Risk Of Parkinson’s Almost Double In Rheumatic Disease Patients

May 29, 2023; Unhurry Expert Research Team

The risk of Parkinson’s Disease (PD) is significantly higher in Autoimmune Rheumatic Disease (ARD) patients. In autoimmune rheumatic diseases (ARDs), the levels of inflammatory mediators are increased, and microglia may be activated, resulting in an inflammatory state and the degeneration of dopaminergic neurons.

A Taiwanese study published in the Annals of Medicine investigated the association between ARDs and Parkinson disease (PD).

What is Parkinson’s Disease?

Following Alzheimer disease, Parkinson disease (PD) is the second most common neurodegenerative disorder, with an incidence of 14 per 100,000 person-years in developed countries PD is a movement disorder that clinically exhibits rigidity, bradykinesia, postural instability and tremors, as well as several nonmotor features, including dementia and depression. The main pathological finding associated with the motor deficits of PD is the degeneration of dopaminergic neurons in the pars compacta of the substantia nigra (SN), leading to a deficiency of dopamine in the striatum. The aetiology of PD may involve genetic or environmental factors or even interactions among aging-related factors, genetic predisposition, and environmental exposure.

The mechanisms of PD may include defective handling of proteins, mitochondrial dysfunction, oxidative stress, and inflammation. One hypothesis is that inflammatory mediators activate immune cells in the brain (microglia), which may cause or contribute to the degeneration of neurons.

Despite intensive research, the cause of the neuronal loss in Parkinson’s disease is poorly understood. Neuroinflammatory mechanisms might contribute to the cascade of events leading to neuronal degeneration.

What is Autoimmune Rheumatic Disease?

Autoimmune diseases form a range of disorders from organ-specific (e.g. Hashimoto’s thyroiditis) to systemic disorders with multiorgan involvement. Disorders that mainly, but not exclusively, affect joints and muscles are grouped together as autoimmune rheumatic diseases (ARDs) and include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren syndrome (SS), progressive systemic sclerosis (PSS), polymyositis (PM), dermatomyositis (DM), vasculitides (including polyarteritis nodosa, Kawasaki disease, hypersensitivity angiitis, Wegener granulomatosis, giant cell arteritis, and Takayasu arteritis) and Behcet disease are chronic diseases characterized by progressive and systemic inflammation.

Patients with ARDs produce chronically high concentrations of inflammatory mediators

Patients with ARDs, such as RA and SLE, produce chronically high concentrations of inflammatory mediators over long periods of time, and these patients are hypothesized to have an increased risk of developing neurodegenerative diseases such as PD.

This hypothesis is supported by post-mortem studies on the brains of Parkinsonian patients; these studies revealed increased levels of proinflammatory mediators and apoptosis-related proteins in the striatal dopaminergic regions of the brain.

However, whether the inflammation is a cause or consequence of PD remains unclear. Recently, higher serum levels of the inflammatory mediator interleukin-6 during a 5-year interval before diagnosis was associated with an increased risk of PD.

In addition, epidemiological studies have suggested that the regular use of anti-inflammatory drugs may be associated with a decreased risk of PD.

To address the possible relationship between immunologically induced inflammation and PD, researchers examined associations between ARDs and the risk of PD in a nationwide, population-based case-control study in Taiwan.

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How was the relationship between immunologically induced inflation and PD assessed?

The study identified ARD patients through the Taiwan National Health Insurance Research Database from 2001 to 2012. They randomly selected a comparison cohort from the general population that was frequency-matched by age (in 5-year increments), sex, and index year. The study analyzed the risk of PD, stratified by sex, age, and comorbidities, by using a Cox regression model.

The primary outcome was the occurrence of PD. A person was considered to have a new onset of PD only if the condition occurred in an inpatient setting or was noted in three or more outpatient visits. All cases were followed from the index date to the date of PD diagnosis by a neurologist, withdrawal from the insurance program, censoring because of death, or 31 December 2012.

Covariates consisted of potential risk factors for PD assessed during the year before the index date.

How was the relationship between PD and ARDs analysed?

The study statistically analysed the middle-aged ARD and control groups. The examined variables were sex, age, age group and comorbidities. The chi-square test and t-test were used to compare the categorical and continuous variables, respectively, between the ARD and comparison groups. A Cox proportional hazards regression model was used to compare the risk of PD between the ARD and comparison groups.

The risk of PD was 1.37 times greater in ARD patients  

The risk of PD was 1.37 times greater in ARD patients than in controls after adjustment for age, sex, and comorbidities. ARD subgroups, such as rheumatoid arthritis and Sjogren syndrome (SS) cohorts, were associated with a significantly higher risk of PD (adjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.03–1.2 and adjusted HR, 1.56; 95% CI, 1.35–1.79, respectively).

Furthermore, primary, and secondary SS patients had significantly higher risks of PD.

The incidence rate of PD in ARDs and non-ARDs

The overall incidence rate of PD was 30% higher in the ARD cohort than in the non-ARD cohort with an adjusted HR of 1.30 after adjustment for age, sex, and comorbidities.

The incidence rate of PD was 1.24 times greater in women with ARDs than in women without ARDs with an adjusted HR of 1.26.

The age-specific incidence rate of PD increased with age in both cohorts. Among subjects aged 75 years or older, the risk of PD was higher in those with ARDs than in those without ARDs.

In this study, the overall incidence rate of PD was 30% higher in the ARD cohort than in the non-ARD cohort, with an adjusted HR of 1.23 after adjustment for age, sex and comorbidities.

The subgroups of the ARD cohort, such as the RA and SS cohorts, also had a significantly higher risk of PD.

Inflammation in patients with ARDs may be a key factor in the development of PD

Currently, neuroinflammation is being considered in the debate on the physio-pathogenesis of PD. Evidence of autoimmune involvement in PD was recently discussed. Tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine involved in SS and other systemic diseases, showed high titers in the blood, cerebrospinal fluid, and striatum of patients with PD. Recent autopsy, genetics, and molecular imaging results suggest that inflammation plays a role in the neurodegenerative process. Therefore, inflammation in patients with ARDs may be a key factor in the development of PD.

“To date, only a few incidental observations of extrapyramidal signs have been described in patients with SS. An exhaustive bibliographic search identified only 14 cases of PD associated with PSS. Our study revealed that the incidence of PD in patients with SS (aged >45 years) was 2.5%. This finding may be due to an autoimmune process directed against the basal ganglia. The pathogenic roles of anti-SSA and anti-SSB remain controversial,” said the report.

“High titers of anti-beta2-glycoprotein IgG were identified in the serum of patients who had PD associated with PSS. This autoantibody is strongly associated with anticardiolipin (aCL) antibodies, antiphospholipid syndrome, and thromboembolic phenomena, but its role in the pathogenesis of PD in SS is still unclear. These patients may present with a subtype of SS in which aCL antibodies directly attack the basal ganglia and cause Parkinsonian symptoms. In addition, the direct toxicity of T cells has been considered after the discovery of lymphocytic infiltration on histological sections of biopsied brain injury tissue,” the report further explained.

Epidemiological evidence has shown that chronic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of PD. The present study revealed that patients with SLE were not associated with a significantly higher risk of PD, whereas the association of PD with immunological diseases such as SLE has been reported.

Limitations of the study

“The strength of our study is the use of population-based data that are highly representative of the general population. However, there were some limitations. First, the database did not include the smoking status and the report of each examination, which are important for both ARDs and PD. Second, this study’s diagnoses were mainly based on ICD in the data set. Third, most of the subjects in our study were Taiwanese, which limited the generalization of the result to patients of other ethnicities. Finally, this study revealed the association but no further analyses about the mechanism were done.

In conclusion, this nationwide, population-based, retrospective cohort study revealed that patients with middle-aged ARDs (except SLE and vasculitis) have an increased risk of PD. Subgroups of the ARD cohort, such as the RA and SS cohorts, were also associated with a significantly higher risk of PD. In addition, patients with primary and secondary SS had a significantly higher risk of PD. Future studies are needed to elucidate the underlying immunologic mechanisms and to translate them into clinical therapeutic options.

Source: https://www.tandfonline.com

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