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Abstract

Background:

A small number of studies have suggested an association between systemic lupus erythematosus (SLE) and Parkinson’s disease (PD).

Objectives:

This study aimed to determine the risk of incident PD among Korean patients with SLE.

Design:

A nationwide retrospective cohort study using the claims database of the National Health Insurance Service of Korea was conducted.

Methods:

Patients above 40 years of age diagnosed with SLE between 2010 and 2015 were included in the study. The primary outcome of the study was incident PD, defined by registration in the rare intractable diseases program for PD and an ICD-10 code of G20. Subjects were followed until PD diagnosis or the end of 2017. We estimated the cumulative incidence of PD among the SLE cohort and compared this to that in a 1:5 age- and sex-matched control group.

Results:

Totals of 11,615 SLE cases and 58,075 matched controls were identified. The cumulative incidence rate of PD was 0.7 per 1000 person-years in the SLE cohort. The crude hazard ratio (HR) of incident PD was 1.71 (95% CI: 1.25–2.36) among the SLE cohort compared to the control group. The HR was 1.59 (95% CI: 1.15–2.20) after adjustment for age, sex, income, and baseline comorbidities.

Conclusion:

This study demonstrated that patients with SLE had an increased risk of incident PD compared to non-SLE controls. Further research is required to determine the mechanism underlying this and to elucidate the precise role of systemic inflammation in the development of PD in patients with SLE.

Keywords

autoimmune neurodegenerative disease Parkinson’s disease systemic lupus erythematosus

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease and poses a great burden on public health.¹ The prevalence and incidence of PD have increased steadily in recent years. In 2016, there were 6.1 million individuals with PD globally, more than doubling from 2.5 million in 1990.² According to one study using the Korean National Health Insurance Service (KNHIS) database, the annual prevalence and incidence of PD were 142.5 and 53.1 per 100,000 population, respectively, in 2013. These figures were both higher than those recorded in 2004.³

Although the precise etiology of PD remains unclear, progressive loss of dopaminergic neurons in the substantia nigra is thought to play a key role in the pathogenesis. The subsequent dopamine deficiency within the basal ganglia incurs a movement disorder characterized by motor symptoms including rigidity, bradykinesia, resting tremor, and postural instability.

Several studies have proposed that immune-mediated neuroinflammatory processes such as microglial activation and oxidative stress are involved in the pathogenesis of PD.^4–9 As such, a number of studies have identified a protective effect of non-steroidal anti-inflammatory drugs (NSAIDs), especially ibuprofen, against PD, thought potentially to be mediated by the peroxisome proliferator-activated receptor γ (PPARγ) pathway.^10–17 Currently, PD treatment remains symptomatic and primarily comprises dopaminergic drugs. Further investigation into the immune-associated pathogenesis of PD may improve our understanding of the disease and provide clues for different treatment options.

Systemic lupus erythematosus (SLE) is a heterogeneous, systemic autoimmune disease.¹⁸ SLE is associated infrequently with movement disorders, the most common of which is chorea, a hyperkinetic movement disorder. Parkinsonism, a hypokinetic movement disorder, has been reported rarely as a neurological manifestation of SLE since its first report in 1930.¹⁹ To our knowledge, no more than 10 cases of central nervous system (CNS) lupus patients presenting with Parkinsonian symptoms have been reported.^20–23

Conflicting results have been observed with respect to the association between idiopathic PD and SLE in a small number of population-based studies. A Swedish study showed no increased risk of PD among patients with SLE (standardized incidence ratio 1.00, 95% confidence interval [CI] 0.43–1.97); however, there were only five cases of incident PD.^24,25 A cohort study of the Taiwanese national health insurance database (n = 12,187) showed that SLE subjects had a lower risk of subsequent PD development (hazard ratio [HR] 0.68, 95% CI: 0.51–0.90) compared to controls.²⁶ However, more recent research in Taiwan (n = 3,055) showed a slightly elevated risk of PD between patients with SLE and controls (HR: 1.29, 95% CI: 0.90–1.84), although no statistical significance was demonstrated due to the small number of SLE patients in the study.²⁷

Given these discordant results, additional research into the association between SLE and PD in various races and large populations is needed. This will improve our insight into these two diseases, which are presumed to share pathophysiology to some extent. Therefore, this study aimed to examine the incidence of PD among patients with SLE using a large sample (n = 11,615) from a nationwide database in Korea.

Methods

Study design and data source

We conducted a population-based nationwide retrospective cohort study using claims data from the KNHIS database. The KNHIS is the mandatory health insurance program that covers nearly 97% of all Korean citizens. The database consists of diagnostic data according to the 10th revised International Classification of Diseases (ICD-10) and prescription, procedural, demographic, and socioeconomic data. The rare intractable diseases (RID) registration program is a part of the KNHIS and covers various rare and intractable diseases including SLE and PD. To be registered, a document written by a physician confirming that the patient fulfills the clinical criteria is mandatory. The KNHIS database is an open database in which all patient information is anonymized to protect privacy. This study was approved by the review committee of the KNHIS (NHIS-2018-1-257) and by the Samsung Medical Center Institutional Review Board (2018-04-050). The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.²⁸

Study cohort and exposure definition

Eligible subjects were patients with SLE older than 40 years. Patients with SLE were defined as those who met the diagnostic code (ICD-10 code M32) and who enrolled in the RID program for SLE in Korea between 2010 and 2015.^29,30 The index date was defined as that of enrollment in the RID program. Patients who had a previous history of claims with the diagnostic code for PD (ICD-10 code G20) before the index date were excluded. For comparison, a 1:5 age- and sex-matched non-SLE cohort was constructed for the same period and assigned a pseudo-index date, which corresponded to the index date of their matched cases. In the non-SLE cohort, subjects with a previous history of claims with diagnostic code of PD were also excluded.

Outcome definition

The primary outcome of this cohort study was occurrence of PD, defined by an ICD-10 code of G20 and new registration in the RID program. To be enrolled as a PD in the RID program, an official document certifying that the patient has met the clinical criteria for PD was submitted by the physician. This definition was used in previous epidemiological studies on PD, and its accuracy is acceptable.^31,32 Subjects were followed up from the index date until the date of first registration in the PD in RID program or to the end of this study, 31 December 2017.

Comorbidity definition

Baseline comorbidity variables potentially associated with PD were assessed by ICD-10 codes and prescriptions. Diabetes (E11-E14), hypertension (I10-I13 and I15), and dyslipidemia (E78) were defined by ICD-10 codes and a minimum of one prescription of relevant medication. Dementia (F00-F03, G30, G231, G310, G311, G318, and F107) and depression (F32-F34) were also defined by ICD-10 codes. Stroke (I63 and I64) and ischemic heart disease (IHD, I20-I25) were defined by ICD-10 codes. Cancer was defined by relevant ICD-10 codes.

Statistical analyses

Data analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Baseline characteristics were reported as mean (standard deviation [SD]) for continuous variables and as numbers with percentages for categorical variables. The chi-square test and t-test were used to compare the categorical and continuous variables between SLE and control cohorts. The incidence rate (IR) of PD for each group during the observation period was presented per 1000 person-years. The cumulative IR of PD in the SLE and control cohorts was compared using a Kaplan–Meier curve. Cox proportional hazards regression models were used to compare the risk of PD development between groups. HR was presented with a 95% CI and adjusted for covariates (model 1, unadjusted; model 2, adjusted for age and sex; model 3, adjusted for age, sex, diabetes, hypertension, dyslipidemia, and low income; model 4, adjusted for variables in model 3+ dementia, and depression). Analyses also were stratified by sex, age, and comorbidities. A p value <0.05 was considered statistically significant.

Results

Baseline characteristics

We identified 22,966 patients with SLE who first enrolled in the RID program for SLE in Korea between 2010 and 2015. Among these, 54 patients with a prior diagnosis of PD were excluded. Ultimately, 11,615 subjects over 40 years of age were included in the SLE cohort. A total of 58,075 age- and sex-matched non-SLE subjects were included in the control group. The baseline characteristics of subjects are summarized in Table 1. Women accounted for 90% of the study population, and the majority of subjects were between 40 and 64 years old. The percentage of individuals with baseline comorbidities was significantly higher among the patients with SLE compared to the controls (p < 0.05 for all comparisons).

Table 1.

Baseline characteristics of study populations.

	Systemic lupus erythematosus		p
	Yes (n = 11,615)	No (n = 58,075)	p
Sex
Female	10,478 (90.2)	52,390 (90.2)	1
Male	1137 (9.8)	5,685 (9.8)	1
Age
Mean	52.3 ± 9.7	52.3 ± 9.7	1
40–64	10,115 (87.1)	50,575 (87.1)	1
⩾65	1,500 (12.9)	7,500 (12.9)	1
Comorbidities
Diabetes	859 (7.4)	3,834 (6.6)	0.0018
Hypertension	3,952 (34.0)	11,131 (19.2)	<0.0001
Dyslipidemia	2,265 (19.5)	7,471 (12.9)	<0.0001
Ischemic heart disease	2,302 (19.8)	4,684 (8.1)	<0.0001
Stroke	821 (7.1)	1,739 (3.0)	<0.0001
Cancer	561 (4.8)	2,112 (3.6)	<0.0001
Dementia	122 (1.1)	436 (0.8)	0.0009
Depression	2,662 (22.9)	6,172 (10.6)	<0.0001
Low income	3,358 (28.9)	14,778 (25.5)	<0.0001

Data are expressed as means ± standard deviation, or n (%).

Primary outcome: incident PD

Table 2 presents the IRs and crude and adjusted HRs for incident PD among the SLE and control groups. During 365,324 person-years of follow-up in the control group, 150 incident PD cases were observed, yielding a cumulative IR of 0.41 per 1000 person-years. For the SLE cohort, 50 incident PD cases were observed during 71,068 person-years of follow-up, yielding a cumulative IR of 0.70 per 1,000 person-years. Unadjusted HR was 1.71 (95% CI: 1.2–2.4). Figure 1 shows the Kaplan–Meier curve comparing the cumulative incidence of PD of the two groups.

Table 2.

The incidence rate and hazard ratios of Parkinson’s disease in systemic lupus erythematosus and control cohorts.

	N	Event	PY	IR	Hazard ratio (95% confidence interval)
	N	Event	PY	IR	Model 1	Model 2	Model 3	Model 4
Control	58,075	150	365,323.9	0.41	1 (Ref.)	1 (Ref.)	1 (Ref.)	1 (Ref.)
SLE	11,615	50	71,068.3	0.70	1.71 (1.25, 2.36)	1.81 (1.31, 2.49)	1.76 (1.28, 2.43)	1.59 (1.15, 2.20)

Model 1: Unadjusted.

Model 2: Adjusted for age and sex.

Model 3: Adjusted for variables in Model 2+ diabetes, hypertension, dyslipidemia, and low income.

Model 4: Adjusted for variables in Model 3+ dementia and depression. In the stratified analysis according to sex, sex was excluded from the adjustment variable.

PY, person-years; IR, incidence rate per 1000 person-years; SLE, systemic lupus erythematosus; Ref., reference group.

Figure 1.

Cumulative incidences of Parkinson’s disease in systemic lupus erythematosus and non-systemic lupus erythematosus cohort.

The increased risk of PD among patients with SLE remained significant after full adjustment for age, sex, diabetes, hypertension, dyslipidemia, low income, dementia, and depression (HR: 1.59, 95% CI: 1.15–2.20). The mean duration until PD diagnosis was 6.1 ± 2.1 years in the SLE cohort and 6.3 ± 2.0 years in the control group (p < 0.0001). The mean age at PD diagnosis was 66.5 ± 8.9 years in the SLE cohort and 68.4 ± 9.0 years in the control group (p < 0.01).

In stratified analysis according to sex and age, an increased risk of PD in SLE patients was observed in all subgroups (Supplementary Table S1). The adjusted HR of PD was slightly higher in women with SLE (Model 4: HR: 1.66, 95% CI: 1.17–2.35). Supplementary Table S2 demonstrates the IRs and HRs of PD stratified by comorbidities. The adjusted HRs of PD in SLE patients were slightly higher in the subgroup without comorbidities such as diabetes, hyperlipidemia, IHD, cancer, and depression. Although not statistically significant, the subgroup with stroke and dementia had slightly higher adjusted HR of PD in SLE patients.

Discussion

Our study showed that patients with SLE are at a higher risk of developing PD compared to non-SLE subjects. This is one of the largest studies that identified an association between SLE and PD development in a nationwide population-based cohort. This result allusively supports the hypothesis that autoimmune-related neuroinflammation is involved in the development of PD.

In the most recent study using the Taiwanese National Health Insurance database, Chang et al.²⁷ reported no significant difference in PD incidence between patients with SLE and a comparison group (HR: 1.21, 95% CI: 0.91–1.61), but this HR value was larger than that for rheumatoid arthritis (RA; HR: 1.15, 95% CI: 1.03–1.28) and was statistically significant. Since the number of SLE patients included in that study was relatively small compared to RA patients (19,542 patients with RA vs 3055 patients with SLE), this might have caused differences in statistical significance. In contrast, our study included 11,615 SLE patients, and a statistically significant association between SLE and PD development was observed.

However, an inverse association between SLE and PD development was observed in a study by Liu et al.²⁶ based on a similar Taiwan claim database. Differences in study populations and outcome definitions were possible causes of conflicting results in the two studies in Taiwan. In the former case, only patients above the age of 45 were included, and in the latter case, the proportion of patients under the age of 50 was close to 80%. Advanced age is an important risk factor for PD, so this study population difference might have caused a difference in outcome. However, in the study of Liu et al., even older than 65 years of age, SLE patients showed a low risk of PD. Liu et al. did not elaborate on the definition of PD but mentioned the possibility that mild PD was omit as a limitation of the study. In the two studies, the IRs were different in those aged 65 years or older (5.36 per 1000 person-years in Liu et al. vs 9.62 per 1,000 person-years in Chang et al.), which might be a result of the difference in definition of PD between the two studies. In our study, not only the diagnosis code, but also the registration code in the RID program was used for definition of PD. The RID program is considered reliable because it is registered by the physician only when the diagnostic criteria are satisfied and is reviewed by the Health Insurance and Review Agency.³³

SLE is a prototype systemic autoimmune disease characterized by multiorgan involvement.¹⁸ The brain and nervous system can be affected by immune-mediated damage in SLE, leading to various neuro-psychiatric manifestations. The relationship between alteration of the dopaminergic system and autoimmune diseases has not been established, although several studies have suggested the importance of dopaminergic regulation in autoimmunity. Dopaminergic receptors seem to play an important role not only in the nervous system, but also in the immune system. Recent research has revealed that various types of immune cells, namely T-cells, B-cells, dendritic cells, and microglia, express functional dopamine receptors.^34–36 Previously, the impairment of dopaminergic regulation has been reported in autoimmune disorders such as SLE.³⁶ However, there are few case reports for the development of PD, among SLE patients showing Parkinsonian features.^37,38

PD is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons in midbrain such as substantia nigra, followed by dopaminergic deafferentation of basal ganglia³⁹ with impaired dopamine metabolism.⁴⁰ The cause of neuronal loss in PD is poorly understood, but previous studies have suggested that immune-mediated neuroinflammatory processes are related to neuronal loss and PD pathogenesis.^41,42 A number of mechanisms underlying this has been proposed, including a glial reaction involving astrocytes and microglial cells, lymphocytic infiltration, and altered blood–brain barrier function in the brains of patients with PD.^43–45 Recent studies have shown that peripheral T-cells infiltrate into the brain parenchyma at the site of neuronal injury in PD, where they play a fundamental role in neurodegeneration.³⁶ Moreover, evidence from post-mortem and in vivo studies has indicated that proinflammatory cytokines and oxidative stress contribute to the progression of neurodegeneration.^4–9 In addition, a protective role of NSAIDs against the development of PD has been suggested, thought to involve the PPARγ pathway.^10–17 Therefore, altered immune system functioning and increased inflammatory molecules in patients with SLE are both likely to promote neurodegeneration and development of PD. The earlier onset of PD in the SLE group compared to the control group in our study suggests the occurrence of early neuronal loss in patients with SLE. Previous studies have reported the presence of anti-dopaminergic antibodies and abnormal findings on dopamine transporter imaging in SLE patients with PD.^37,38 In lupus-prone mice model, autoimmune manifestations such as elevated spleen weight, circulating antinuclear antibodies, and tumor necrosis factor (TNF)-α levels in serum and cerebrospinal fluid coincided with behavioral deficit and neurodegeneration of the substantia nigra and ventral tegmental area as revealed by Fluoro Jade B staining, suggesting systemic autoimmunity and inflammation may induce damage to dopaminergic neurons in mesonigral and mesolimbic pathways.⁴⁶ In addition, antiphospholipid antibodies, vascular damage, and extrapontine myelinolysis have been suggested to play a role in the pathogenesis of Parkinsonism in SLE.⁴⁷ Further investigation is needed on whether the aforementioned factors are involved in the development of PD in SLE patients.

The disparities observed in previous Swedish population-based studies with respect to risk of PD among patients with SLE might have resulted from differences in race and genetic predisposition. The Swedish study noted no difference in incidence of PD between SLE patients and a general population, contrast to our study results.²⁵ For example, SLE tends to affect Asian, Black, and Hispanic populations more severely than Caucasians.¹⁸ In addition, the sex ratio of PD has shown differences between races. Male predominance has been reported in most Western populations, whereas the incidence of PD in Korea was shown to be higher in women.^3,48

In this study, SLE was associated with increased risk of PD even after various stratifications by age, sex, and a range of comorbidities. These findings suggest that the increased PD incidence in patients with SLE is a robust association between SLE and development of PD, not merely due to such potential confounders.

There are limitations to this study. As a retrospective observational study using an insurance database, information about disease activity, organ involvement of SLE, laboratory results, and lifestyle factors such as smoking and dairy and alcohol intake were not available and could not be adjusted for during the analysis. Since the disease activity and severity of SLE were unknown, it is not clear whether the increased PD risk is a direct result of immune-mediated active inflammation or due to non-specific and multifactorial degenerative damage. In addition, an analysis of drug exposure including NSAIDs, glucocorticoids, immunosuppressants, and other medications used for treatment of comorbidities was not conducted in our study, given the complexity and change of drug usage over time. Additional well-designed prospective studies including analysis of disease activity, severity, and drug usage are required to determine the factors related to PD risk in patients with SLE. In addition, there may be a detection bias in PD diagnosis due to differences in health care utilization between SLE patients and non-SLE controls.⁴⁹ In our study, however, the registration code of the RID program was used to operationally define PD. In order for a patient to be enrolled in the RID program as having PD, a confirmative diagnosis from a neurologist must be obtained. Most patients with PD eventually seek medical attention and only patients enrolled in the RID program through confirmation by a neurologist are defined as PD cases in our study, so this process can contribute to reducing the detection bias. Finally, since our study was conducted with Koreans, there is a limitation to generalizing our findings to other races.

Despite these limitations, this study has the following clinical and research implications. Our study showed an increased risk of PD in the Korean SLE population compared to the general population. Although the mechanism underlying this and the precise role of inflammation are not elucidated, a high index of suspicion for PD is required by all clinicians treating patients with SLE. Further studies investigating increased neurodegeneration in patients with SLE will improve our understanding of both diseases and contribute to development of novel therapeutic agents.

Conclusion

Our nationwide retrospective cohort study demonstrated that Korean adult patients with SLE have a significantly higher risk of PD compared to non-SLE subjects.

Supplemental Material

sj-docx-1-tab-10.1177_1759720X231152653 – Supplemental material for Systemic lupus erythematosus is associated with increased risk of Parkinson’s disease

Supplemental material, sj-docx-1-tab-10.1177_1759720X231152653 for Systemic lupus erythematosus is associated with increased risk of Parkinson’s disease by In Young Kim, Yeonghee Eun, Jaejoon Lee, Kyungdo Han, Da Hye Kim, Ju-Hong Min, Hoon-Suk Cha, Eun-Mi Koh, Dong Wook Shin and Hyungjin Kim in Therapeutic Advances in Musculoskeletal Disease

Footnotes

Acknowledgements

The authors would like to thank the staff at the KNHIS for providing data and administrative support.

Declarations

ORCID iDs

Yeonghee Eun

Hoon-Suk Cha

Hyungjin Kim

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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