Journal of Affective Disorders 227 (2018) 31–37

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Research paper

Systemic autoimmune diseases are associated with an increased risk of T

bipolar disorder: A nationwide population-based cohort study
⁎
Ling-Yi Wanga, Jen-Huai Chiangb, Shih-Fen Chenc, Yu-Chih Shend,
a
Epidemiology and Biostatistics Consulting Center,Department of Medical Research and Department of Pharmacy, Tzu Chi General Hospital, Hualien, Taiwan
b
Management Office for Health Data, China Medical University Hospital at Taichung, and College of Medicine, China Medical University, Taichung, Taiwan
c
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan
d
Department of Psychiatry, Tzu Chi General Hospital at Hualien, and School of Medicine, Tzu Chi University, Hualien, Taiwan

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Studies suggested autoimmunity plays a role in the etiology of bipolar disorder (BD). This study
Bipolar disorder (BD) aimed to investigate the association between systemic autoimmune diseases (SADs) and the subsequent devel-
Systemic autoimmune diseases (SADs) opment of BD, and examine the potential risk factors for developing BD.
Methods: Patients with SADs were identified in the Taiwan National Health Insurance Program (NHIP). A
comparison cohort was created by matching patients without SADs with age. The SADs cohort consisted of
65,498 while the comparison cohort consisted of 261,992 patients. The incidence of BD was evaluated in both
cohorts.
Results: The major finding was the discovery of a higher incidence of subsequent BD among patients with SADs
(adjusted hazard ratio: 1.98). Specifically, the risk of BD was observed to be significant increase in systemic
lupus erythematosus, rheumatoid arthritis, autoimmune vasculitis, Sicca syndrome and Crohn's disease.
Furthermore, our study revealed some potential risk factors for developing BD including female, younger age
and patients who lived in eastern Taiwan. Also, some comorbidities including dyslipidemia, chronic obstructive
pulmonary disease, diabetes mellitus, asthma, cerebrovascular disease, alcohol used disorder, liver cirrhosis, and
malignancies were potential risk factors for incident BD.
Limitations: The diagnosis of SADs was based on the catastrophic illness certificate defined by Taiwanese NHIP.
Thus, not every form of SADs was explored for subsequent developing BD.
Conclusion: This study confirms that SADs are associated with higher incidence of BD, suggesting that abnormal
autoimmune process is associated with increased expression of psychiatric disturbances.

1. Introduction
Bipolar disorder (BD), also known as manic-depressive illness, is a
mental disorder that causes unusual shifts in mood, energy, activity
levels, and the ability to carry out day-to-day tasks. It is a relatively
common, long-term, and disabling psychiatric illness that is associated
with high levels of functional impairment, morbidity, mortality, and an
increased risk of suicide (Cassidy, 2011; Kessing et al., 2015). Previous
studies reported that more than half of all BD patients did not obtain
treatment for 5 years after they experienced their first symptoms, and
on average they did not receive correct diagnosis until 8 years after they
first sought treatment (Regier et al., 1993; Schaffer et al., 2006). In,
Taiwan, the annual treated incidence was around 48–71 per 100,000
per year during 1997–2003 (Bih et al., 2008). Compared to previous
studies, which reported a range of incidence between 7 per 100,000
population and 33 per 100,000 population in other countries (Boyd and
Weissman, 1981), the difference might be attributed to that Taiwan
implemented a National Health Insurance Program (NHIP) in 1995 to
offer a comprehensive medical care to all citizens. In the survey of
treated incidence of BD from Taiwan during 1997–2003, higher in-
cidence was detected in the 45–64 and 65 years or older age groups,
female, those with lower socioeconomic status (SES) and those who
lived in the eastern Taiwan (Bih et al., 2008).
The cause of BD is not entirely known. Genetic studies have sug-
gested that many chromosomal regions and candidate genes are related
to BD susceptibility with each gene exerting a mild to moderate effect
(Goes, 2016). Genetic influences are believed to account for 60–80% of
the risk of developing BD indicating a strong hereditary component
(Kerner, 2014). Otherwise, environmental factors play a significant role
in the development and course of BD, and individual psychosocial

⁎
Correspondence to: Department of Psychiatry, Tzu-Chi General Hospital, 707, Section 3, Chung Yang Rd, Hualien 970, Taiwan.
E-mail address: shengmp@gmail.com (Y.-C. Shen).

http://dx.doi.org/10.1016/j.jad.2017.10.027
Received 9 August 2017; Received in revised form 21 September 2017; Accepted 6 October 2017
Available online 07 October 2017
0165-0327/ © 2017 Elsevier B.V. All rights reserved.
L.-Y. Wang et al.
variables may interact with genetic dispositions. It is probable that
recent life events and interpersonal relationships contribute to the onset
and recurrence of bipolar mood episodes (Serretti and Mandelli, 2008).
Furthermore, BD may occur as a result of or in association with a
neurological condition or injury such as stroke, traumatic brain injury,
autoimmune diseases, and rarely temporal lobe epilepsy (Satzer and
Bond, 2016).
Recently, evidence has accumulated suggesting BD was associated
with immune dysfunction such as chronic low-grade inflammatory re-
sponses, activation of cell-mediated immunity, increased oxidative
stress, and autoimmune responses (Leboyer, 2015). The association of
systemic autoimmune diseases (SADs) and auto-antibodies with BD has
been reported in several epidemiological studies (Rosenblat and
McIntyre, 2015). Patients with SADs presented a higher risk for BD,
while BD patients exhibited higher incidence of SADs.
In a large population-based study of all people born in Denmark
between 1945 and 1996 (3.57 million people) (Eaton et al., 2010), the
relative risk for patients with any form of SADs having delayed BD was
1.2. More specifically, a diagnosis of Guillain–Barre syndrome (GBS),
Crohn's disease and autoimmune hepatitis were associated with raised
risk of BD (Eaton et al., 2010). Additionally, in a nationwide popula-
tion-based study from Taiwan (Hsu et al., 2014), the incidence of BD
was found to be 2.13-fold increased among patients with rheumatoid
arthritis (RA) than among control patients. Furthermore, systemic lupus
erythematosus (SLE) and psoriasis were also found to increase the
prevalence of BD by 4 and 2-fold, respectively (Bachen et al., 2009; Han
et al., 2011). Finally, autoimmune thyroiditis was found to increase the
relative risk of BD (Kupka et al., 2002). The prevalence of thyroper-
oxidase antibodies was higher in BD patients (28%) compared to health
controls and psychiatric in-patients (3–18%).
The observed associations support a possible immunological con-
tribution in subgroups of patients with BD. Genetically vulnerable in-
dividuals might be at a particular risk of developing BD as a con-
sequence of autoimmune reactions and inflammation affecting the
brain. Following the theoretical link, we hypothesized that a history of
SADs is associated with an increased risk of the subsequent onset of BD.
To test our hypothesis, we designed a nationwide population based
study to investigate the incidence of BD among patients with SADs.
Knowing whether SADs are associated with an increased risk of de-
veloping BD may lead to a better understanding of the role that the
immune system plays in this disorder, and also help guiding gene-en-
vironment interaction studies.
2. Materials and methods
2.1. Data source
The NHIP was implemented on 1 March 1995 in Taiwan. In 2011,
22.6 million individuals from a total population of 23 million were
enrolled in this insurance program. Currently, 99.6% of residents were
covered by NHIP. The National Health Insurance Research Database
(NHIRD) consisted almost every medical record reimbursed by the
NHIP. The NHIRD scrambled patient and hospital's identification
numbers. It also contained demographic information, such as dates of
birth, gender, clinical diagnoses, department of clinical visit, ambula-
tory and inpatient care claims. The diagnosis codes were based on
International Classification of Diseases, 9th Revision, Clinical
Modification (ICD-9-CM). Two subsets of NHRID: Longitudinal Health
Insurance Database 2000 (LHID2000) and Registry for Catastrophic
Illness Database (RCID) were used for this study.
2.1.1. LHID2000
LHID2000 was representative of the entire NHIRD. It contained all
the original claim data of 1,000,000 individuals (approximately 4% of
Taiwan's population) randomly sampled from the registry for bene-
ficiaries of the NHIRD in 2000. There were no statistically significant
32
Journal of Affective Disorders 227 (2018) 31–37
differences in age, gender, and medical costs between the patients in
the LHID2000 and the original NHIRD.
2.1.2. RCID
In the Taiwanese NHIP, the government defined several categories
of serious illnesses or injuries as “catastrophic illnesses”. Patients
needed to undergo rigorous regulatory review before they were issued
with a Catastrophic Illness Certificate (CIC). These individuals were
parts of the NHIRD and were further classified as RCID. Patients with
CIC received free medical care for the duration of the certificate's va-
lidity. Similar to the NHIRD, the RCID included all relevant information
regarding CIC status, such as diagnosis, date of diagnosis, date of death,
and outpatient/inpatient claims data for the beneficiaries of individuals
with catastrophic illnesses during the period 2000–2011.
2.2. Definition of SADs
SADs was one of the 30 categories of serious illnesses or injuries.
Patients being diagnosed with such serious illnesses would be issued
with a CIC. SADs were consisted of SLE (ICD-9-CM: 710.0), RA (714.0),
polyarticular juvenile RA (714.30–714.33), systemic sclerosis (710.1),
multiple sclerosis (340), polymyositis (710.4), dermatomyositis
(710.3), autoimmune vasculitis (polyarteritis nodosa (446.0), hy-
persensitivity angiitis (446.2), Wegener's granulomatosis (446.4), giant
cell arteritis (446.5), thromboangiitis obliterans (443.1), Takayasu's
disease (446.7), acute febrile mucocutaneous lymph node syndrome
(446.1), Behçet's syndrome (136.1)), pemphigus (694.4), Sicca syn-
drome (710.2), Crohn's disease (555) and ulcerative colitis
(556.0–556.6, 556.8–556.9).
2.3. Study participants
We identified the SADs cohort from the RCID. The index date was
defined as the first diagnosis date of any SADs. The compared cohort
(control group) was free from any of the SADs sampled from LHID2000.
We excluded those patients with missing data for birthday or gender
information, those diagnosed with BD (ICD-9-CM: 296.0X, 296.1X,
296.4X, 296.5X, 296.6X, 296.7X, 296.80, or 296.89) prior to index
date, and those with mood disorders resulting from a general medical
condition (ICD-9-CM: 293.83). We then selected 4 control patients for
each SADs patient matching by age and index year.
We then collected demographic characteristics of both cohort in-
cluding gender, age (less than 25, 25–50, and over 50 year-old), en-
rollee category (a proxy measure of SES), urbanization degree, geo-
graphic area (northern, central, southern and eastern), and follow-up
duration. Detailed information regarding enrollee and urbanization
degree was provided elsewhere (Chen et al., 2008).
We also investigated any potential risk factors in this study in-
cluding the baseline comorbidities and the frequency of steroid use. The
baseline comorbidities comprised of hypertension (ICD-9-CM:
401–405), hyperlipidemia (272), chronic obstructive pulmonary dis-
ease (COPD, 491–492, 494 and 496), diabetes mellitus (DM, 250),
asthma (493), chronic kidney disease (585), cerebrovascular disease
(430−438), alcohol use disorder (303), liver cirrhosis (571), malig-
nancies (140−239) and coronary artery disease (414). The frequency
of steroid use was categorized as no use, infrequent user (the duration
of steroid use was less than the median duration of steroid use in this
data-set), and frequent user (the duration of steroid use was equal to or
longer than the median duration).
2.4. Incidence of BD
All study patients were followed up until newly diagnosed BD
withdrawn from the NHIP or December 31, 2011 (whichever came
first). A newly BD had to meet following criteria: (1) At least 2 clinical
visits of BD diagnoses (ICD-9-CM: 296.0X, 296.1X, 296.4X, 296.5X,
L.-Y. Wang et al. Journal of Affective Disorders 227 (2018) 31–37

296.6X, 296.7X, 296.80, or 296.89) given by a clinical psychiatrist after Table 1

the index date, and (2) To ensure that the BD diagnoses in the database Demographic characteristics of the patients with and without SADs.
were reliable, we collected information on the use of drugs approved by
Variable SADs patients P-value
the Food and Drug Administration of Taiwan for treating one (or more)
phases of BD, including lithium, valproate, carbamazepine, lamotrigine, No Yes
aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. Only n = 261,992 (80%) n = 65,498 (20%)
patients who were prescribed these drugs for at least 28 cumulative
n % n %
days after diagnosed date of BD were included in our study.
a
Gender < 0.0001
2.5. Statistical analysis Female 129,945 49.6 50,223 76.68
Male 132,047 50.4 15,275 23.32
Age at baseline, 0.99
We compared baseline characteristic between patients with and yearsa
without SADs using χ2-tests (gender, age, enrollee category, urbani- < 25 36,740 14.02 9185 14.02
zation degree, geographic area, baseline comorbidities and the fre- 25–50 102,592 39.16 25,648 39.16
quency of steroid use) and Wilcoxon's rank-sum test (follow-up dura- > 50 122,660 46.82 30,665 46.82
Mean (SD) 46.41 (19.50) 46.77 (19.12) < 0.0001
tion). Incidence rates (per 10,000 person-years) of BD between patients
Enrollee < 0.0001
with and without SADs were compared using a Cox proportional hazard categorya
model to estimate the Hazard Ratio (HR) and 95% confidence interval I (highest) 3588 1.37 2071 3.16
(95% CI). Then stratification analysis was performed to examine the II 21,238 8.11 4599 7.02
whether the HR differ across different gender and age groups, and the III 61,039 23.3 24,221 36.98
IV (lowest) 176,127 67.23 34,607 52.84
interaction between stratification variables and SAD were also ex- Urbanization < 0.0001
amined. The cumulative incidence of BD was estimated using the degreea
Kaplan-Meier method, and differences between cohorts were evaluated I (highest) 79,694 30.44 19,006 29.02
using the log-rank test. A p-value < 0.05 was considered as statistical II 77,668 29.67 20,459 31.24
III 45,556 17.4 10,508 16.04
significant. SAS 9.4 (SAS Institute Inc., Cary, NC) was used for statis-
IV 34,551 13.2 9142 13.96
tical analysis. V (lowest) 24,338 9.3 6379 9.74
Geographic areaa < 0.0001
2.6. Sensitivity analysis Northern 129,669 49.49 30,205 46.68
Central 47,763 18.23 13,933 21.53
Southern 78,242 29.86 18,851 29.13
The sensitivity analysis was performed with the purpose to examine
Eastern 6313 2.41 1716 2.6
whether the main finding was robust. We applied more restrictive de- Comorbiditiesa
finition of incident BD patients as follows. (1) An incident BD that re- Hypertension 67,100 25.61 18,081 27.61 < 0.0001
quired hospitalization, and (2) took traditional mood stabilizers such as Dyslipidemia 45,134 17.23 10,971 16.75 0.0037
COPD 24,534 9.36 8723 13.32 < 0.0001
lithium or valproate during the hospitalization.
Diabetes mellitus 30,772 11.75 7734 11.81 0.6564
Asthma 18,163 6.93 6412 9.79 < 0.0001
2.7. Ethics statement Chronic kidney 3440 1.31 1469 2.24 < 0.0001
disease
This study was approved by the Institutional Review Board of China Cerebrovascular 22,300 8.51 6103 9.32 < 0.0001
disease
Medical University (CMUH104-REC2-115).
Alcohol use 773 0.3 148 0.23 0.0028
disorder
3. Result Liver cirrhosis 33,473 12.78 12,757 19.48 < 0.0001
Malignancies 48,562 18.54 19,471 29.73 < 0.0001
Coronary artery 22,924 8.75 6968 10.64 < 0.0001
3.1. Patient characteristics
disease
Frequency of < 0.0001
A total of 65,498 SADs patients and 261,992 age-matched control steroid usea
patients were included in our analysis. Table 1 showed baseline char- No use 115,860 44.22 8291 12.66
acteristics of patients with and without SADs. In general, the distribu- Infrequent user 70,995 27.1 4535 6.92
Frequent user 75,137 28.68 52,672 80.42
tion of gender, enrollee category, urbanization degree, and geographic
Follow-up 7.75 (7.59) 5.74 (5.51) < 0.0001
area were significantly different between the SAD and control cohort. period, years,
Compared to the control cohort, the SADs cohort displayed a higher medianb
prevalence of female (76.68% vs. 23.32%) which was consistent with
the current understanding of SADs population. The mean age in both Abbreviation: SADs: systemic autoimmune diseases; SD: standard deviation; COPD:
chronic obstructive pulmonary disease.
cohorts were around 46 and the mean follow-up years were 5.74 and a
Chi-square test.
7.75 years for SADs and control cohort, respectively. The majority of b
Wilcoxon's rank-sum Test.
comorbidities listed and the frequency of steroid use showed statisti-
cally different between the two groups. Similar results were obtained in our sensitivity analysis. After mod-
ifying the incident BD definition, the SAD cohort still had higher BD
3.2. Incidence of BD incidence rate (1.36 per 10,000 person-years) than the control cohort
(0.7 per 10,000 person-years), and the aHR is 2.55.
As shown in Table 2, there were totally 936 incident BD patients Additionally, females had higher incidence rate of BD than males
during the follow-up period. The SADs cohort had almost 2 fold in- (aHR: 1.34). Subjects less than or equal to 50 year-old had higher BD
cidence rate than the control cohort (6.35 vs. 3.43 per 10,000 person- incidence rate than subjects over 50 year-old (aHR: 1.57 for patients
years). The adjusted HR (aHR) is 1.98 after adjusted for other demo- aged less than 25 year-old and 2.23 for patients aged between 25 and
graphic characteristics. Kaplan-Meier analysis demonstrated that the 50 year-old). Furthermore, enrollee category I-III had lower incidence
cumulative incidence curves of BD was significantly higher in SADs rate of BD than enrollee category IV which has the lowest wages (aHR:
cohort than in the control cohort (log-rank test, P < 0.0001) (Fig. 1).

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L.-Y. Wang et al. Journal of Affective Disorders 227 (2018) 31–37

Table 2
Association between BD incidence and SADs status.

Variable BD Person years IR† Crude* Adjusted‡

no. (n = 936) HR (95%CI) p-value HR (95%CI) p-value

SADs
No 697 2031663 3.43 1 reference 1 reference
Yes 239 376142 6.35 1.82 (1.57–2.11) < 0.0001 1.98 (1.67–2.36) < 0.0001
Gender
Female 596 1310038 4.55 1.47 (1.28–1.67) < 0.0001 1.34 (1.16–1.54) < 0.0001
Male 340 1097767 3.1 1 reference 1 reference
Age at baseline, years
< 25 122 372983 3.27 1.06 (0.86–1.3) 0.597 1.57 (1.23–2.01) 0.0004
25–50 485 990086 4.9 1.57 (1.37–1.81) < 0.0001 2.23 (1.88–2.65) < 0.0001
> 50 329 1044737 3.15 1 reference 1 reference
Enrollee category
I (highest) 11 40607 2.71 0.63 (0.35–1.15) 0.1349 0.5 (0.27–0.91) 0.0228
II 57 195918 2.91 0.68 (0.52–0.9) 0.006 0.67 (0.51–0.88) 0.0041
III 209 624684 3.35 0.78 (0.67–0.92) 0.0023 0.71 (0.61–0.84) < 0.0001
IV (lowest) 659 1546597 4.26 1 reference 1 reference
Urbanization degree
I (highest) 309 730761 4.23 1 reference 1 reference
II 289 723773 3.99 0.94 (0.8–1.11) 0.4817 1.05 (0.88–1.25) 0.5779
III 149 413317 3.6 0.85 (0.7–1.04) 0.1083 1.02 (0.83–1.26) 0.8425
IV 112 317619 3.53 0.83 (0.67–1.03) 0.0973 1 (0.79–1.28) 0.969
V (lowest) 77 220907 3.49 0.82 (0.64–1.06) 0.1263 0.98 (0.73–1.3) 0.8666
Geographic area
Northern 499 1181602 4.22 1 reference 1 reference
Central 166 450306 3.69 0.87 (0.73–1.04) 0.1261 0.93 (0.77–1.12) 0.425
Southern 230 713012 3.23 0.76 (0.65–0.89) 0.0007 0.81 (0.68–0.95) 0.0115
Eastern 39 58965 6.61 1.57 (1.13–2.17) 0.0069 1.69 (1.19–2.39) 0.0033
Comorbidities
Hypertension 241 558139 4.32 1.13 (0.98–1.31) 0.0936 1.01 (0.83–1.24) 0.896
Dyslipidemia 196 371007 5.28 1.44 (1.23–1.68) < 0.0001 1.27 (1.05–1.55) 0.0156
COPD 130 204278 6.36 1.71 (1.42–2.06) < 0.0001 1.55 (1.25–1.92) < 0.0001
Diabetes mellitus 136 246562 5.52 1.47 (1.23–1.76) < 0.0001 1.27 (1.03–1.58) 0.029
Asthma 91 154958 5.87 1.54 (1.24–1.91) < 0.0001 1.27 (1–1.61) 0.0457
Chronic kidney disease 15 25345 5.92 1.49 (0.9–2.48) 0.1249 1.12 (0.67–1.88) 0.6708
Cerebrovascular disease 111 173230 6.41 1.71 (1.4–2.09) < 0.0001 1.59 (1.27–2) < 0.0001
Alcohol use disorder 25 5271 47.43 12.23 (8.22–18.2) < 0.0001 9.31 (6.15–14.11) < 0.0001
Liver cirrhosis 194 299474 6.48 1.82 (1.55–2.13) < 0.0001 1.45 (1.21–1.73) < 0.0001
Malignancies 254 433650 5.86 1.67 (1.44–1.93) < 0.0001 1.38 (1.18–1.61) < 0.0001
Coronary artery disease 102 182093.5 5.6 1.47 (1.19–1.8) 0.0003 1.2 (0.94–1.53) 0.1445
Frequency of steroid use
No use 381 842693.3 4.52 1 reference 1 reference
Infrequent user 191 609888 3.13 0.7 (0.59–0.84) < 0.0001 0.67 (0.56–0.8) < 0.0001
Frequent user 364 955224 3.81 0.86 (0.74–0.99) 0.0324 0.58 (0.49–0.69) < 0.0001

†
IR: incidence rates, per 10,000 person-years; Crude HR＊ represented relative hazard ratio; Adjusted HR‡ represented adjusted hazard ratio: mutually adjusted for SADs, gender, age,
enrollee category, urbanization degree, geographic area, baseline comorbidities and the frequency of steroid use in Cox proportional hazard regression.
Abbreviation: BD: bipolar disorder; SADs: systemic autoimmune diseases; HR: hazard ratio; CI: confidence interval; COPD: chronic obstructive pulmonary disease.

0.5, 0.67 and 0.71 for enrollee category I-III, respectively).
Urbanization degree had no significant influence on BD incidence rate.
The BD incidence rate was lower in southern region (aHR: 0.81) but
higher in eastern region (1.69) when compared to northern region of
Taiwan.
As to other comorbidities, dyslipidemia (aHR: 1.27), COPD (1.55),
diabetes mellitus (1.27), asthma (1.27), cerebrovascular disease (1.59),
alcohol used disorder (9.31), liver cirrhosis (1.45), and malignancies
(1.38) might be the potential risk factors for incident BD. Furthermore,
higher frequency of steroid use might have the protective association
with incident BD (aHR: 0.67 and 0.58 for infrequent and frequent user,
respectively).
Table 3 showed the stratification analysis by gender and age. Both
genders had significantly higher incidence rate of BD in SADs cohort.
The aHR was 2.19 for males and 2.01 for females (p-value for interac-
tion was 0.7373, indicating there was no significant difference between
aHR across gender). SADs was associated with an increased risk of BD
in age group less than 25 and between 25 and 50 (aHR: 1.89 and 2.64,
respectively) but not in age group over 50 year-old (p-value for inter-
action was 0.588).
Table 4 revealed that SLE (aHR: 3.40), RA (1.70), autoimmune
vasculitis (1.94), Sicca syndrome (2.39) and Crohn's disease (4.16) had
a higher risk of developing subsequent BD among the studied SADs.
4. Discussion
This population-based cohort study systematically examined whe-
ther SADs were associated with an increased risk of the subsequent
onset of BD by using an age-matched cohort and a maximal follow-up
period of 10 years. The major finding of our study was the discovery of
a higher incidence of subsequent BD among patients with SADs.
Stratification analysis revealed that this finding were seen in both
genders and in younger age (less than or equal to 50 year-old).
Specifically, the risk of BD was observed to be significant increase in
SLE, RA, autoimmune vasculitis, Sicca syndrome and Crohn's disease.
Furthermore, our study revealed some potential risk factors for devel-
oping BD including female, younger age (less than or equal to 50 year-
old) and patients who lived in eastern Taiwan (compared with northern
Taiwan). Also, some comorbidities including dyslipidemia, COPD,
diabetes mellitus, asthma, cerebrovascular disease, alcohol used dis-
order, liver cirrhosis, and malignancies were potential risk factors for
incident BD. Finally, our study revealed some potential protective

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L.-Y. Wang et al. Journal of Affective Disorders 227 (2018) 31–37

(Anderson and Maes, 2015; Foldager et al., 2014). For example,

proinflammatory cytokines activating the tryptophan-kynurenine
pathway, regulating serotonin production together with N-methyl-D-
aspartate glutamate receptor activity and may indirectly affect dopa-
mine regulation, and result in BD (Anderson and Maes, 2015).
Third, subclinical BD acting as a nonspecific stress factor may have
increased the vulnerability to SADs. Retrospective studies in SADs have
found that up to 80% of patients report uncommon emotional stress
before disease onset (Stojanovich and Marisavljevich, 2008). Chronic
stress can cause glucocorticoid receptor resistance which may prevent
its anti-inflammatory effect resulting in both SADs and BD (Cohen et al.,
2012).
Fourth, SADs and BD have a shared etiology. This possibility can be
supported by inflammatory cascades may be genetically varied in BD
patients and some SADs and BD co-aggregate in families (Drago et al.,
2015; Hillegers et al., 2007). However, the available studies have been
generally under-powered to examine the association with each SAD and
require replication.
Several epidemiological studies have documented a direct link be-
tween some SADs (GBS, Crohn's disease, autoimmune hepatitis, RA,
SLE, psoriasis and autoimmune thyroiditis) and the subsequent BD
(Rosenblat and McIntyre, 2015). Except for above listed SADs, our
Fig. 1. Cumulative incidence of BD for patients with SADs and without SADs. Figure
analysis further revealed that Sicca syndrome and autoimmune vascu-
legend: Kaplan-Meier analysis demonstrated that the cumulative incidence curves of BD
litis also had a higher risk of developing subsequent BD.
was significantly higher in patients with SADs than in patients without SADs (log-rank
test, P < 0.0001). Sicca syndrome is characterized by chronic inflammation and lym-
phocytic infiltration of exocrine lacrimal and saliva glands, causing dry
mouth and dry eye (Mavragani and Moutsopoulos, 2014). Other than
factors are associated with developing BD including higher SES, pa-
affecting glandular organs, Sicca syndrome can also have brain mani-
tients who lived in southern Taiwan (compared with northern Taiwan),
festations, including focal neurological deficits, diffuse cerebral in-
and use of steroid.
volvement, and psychiatric disorders (Cox and Hales, 1999). There was
This study revealed that patients with SADs were at a higher risk of
one study revealing that manic and depressive symptoms are frequently
subsequent BD. The following possible hypotheses are worth con-
observed in Sicca syndrome (Watanabe et al., 1994). Our study pro-
sidering:
vided further evidence supporting a higher incidence of subsequent BD
First, chronic peripheral inflammatory process activated by SADs
in patients with Sicca syndrome.
might cause the upregulation of CNS inflammation resulting in BD
Autoimmune vasculitis are a group of rare chronic illnesses char-
(Goldstein et al., 2009; Hamdani et al., 2012). Animal models have
acterized by inflammation of blood vessels and can affect and damage
indicated that peripheral cytokines reach the brain through various
to a variable degree of many organ systems including brain (Berlit,
mechanisms, including a leaky brain barrier, active transport, activa-
2010; Jennette and Falk, 2007; Pomper et al., 1999). There were only
tion of endothelial cells, and binding to cytokine receptors (Miller et al.,
few reports describing the psychiatric comorbidity of autoimmune
2009). In short, cytokines created through autoimmune processes play a
vasculitis including fatigue, insomnia, anxiety, depression, mania and
vital role in mediating the cross-talk between the immune system and
psychosis (Bozikas et al., 2015, 2001; Koutantji et al., 2000; McKeith,
the brain and are therefore possible contributors to the development of
1985; Yoshimura et al., 2012). Our study provided further evidence
BD (Brietzke et al., 2009; Rege and Hodgkinson, 2013).
supporting a higher incidence of subsequent BD in patients with auto-
Second, SADs exacerbate the BD syndrome in the presence of sub-
immune vasculitis.
clinical BD vulnerability. The mechanisms could be direct (acting on
Our study revealed some potential risk factors for developing BD
the biological substrate of BD) or indirect (acting on vulnerability to
including female, younger age and patients who lived in eastern
depression or other anxiety disorder that might then exacerbate BD)

Table 3
The study hazard ratios and 95% CIs for SAD cohort compared with control cohort across gender and age groups.

Variable SADs Crude HR Adjusted HRb P for interaction

Non-SADs SADs

Event Person years IRa Event Person years IRa

Gender 0.7373
Female 404 1017583 3.97 192 292455 6.57 1.64 (1.38–1.95)c 2.01 (1.65–2.46)c
Male 293 1014080 2.89 47 83686 5.62 1.88 (1.38–2.57)c 2.19 (1.57–3.05)c
Age group, year 0.588
< 25 89 314119 2.83 33 58864 5.61 2.00 (1.34–3.00)c 1.89 (1.17–3.08)c
25–50 334 834742 4 151 155344 9.72 2.36 (1.95–2.87)c 2.64 (2.08–3.36)c
> 50 274 882803 3.1 55 161934 3.4 1.08 (0.81–1.44) 1.32 (0.96–1.81)

Abbreviations: BD: bipolar disorder; SADs: systemic autoimmune diseases; HR: hazard ratio; CI: confidence interval.
a
IR: incidence rates, per 10,000 person-years.
b
Represented adjusted hazard ratio: mutually adjusted for SADs, gender, age, enrollee category, urbanization degree, geographic area, baseline comorbidities and the frequency of
steroid use in Cox proportional hazard regression.
c
< 0.05.

35
L.-Y. Wang et al. Journal of Affective Disorders 227 (2018) 31–37

Table 4
Incidence of BD among patients with different SADs.

SADs n No. of BD person-years IRa Crude HR (95%CI) Adjusted HRb (95%CI)

Systemic lupus erythematosus 12,195 68 73334 9.27 2.67 (2.08–3.43)c 3.40 (2.56–4.52)c
Rheumatoid arthritis 29,795 87 179368 4.85 1.40 (1.12–1.75)c 1.70 (1.33–2.17)c
Systemic sclerosis 1512 3 8191 3.66 1.05 (0.34–3.27) 1.21 (0.39–3.78)
Multiple sclerosis 1060 4 5955 6.72 1.93 (0.72–5.16) 2.16 (0.80–5.83)
Polymyositis 727 3 3644 8.23 2.37 (0.77–7.36) 2.59 (0.83–8.11)
Dermatomyositis 985 1 5004 2 0.58 (0.08–4.09) 0.77 (0.11–5.48)
Vasculitis 4732 15 29579 5.07 1.46 (0.88–2.44) 1.94 (1.15–3.28)c
Pemphigus 945 0 4813 0 – –
Sicca syndrome 11,812 53 59146 8.96 2.55 (1.92–3.37)c 2.39 (1.77–3.22)c
Crohn's disease 507 3 2681 11.19 3.22 (1.03–9.99)c 4.16 (1.33–12.99)c
Ulcerative colitis 1281 2 4675 4.28 1.19 (0.30–4.77) 1.51 (0.37–6.05)

Abbreviations: BD: bipolar disorder; SADs: systemic autoimmune diseases; HR: hazard ratio; CI: confidence interval.
a
IR: incidence rates per 10,000 person-years.
b
Represented adjusted hazard ratio: mutually adjusted for gender, age, enrollee category, urbanization degree, geographic area, baseline comorbidities and the frequency of steroid
use in Cox proportional hazard regression.
c
< 0.05.

Taiwan, which were similar with previous survey except for age (Bih
et al., 2008). The gender difference in our study was possibly explained
by that females with BD were more likely to search for treatment than
did males (Schaffer et al., 2006). The age difference between our study
(period: 2000–2011) and previous survey (1997–2003) may mean that
BD patients have received treatment early in their course of illness in
Taiwan. With regard to regional difference, in fact, there were two large
mental hospitals with several thousand beds in the eastern Taiwan and
some BD patients who lived in western Taiwan were brought to eastern
Taiwan for long-term care, which may explain this finding.
Our analysis revealed that several medical conditions (dyslipidemia,
COPD, diabetes mellitus, asthma, cerebrovascular disease, alcohol used
disorder, liver cirrhosis, and malignancies) were potential risk factors
for developing BD. Several epidemiological studies have found an in-
creased incidence rate of BD in patients with above disorders, and pa-
tients with BD were also at increased risk of developing above disorders
(Perugi et al., 2015; Rosenblat and McIntyre, 2015; SayuriYamagata
et al., 2017). The effects appeared to be bidirectional in nature. These
associations can be partially explained by unhealthy behaviors (e.g.
smoking, physical inactivity, poor diet), psychosocial functioning and
chronic medication exposure (Kupfer, 2005; Leboyer et al., 2012).
Otherwise, immune dysfunction might provide another explanation.
Immune dysfunction has frequently been noted in the pathophysiology
of above disorders where anti-inflammatory cytokines are inadequately
counterbalancing an inflammatory response or where the immune
system is chronically in a low-grade inflammatory state (Rosenblat and
McIntyre, 2015; SayuriYamagata et al., 2017). Moreover, BD has been
shown to be associated with chronic low-grade inflammation (Anderson
and Maes, 2015; Hamdani et al., 2012). Taken together, immune dys-
function may conceive as key mediators of the associations between BD
and above medical comorbidities.
Our study revealed some potential protective factors for developing
BD including higher SES, patients who lived in southern Taiwan, and
use of steroid, which were partially similar with previous survey (Bih
et al., 2008). Since previous study has reported the odds of those in the
lowest SES having any psychiatric disorder were about 2.5 times that of
those in the highest SES (Regier et al., 1993), our analysis was con-
sistent with previous finding. With regard to regional difference, this
was possibly explained by lower resource accessibility and less psy-
chiatric services in southern Taiwan resulting in lower treated BD in-
cidence. When considering for the use of steroid, there was studies
reporting mood symptoms resulting from the use of steroid (Brown and
Suppes, 1998). However, in our SAD cohort, BD might be a con-
sequence of autoimmune reactions affecting the brain and use of ster-
oids might decrease the inflammation resulting in lower BD incidence.
Our study aims to examine SADs as a risk factor for the development
of BD. An age-matched cohort study design comprising a population-
based cohort of patients with SADs and adequate controls for co-
morbidity constitute the strengths of our study. However, several lim-
itations that are inherent in the use of claims databases should be
considered. First, the diagnosis of SADs was based on the issuance of a
CIC defined by Taiwanese NHIP. Thus, not every form of SADs was
explored for subsequent developing BD as previous Denmark cohort
study (Eaton et al., 2010). For example, GBS, autoimmune hepatitis and
autoimmune thyroiditis were not enrolled in our analysis. Second, the
causal relationship was assessed mainly according to the chronological
order in which the SADs and BD were diagnosed. However, both con-
ditions might require long-term treatment, and the possibility that BD
causes SADs cannot be excluded entirely. Third, information was un-
available on several demographic variables such as smoking, education
level, life style and family history, which might have provided useful
information regarding factors that are potentially associated with SADs
and BD. For example, previous studies have suggested smoking might
be a probably confounder masking the presumed association of some
SADs and BD (Farhi et al., 2016; Tiosano et al., 2017). Finally, the
current study is an observational design rather than an experimental
design, and since both BD and SADs are progressive diseases, it is hard
to distinguish which disease began to grow first before the clinical
symptoms appears, thus, further in vitro/in vivo studies are desired to
unravel the mechanism.
5. Conclusion
This study revealed that SADs were associated with an increased
risk of BD development, suggesting that the abnormal autoimmune
process was associated with increased expression of psychiatric dis-
turbances. Further prospective clinical studies on the relationship be-
tween SADs and BD are warranted.
Acknowledgement
This study is supported in part by Taiwan Ministry of Health and
Welfare Clinical Trial Center (MOHW106-TDU-B-212-113004), China
Medical University Hospital, Academia Sinica Taiwan Biobank Stroke
Biosignature Project (BM10601010036), Taiwan Clinical Trial
Consortium for Stroke (MOST 106-2321-B-039-005), Tseng-Lien Lin
Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation,
Taipei, Taiwan, and Katsuzo and Kiyo AoshimaMemorial Funds, Japan.
Role of funding source
The funding source has no further role in study design; in the

36
L.-Y. Wang et al.
collection, analysis and interpretation of data; in the writing of the
report; and in the decision to submit the paper for publication.
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