Autoimmune rheumatic diseases increase dementia risk in middle-aged patients: A nationwide cohort study
Autoimmune rheumatic diseases increase dementia risk in middle-aged patients: A nationwide cohort study
Tzu-Min Lin 1 2 3
Wei-Sheng Chen 1 2
Jau-Jiuan Sheu 0 1 2
Yi-Hsuan Chen 1 2
Jin-Hua Chen 1 2
Chi- Ching Chang 1 2 3
0 Department of Neurology, Taipei Medical University Hospital , Taipei, Taiwan , 4 Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan, 5 Biostatistics Center , College of Management, Taipei Medical University , Taipei, Taiwan , 6 Biostatistics Center and School of Health Care Administration, College of Management, Taipei Medical University , Taipei, Taiwan , 7 Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University , Taipei , Taiwan
1 Data Availability Statement: The data underlying this study are from the National Health Insurance Research Database (NHIRD), which has been transferred to the Health and Welfare Data Science Center (HWDC). Interested researchers can obtain the data through formal application to the HWDC, Department of Statistics, Ministry of Health and Welfare , Taiwan (
2 Editor: Valli De Re, Istituto di Ricovero e Cura a Carattere Scientifico Centro di Riferimento Oncologico della Basilicata , ITALY
3 Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Taipei Medical University Hospital , Taipei, Taiwan , 2 Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Taipei Veterans General Hospital, National Yang-Ming University , Taipei , Taiwan
The study enrolled 34,660 middle-aged ARD patients (77% female, mean age = 59.8 years)
and 138,640 controls. The risk of developing dementia was 1.18 times higher for
middleaged patients with ARDs compared with patients without ARDs after adjustment for age,
sex, and comorbidities. Among the patients with ARDs, the subgroups with rheumatoid
arthritis, systemic lupus erythematosus, and SjoÈ gren syndrome (SS) were associated with a
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
significantly higher dementia risk (adjusted hazard ratio [HR] 1.14, 95% confidence index
[CI] 1.06±1.32; adjusted HR 1.07, 95% CI 0.86±1.34; adjusted HR 1.46, 95% CI 1.32±1.63,
respectively). Furthermore, primary SS and secondary SS patients had the highest risks of
dementia among all the ADR subgroups (adjusted HR 1.35, 95% CI 1.18±1.54; adjusted HR
1.67, 95% CI 1.43±1.95 respectively).
This nationwide retrospective cohort study demonstrated that dementia risk is significantly
higher in middle-aged patients with ARDs compared with the general population.
Dementia is a common disorder characterized by a decline in one or more cognitive functions
that can impair the performance of daily activities [
]. Alzheimer disease (AD) is the most
common type of dementia, accounting for 60% of all dementia cases. Other types of dementia
are Parkinson disease dementia, frontotemporal dementia, and Lewy body dementia [
types of neurodegenerative dementia are associated with neuroinflammation, which is
characterized by reactive microgliosis, oxidative damage, and mitochondrial dysfunction.
Autoimmune rheumatic diseases (ARDs), such as rheumatoid arthritis (RA), systemic lupus
erythematosus (SLE), SjoÈgren syndrome (SS), progressive systemic sclerosis, polymyositis,
dermatomyositis, vasculitis, and BehcËet disease, also result from the dysregulation of the
immune system and are characterized by progressive and systemic inflammation. A recent
study suggested that dementia may occur when the body's immune system attacks the cells of
the brain, suggesting that some types of dementia may be similar to ARDs [3±4]. Moreover,
multiple studies have revealed that ARDs increase the risk of vascular events such as ischemic
stroke, acute myocardial infarction, and peripheral arterial occlusive disease [5±10].
Furthermore, several proinflammatory cytokines (IL-1b, IL-6, and TNF-α) participate in and increase
the risk of dementia and AD as well as participate in the pathogenesis of ARDs [11±13].
However, most data on the association between ARDs and dementia are from studies with
conflicting results that have used a case±control design or are small case series [14±19]. Therefore, the
association between ARDs and dementia has not been fully established.
We hypothesize that ARDs predispose patients to the development of dementia. To verify
this hypothesis, this cohort study examined the relationship between middle-aged patients (45
years or older) with ARDs and dementia by analyzing a large population-based database.
The National Health Insurance (NHI) program was initiated in 1995 to provide thorough
healthcare for citizens and residents of Taiwan. Enrollment in this program is mandatory,
resulting in a coverage rate of almost 99% [
]. The Taiwan National Health Insurance
Research Database (NHIRD), which is maintained by the Department of Health and the
National Health Research Institutes of Taiwan, comprises comprehensive medical care
information available for research purposes. This database provides basic information about each
person insured by the NHI, including patient characteristics, records of outpatient visits,
hospital admissions, drug prescriptions, and disease status and management. The diagnostic
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codes used are formatted in accordance with the International Classification of Diseases,
Ninth Revision, Clinical Modification (ICD-9-CM). At the time of this study, the NHIRD was
electronic with patients' personal information being encrypted for privacy protection. The
study was approved by the Institutional Review Board of Taipei Medical University (approval
number N201509007) and was performed according to the relevant guidelines. Informed
consent of the study patients was not required because the dataset used in this study comprised
deidentified secondary data released for research purposes. Patient consent was not required
to access the NHIRD.
Patients diagnosed with ARDs between 2001 and 2012 were identified from the catastrophic
illness registry in the NHIRD. In Taiwan, patients with ARDs are eligible for a catastrophic
illness certificate after a rheumatology specialist diagnoses them on the basis of clinical
manifestations, laboratory data, and the criteria set by the American College of Rheumatology, which
is reviewed by rheumatologists commissioned by the NHI. Thus, the catastrophic illness
patient data are highly accurate and reliable. Several autoimmune diseases are defined as
catastrophic illnesses by the NHI with the related certification requiring precise fulfillment of the
following classification criteria: the American College of Rheumatology (ACR) 1997 revised
criteria for SLE (ICD-9-CM: 710.0) [
]; the American Rheumatism Association 1987 revised
criteria for RA (ICD-9-CM: 714.0) [
]; the ACR criteria for systemic sclerosis (ICD-9-CM:
]; the American±European Consensus Group 2002 revised criteria for SS
(ICD9-CM: 710.2) [
]; the Bohan and Peter 1975 criteria for polymyositis and dermatomyositis
(ICD-9-CM: 710.3) [
]; the International Study Group 1990 criteria for BehcËet disease
(ICD-9-CM: 136.1) ; and the ACR 1990 criteria for temporal arteritis (ICD-9-CM: 443.1)
], granulomatosis polyangiitis (ICD-9-CM: 446.4) [
], and Takayasu arteritis (ICD-9-CM:
]. The date of the earliest ARD diagnosis was used as the index date. Patients with a
history of dementia or who were younger than 45 years were excluded. Finally, 34,660 patients
with ARDs were selected as the study patients and were designated as the ARD cohort. For
each ARD patient, four non-ARD patients were randomly selected from the same study period
according to the same exclusion criteria and were frequency-matched with the ARD patients
according to age and sex to construct the non-ARD cohort, which comprised 138,640 patients.
Outcome measurement and comorbidities
Each study patient was followed until receiving their first diagnosis of any type of dementia by
a neurologist during two visits to the outpatient department or one hospital admission. The
dementia types included Alzheimer disease (ICD-9-CM: 331.0), arteriosclerotic dementia
(ICD-9-CM: 290.4), and unspecified dementia (ICD-9-CM: 290.0±290.3, 294.1, 331.1±331.2,
and 331.82). The patients who recorded ICD-9-CM 290.4 in the claims data were classified as
having vascular dementia. All remaining patients with dementia who did not belong to the
vascular dementia group were defined as having nonvascular dementia. We also differentiated
patients with Alzheimer's disease from those with non-vascular dementia by searching for
ICD9-CM code 331.0. The patient was considered lost to follow-up on death, withdrawal from
the database, or the end of 2012. At the baseline, major comorbidities such as diabetes
(ICD9-CM 250), hyperlipidemia (ICD-9-CM 272), hypertension (ICD-9-CM 401±405), heart
failure (ICD-9-CM 428, I50.2, I50.3), cardiovascular disease (ICD-9 codes 393±398, 410±414,
420±429, 440±449, 451±459), stroke (ICD-9-CM 430±438), major psychosis or a
substancerelated disorder (ICD-9-CM codes 291±299, 303±305), and traumatic brain injury (ICD-9 CM
codes 801±804, 850±854 were considered covariates.
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This was a nationwide retrospective cohort study. The baseline characteristics were sex, age,
and certain comorbidities. The baseline characteristics were matched between the ARD and
non-ARD patients according to age and sex and were compared using a chi-square test for
categorical variables and a t-test for continuous variables. We observed the time-to-event data in
the ARD and non-ARD cases and used a multiple Cox proportional hazards model to explore
the association between dementia and the ARDs adjusted for sex, age, and comorbidities. The
adjusted hazard ratios (HRs) indicated that after adjusting for covariates, the ARD cases had a
higher dementia risk than did the non-ARD cases when HR > 1. The 95% confidence intervals
(CIs) of the HRs were also calculated.
To perform a stratified analysis, we separately calculated the incident rate ratio and HRs
adjusted for sex, age, comorbidities, and some types of ARDs (including RA, SLE, and SS) for
the age groups of less than 65 years and 65 or more years. We used the Kaplan±Meier method
to calculate the incidence rates for the ARD, RA, primary SS, secondary SS, and SLE groups
over the follow-up period. We then plotted the results in cumulative incidence plots with each
comparison group's cumulative incidence rate. All analyses were performed using SAS version
9.4 (SAS Institute, Cary, NC).
A total of 34,660 cases of ARDs and 138,640 matched control cases were selected from the
NHIRD during the defined period of interest. Of the ARD and the non-ARD patients, 39%
were 45±54 years of age and 77% were female (Table 1). The ARD cohort was more likely than
the non-ARD cohort to experience diabetes (14.54% vs. 12.98%, p < 0.001), hyperlipidemia
(16.66% vs. 14.21%, p < 0.001), psychosis (4.09% vs. 2.4%, p < 0.001), heart failure (4.71% vs.
1.91%, p < 0.001), hypertension (34.99% vs. 27.69%, p < 0.001), stroke (7.18% vs. 4.85%,
p < 0.001), traumatic brain injury (1.47% vs. 1.23%, p < 0.001), or cardiovascular disease
(34.01% vs. 16.42%, p < 0.001). The mean follow-up period was 5.97 years (standard deviation
[SD] 3.05) and 6.37 years (SD 2.95) for the ARD and the non-ARD cohorts, respectively.
Table 2 lists the dementia incidence densities for the ARD and non-ARD cohorts. During
the observation period, 4280 patients in the non-ARD cohort (incidence rate of 48.43 per
10,000 person-years) and 1305 patients in the ARD cohort (incidence rate of 63.08 per 10,000
person-years) developed dementia. When stratified by sex, age, and comorbidities, the patients
in the ARD cohort, particularly male patients (HR 1.23, 95% CI 1.09±1.4) and patients aged
75 years (HR 1.26, 95% CI 1.13±1.40), were associated with an increased dementia risk.
We further divided the ARD cohort into RA, SLE, primary SS, secondary SS, and other
ARDs subgroups. An HR of 1.23 (95% CI 1.15±1.31, p < 0.001) was obtained for the ARD
cohort (Table 3), and the adjusted HRs for dementia for the RA, SLE, and SS subgroups were
1.14, 1.07, and 1.46, respectively. Furthermore, primary SS and secondary SS patients had the
highest dementia risk among all patients with ARDs, with the adjusted HRs for dementia
being 1.35 and 1.67, respectively. Specifically, the secondary SS subgroup had the highest
dementia risk overall (HR 1.67, 95% CI 1.43±1.95, p < 0.001). In the age group of less than 65
years, the adjusted HRs for dementia for the RA, SLE, primary SS, secondary SS, and other
ARDs subgroups were 1.08, 0.88, 1.49, 1.64, and 0.95, respectively. In this age group, secondary
SS had the highest risk of dementia (HR 1.64, 95% CI 1.2±2.25, p < 0.01). In the age group of
65 years or older, the adjusted HRs for dementia for the RA, SLE, primary SS, secondary SS,
and other ARDs subgroups were 1.15, 1.19, 1.35, 1.66, and 1.33, respectively. In this age group
also, secondary SS had the highest risk of dementia (HR 1.66, 95% CI 1.39±1.99, p < 0.001).
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Fig 1(A) presents a comparison of the cumulative incidence of dementia for the ARD and
non-ARD patient groups. The incidence of dementia (log rank test, p < 0.001) was
significantly higher for patients in the ARD cohort than it was for patients without ARDs. Fig 1(B)±1
(D) presents a comparison of the cumulative incidence of dementia for the subgroups of the
ARD and non-ARD cohorts. Except for the SLE subgroup, the incidence of dementia (log
rank test, p < 0.001) was significantly higher for the patients in the subgroups of the ARD
cohort than it was for the non-ARD cohort.
To the best of our knowledge, this is the first nationwide population-based study evaluating
the relationship between middle-aged patients with ARDs and dementia. In this study, the
overall incidence rate of dementia was 30% higher for the ARD cohort than for the non-ARD
cohort, with an HR of 1.18 after adjustment for age, sex, and comorbidities. Moreover, ARD
subgroups such as the RA and SS subgroups were associated with a significantly higher risk of
dementia than was the non-ARD cohort. We therefore postulate that patients with ARDs
(except SLE and vasculitis) have an increased risk of dementia.
Young-onset dementia (YOD) is defined as a neurological syndrome that affects the
behavior and cognition of patients aged 45±64 years. In the present study, the patients were divided
into two age groups, <65 and 65 years, for analysis. The age of the patients and follow-up
suggested that the association is not restricted to YOD and also involves late-onset dementia.
Speculations of a potential association between ARDs and neuropsychiatric affections,
including affective disorder, neurotic disorder, personality disorder, dementia, and delirium, have
]. The present study highlighted major psychosis or substance-related
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disorders (ICD-9-CM: 291±299 and 303±305) as covariates to differentiate between psychosis
and dementia in SLE. Several substantial interactions between covariate conditions and ARDs
have been reported to increase the risk of dementia. Microgial cell activation is a major
component of neuroinflammation in degenerative dementia [33±35]. An activated microgial cell
can be divided as either M1 (classical phenotype) or M2 (alternatively activated phenotype)
. Microglia develop into an M1 phenotype in the presence of interferon and tumor
necrosis factor and release massive inflammatory cytokines such as IL1β, IL-12, TNF-α, and
inducible nitric oxide synthase. These inflammatory cytokines have also been observed in ARDs.
Additionally, the M2 phenotype develops in the presence of IL-4 and IL-13 and has an
antiinflammatory profile. The switch between the M1 and M2 phenotype is a dynamic process and
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§ Incidence per 10,000 person-years
*: p value for HR < 0.05
**: p value for HR < 0.01
***: p value for HR < 0.001
a HR adjusted by age group, sex, and comorbidities
is dependent on the presence of a peripheral inflammation state [
]. However, a specific type
of M1 is predominant in ARDs, as reported by Jimenz et al. [
], who identified a
distinctive shift from M2 to M1 in brains with AD. Therefore, glial cells can be activated by systemic
inflammation and consequently deteriorate, presenting clinical symptoms of AD and
Parkinson disease . Neuroinflammation results in synaptic impairment, and neuronal death and
contributes to neurodegeneration within the brain [
]. Therefore, middle-aged patients with
ARDs may have an increased risk of dementia. Some animal models of AD [
histochemical analyses of human brain serial sections  also indicate an aggregation of activated
microglia around amyloid plaques in animal [
] and human brains [44±47], respectively.
Soluble Aβ may be involved [
] and may trigger neuroinflammation at the BBB level [
indicating that inflammation is an early process in AD pathogeny.
Kang et al. [
] demonstrated that after adjustment for demographics and comorbidities,
the dementia risk did not differ significantly in their ARD and comparison groups.
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Fig 1. Cumulative incidence plot of dementia among ARD and non-ARD patient group. (a) presents a comparison of the cumulative
incidence of dementia for the ARD and non-ARD patient groups. (b) presents a comparison of the cumulative incidence of dementia for RA and
non-ARD cohorts. (c) presents a comparison of the cumulative incidence of dementia for SS (primary SS and secondary SS) and non-ARD
cohorts. (d) presents a comparison of the cumulative incidence of dementia for SLE and non-ARD cohorts.
Furthermore, neuroinflammation may have some protective effects against ARD.
Additionally, de Simone et al. investigated the phospholipid phosphatidylserine expressed on the
surface of apoptotic neurons and reported that its presence may induce a shift in the microglial
expression of cytokines from being deleteriously inflammatory (IL-1, TNF-α, NO) to
protective (TGF-β and NGF) [
]. Toll-like receptors (TLRs) are believed to promote the
proinflammatory pathways. However, studies have reported that TLR2 and TLR4 are present in amyloid
] and are involved in the uptake of Aβ and other aggregated proteins, promoting
their clearance from the central nervous system [
]. Another toll-like receptor, TLR3, can
enhance neuronal survival and endothelial cell growth, promoting neuroprotective responses
]. These findings may be due to neuroinflammation having both neurodestructive and
neuroprotective effects. The hypothesis that inflammation leads to dementia implies a
predominance of the neurodestructive effects over the neuroprotective effects [
Among the ARD subgroups in this study (RA, SLE, primary SS, secondary SS, and other
ARDs), the secondary SS subgroup had the highest dementia risk after adjustment for
demographics and comorbidities. Conversely, the SLE subgroup had the lowest dementia risk
compared with the other ARD subgroups. These findings are consistent with those of Trysberg
et al. [47±49], who reported low levels of amyloid β in SLE patients. This may be a consequence
of diminished production of the amyloid precursor protein, which is believed to be mediated
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by heavy anti-inflammatory or immunosuppressive therapy. Therefore, the effects of
antiinflammatory or immunosuppressive therapy on patients deserves consideration.
A strength of our study was the use of a nationwide population-based database with
sufficient sample size and statistical power. However, our study had several limitations. First,
although the NHIRD includes data on patients that received treatment for ARDs and
dementia, in Taiwan, most ARD patients with a catastrophic illness certificate have been treated with
anti-inflammatory or immunosuppressive therapy. Additionally, in Taiwan, stopping
antiinflammatory or immunosuppressive therapy in ARD patients with a catastrophic illness
certificate is unacceptable. Therefore, we could not adjust for treatment-related effects in our
study. Although some studies have revealed that NSAID use reduces the risk of dementia in
patients with RA, our data demonstrated an increased risk of dementia (adjusted HR: 1.14) in
the RA subgroup. Such conflicting results may have been obtained because the present study
did not consider the effects of NSAID use. Second, the NHIRD does not contain parameters
such as clinical severity, laboratory data, body mass index, smoking habits, intelligence, and
education level, all of which have been also associated with ARDs and dementia [9±10]. Third,
dementia is more likely to occur in the elderly; however, patients of varying ages were enrolled
to study the different ARDs. Therefore, we did not fully account for the effects of age in our
study. Future analysis of each type of ARD may yield more concise results.
In conclusion, this nationwide population-based retrospective cohort study determined
that middle-aged patients with ARDs (excluding SLE and vasculitis) have an increased risk of
dementia. Among the ARD subgroups, the RA and SS subgroups were associated with a
significantly higher risk of dementia, with both the primary and secondary SS subgroups having the
highest overall risk of dementia. The underlying mechanism of these results is not fully
understood and warrants further research.
Conceptualization: Tzu-Min Lin.
Data curation: Wei-Sheng Chen, Jau-Jiuan Sheu, Yi-Hsuan Chen.
Formal analysis: Wei-Sheng Chen, Jau-Jiuan Sheu.
Investigation: Jin-Hua Chen.
Supervision: Chi-Ching Chang.
Writing ± original draft: Tzu-Min Lin, Yi-Hsuan Chen.
Writing ± review & editing: Jin-Hua Chen, Chi-Ching Chang.
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[V717I] transgenic mice. Journal of Neuroinflammation. 2005; 2:22.
https://doi.org/10.1186/1742-20942-22 PMID: 16212664
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