorphisms or deep sequencing human leukocyte antigen regions may shed more light on the nature of the common shared genetic components of schizophrenia and autoimmune diseases.

Strengths and limitations

This study has several strengths. First, the NHIP in Taiwan is a single-payer compulsory social insurance plan that centralises the disbursement of healthcare funds. The system promises equal access to healthcare for all citizens, and it covers nearly all clinical activities in Taiwan. More importantly, as mentioned earlier, the NHIP covers over 98% of the total population in Taiwan. Second, unlike several national registry databases that exist in European countries such as Iceland, Finland and Denmark, NHIRD in Taiwan is the only national database that exists among Asian countries. Third, the sample size in this study is sufficient since it is based on the NHIRD data (i.e. on national data). Since autoimmune diseases and schizophrenia are both considered rare diseases, a large sample size makes it feasible to investigate the relationship between them.

However, some limitations should also be considered. First, the NHIRD did not collect laboratory data to validate the physician diagnosis or the severity of autoimmune diseases. However, most autoimmune diseases examined in this study were selected based on the list of catastrophic illness of rheumatology provided by the NHIP. Based on standard clinical guidance for the list of catastrophic illnesses in the NHIP, it requires three board-certified rheumatologists to independently diagnose individuals with the explicit ICD-9-CM code for the autoimmune diseases on the list of catastrophic illnesses. As such, the diagnosis of autoimmune diseases was relatively reliable. Second, due to the nature of the cross-sectional design, this study cannot investigate temporal/causal relationships between autoimmune disorders and schizophrenia, but can only document the prevalence and association between schizophrenia and autoimmune diseases. Indeed, the observed excess in autoimmune diseases associated with schizophrenia may be partly explained by non-aetiological causational mechanisms. For example, because of the long course of treatment, people with schizophrenia were more likely to be treated as compared with individuals in the community without schizophrenia. It will be of importance to further investigate the causal relationship between schizophrenia and autoimmune diseases using a prospective cohort. Finally, this is the first study of its kind to be conducted in an Asian population. Therefore, the results observed in this study may or may not be generalised to other ethnic groups, and caution is needed when interpreting the results of this study.

Further research

In the present study, we documented that in an Asian population schizophrenia was associated with a wider variety of autoimmune diseases than was expected. The findings of comorbidity suggest that shared genetic components and shared aetiological pathways may occur in autoimmune diseases and schizophrenia. Further investigation of the interplay between genetic, immune and pathological mechanisms will provide a better understanding of the underlying aetiology of both schizophrenia and autoimmune diseases.

Appendix

Autoimmune disease included in analysis with ICD-9-CM codes

Graves’ disease (242, 242.01), Crohn's disease (555.0, 555.1, 555.2, 555.9), psoriasis (696, 696.1, 696.8), systemic lupus erythematosus (710.0), rheumatoid arthritis (714), ankylosing spondylitis (720), Guillain–Barré syndrome (357.0), type 1 diabetes (250.01, 250.03, 250.11, 250.13, 250.21, 250.23, 250.31, 250.33, 250.41, 250.43, 250.51, 250.53, 250.61, 250.63, 250.71, 250.73, 250.81, 250.83, 250.91, 250.93), Sjögren syndrome (710.2), myasthenia gravis (358), pernicious anaemia (281), hereditary haemolytic anaemia (282), polyarteritis nodosa (446), celiac disease (579), uveitis (364.00, 364.01), polymyalgia rheumatica (725), dermatomyositis (710.3), Hashimoto's thyroiditis (245.2), hypersensitivity vasculitis (446.2, 446.29), Behcet's disease (136.1), polymyositis (710.4), alopecia areata (704.01), Wegener's granulomatosis (446.4), ulcerative colitis (556.0, 556.6, 556.8, 556.9), autoimmune haemolytic anaemia (283), pemphigus (694.4), multiple sclerosis (340), systemic sclerosis (710.1), juvenile rheumatoid arthritis (714.30, 714.33), Goodpasture syndrome (446.21), giant cell arteritis (446.5), thromboangitis obliterans (443.1), arteritis obliterans (446.7) and Kawasaki disease (446.1).

Funding

This study was supported in part by grants from the National Health Research Institutes (, ).

Acknowledgements

Our thank to Drs Kuan-Yi Wu and Hsin-Yi Liang for their comments on the manuscript, Lan-Chao Wang for his assistance with data management and Tami R. Bartell for English editing. This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by the National Health Research Institutes of Taiwan.

Footnotes

See editorial, pp. 353–355, this issue.

This study was supported in part by grants from the National Health Research Institutes (PH-099-PP-56, PH-100-PP-14).

Declaration of interest

None.

References

1 van Os, J, Kapur, S. Schizophrenia. Lancet 2009; 374: 635–45.CrossRefGoogle ScholarPubMed
2 O'Donovan, MC, Craddock, NJ, Owen, MJ. Genetics of psychosis: insights from views across the genome. Hum Genet 2009; 126: 312.CrossRefGoogle ScholarPubMed
3 Leucht, S, Burkard, T, Henderson, J, Maj, M, Sartorius, N. Physical illness and schizophrenia: a review of the literature. Acta Psychiatr Scand 2007; 116: 317–33.CrossRefGoogle ScholarPubMed
4 Jones, AL, Mowry, BJ, Pender, MP, Greer, JM. Immune dysregulation and self-reactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis? Immunol Cell Biol 2005; 83: 917.CrossRefGoogle ScholarPubMed
5 Strous, RD, Shoenfeld, Y. Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. J Autoimmun 2006; 27: 7180.CrossRefGoogle ScholarPubMed
6 Kirch, DG. Infection and autoimmunity as etiologic factors in schizophrenia: a review and reappraisal. Schizophr Bull 1993; 19: 355–70.CrossRefGoogle ScholarPubMed
7 Chengappa, KN, Nimgaonkar, VL, Bachert, C, Yang, ZW, Rabin, BS, Ganguli, R. Obstetric complications and autoantibodies in schizophrenia. Acta Psychiatr Scand 1995; 92: 270–3.CrossRefGoogle Scholar
8 Li, T, Underhill, J, Liu, XH, Sham, PC, Donaldson, P, Murray, RM, et al. Transmission disequilibrium analysis of HLA class II DRB1, DQA1, DQB1 and DPB1 polymorphisms in schizophrenia using family trios from a Han Chinese population. Schizophr Res 2001; 49: 73–8.CrossRefGoogle ScholarPubMed
9 Schwab, SG, Hallmayer, J, Lerer, B, Albus, M, Borrmann, M, Honig, S, et al. Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis. Am J Hum Genet 1998; 63: 1139–52.CrossRefGoogle ScholarPubMed
10 Palmer, CG, Hsieh, HJ, Reed, EF, Lonnqvist, J, Peltonen, L, Woodward, JA, et al. HLA-B maternal-fetal genotype matching increases risk of schizophrenia. Am J Hum Genet 2006; 79: 710–5.CrossRefGoogle ScholarPubMed
11 Eaton, WW, Byrne, M, Ewald, H, Mors, O, Chen, CY, Agerbo, E, et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006; 163: 521–8.CrossRefGoogle ScholarPubMed
12 Chang, SH, Chiang, SY, Chiu, CC, Tsai, CC, Tsai, HH, Huang, CY, et al. Expression of anti-cardiolipin antibodies and inflammatory associated factors in patients with schizophrenia. Psychiatry Res 2011; 187: 341–6.CrossRefGoogle ScholarPubMed
13 Chen, CY, Liu, CY, Su, WC, Huang, SL, Lin, KM. Factors associated with the diagnosis of neurodevelopmental disorders: a population-based longitudinal study. Pediatrics 2007; 119: e43543.CrossRefGoogle Scholar
14 World Health Organization. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD–9–CM). WHO, 1979.Google Scholar
15 Chien, IC, Hsu, JH, Lin, CH, Bih, SH, Chou, YJ, Chou, P. Prevalence of diabetes in patients with schizophrenia in Taiwan: a population-based National Health Insurance study. Schizophr Res 2009; 111: 1722.CrossRefGoogle ScholarPubMed
16 Chen, CY, Liu, CY, Su, WC, Huang, SL, Lin, KM. Urbanicity-related variation in help-seeking and services utilization among preschool-age children with autism in Taiwan. J Autism Dev Disord 2008; 38: 489–97.CrossRefGoogle ScholarPubMed
17 Benjamini, Y, Drai, D, Elmer, G, Kafkafi, N, Golani, I. Controlling the false discovery rate in behavior genetics research. Behav Brain Res 2001; 125: 279–84.CrossRefGoogle ScholarPubMed
18 Messias, EL, Chen, CY, Eaton, WW. Epidemiology of schizophrenia: review of findings and myths. Psychiatr Clin North Am 2007; 30: 323–38.CrossRefGoogle ScholarPubMed
19 Youinou, P, Pers, JO, Gershwin, ME, Shoenfeld, Y. Geo-epidemiology and autoimmunity. J Autoimmun 2010; 34: J1637.CrossRefGoogle ScholarPubMed
20 Manji, N, Carr-Smith, JD, Boelaert, K, Allahabadia, A, Armitage, M, Chatterjee, VK, et al. Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype. J Clin Endocrinol Metab 2006; 91: 4873–80.CrossRefGoogle ScholarPubMed
21 Weetman, AP. Graves' disease. N Engl J Med 2000; 343: 1236–48.CrossRefGoogle ScholarPubMed
22 Othman, SS, Abdul Kadir, K, Hassan, J, Hong, GK, Singh, BB, Raman, N. High prevalence of thyroid function test abnormalities in chronic schizophrenia. Aust N Z J Psychiatry 1994; 28: 620–4.CrossRefGoogle ScholarPubMed
23 Wright, P, Sham, PC, Gilvarry, CM, Jones, PB, Cannon, M, Sharma, T, et al. Autoimmune diseases in the pedigrees of schizophrenic and control subjects. Schizophr Res 1996; 20: 261–7.CrossRefGoogle ScholarPubMed
24 Eaton, WW, Hayward, C, Ram, R. Schizophrenia and rheumatoid arthritis: a review. Schizophr Res 1992; 6: 181–92.CrossRefGoogle ScholarPubMed
25 Mors, O, Mortensen, PB, Ewald, H. A population-based register study of the association between schizophrenia and rheumatoid arthritis. Schizophr Res 1999; 40: 6774.CrossRefGoogle ScholarPubMed
26 Oken, RJ, Schulzer, M. At issue: schizophrenia and rheumatoid arthritis: the negative association revisited. Schizophr Bull 1999; 25: 625–38.CrossRefGoogle ScholarPubMed
27 Torrey, EF, Yolken, RH. The schizophrenia-rheumatoid arthritis connection: infectious, immune, or both? Brain Behav Immun 2001; 15: 401–10.CrossRefGoogle ScholarPubMed
28 Scott, DL, Wolfe, F, Huizinga, TW. Rheumatoid arthritis. Lancet 2010; 376: 1094–108.CrossRefGoogle ScholarPubMed
29 Shapira, Y, Agmon-Levin, N, Shoenfeld, Y. Defining and analyzing geoepidemiology and human autoimmunity. J Autoimmun 2010; 34: J16877.CrossRefGoogle ScholarPubMed
30 Zeng, QY, Chen, R, Darmawan, J, Xiao, ZY, Chen, SB, Wigley, R, et al. Rheumatic diseases in China. Arthritis Res Ther 2008; 10: R17.CrossRefGoogle Scholar
31 Raychaudhuri, SP, Farber, EM. The prevalence of psoriasis in the world. J Eur Acad Dermatol Venereol 2001; 15: 16–7.CrossRefGoogle Scholar
32 Chan, JC, Liu, HS, Kho, BC, Lau, TK, Li, VL, Chan, FH, et al. Longitudinal study of Chinese patients with pernicious anaemia. Postgrad Med J 2008; 84: 644–50.CrossRefGoogle ScholarPubMed
33 Cummins, AG, Roberts-Thomson, IC. Prevalence of celiac disease in the Asia-Pacific region. J Gastroenterol Hepatol 2009; 24: 1347–51.CrossRefGoogle ScholarPubMed
34 Watts, RA. Epidemiology of vasculitis in India – what is known? J Indian Rheumatol Assoc 2005; 13: 815.Google Scholar
35 Jia, P, Wang, L, Meltzer, HY, Zhao, Z. Common variants conferring risk of schizophrenia: a pathway analysis of GWAS data. Schizophr Res 2010; 122: 3842.CrossRefGoogle ScholarPubMed
36 O'Dushlaine, C, Kenny, E, Heron, E, Donohoe, G, Gill, M, Morris, D, et al. Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. Mol Psychiatry 2011; 16: 286–92.CrossRefGoogle ScholarPubMed
37 Gregersen, PK, Olsson, LM. Recent advances in the genetics of autoimmune disease. Annu Rev Immunol 2009; 27: 363–91.CrossRefGoogle ScholarPubMed
38 Shi, J, Levinson, DF, Duan, J, Sanders, AR, Zheng, Y, Pe'er, I, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009; 460: 753–7.Google ScholarPubMed
39 Zenewicz, LA, Abraham, C, Flavell, RA, Cho, JH. Unraveling the genetics of autoimmunity. Cell 2010; 140: 791–7.CrossRefGoogle ScholarPubMed
40 Trowsdale, J. HLA genomics in the third millennium. Curr Opin Immunol 2005; 17: 498504.CrossRefGoogle ScholarPubMed

Chen et al. supplementary material

Supplementary Table S1

PDF 23 KB
Submit a response

eLetters

No eLetters have been published for this article.

Altmetric attention score

Full text views

Full text views reflects PDF downloads, PDFs sent to Google Drive, Dropbox and Kindle and HTML full text views.

Total number of HTML views: 168
Total number of PDF views: 560 *
View data table for this chart

* Views captured on Cambridge Core between 02nd January 2018 - 22nd January 2021. This data will be updated every 24 hours.

Access
Hostname: page-component-76cb886bbf-r88h9 Total loading time: 0.482 Render date: 2021-01-22T10:48:25.889Z Query parameters: { "hasAccess": "1", "openAccess": "0", "isLogged": "0", "lang": "en" } Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": false, "newCiteModal": false }

Send article to Kindle

To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study
Available formats
×

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study
Available formats
×

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study
Available formats
×
×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *