Primary Sjogren’s syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands [1]. It often extends beyond glandular manifestations to affect various systems, including the vascular, nervous, pulmonary, and renal systems [2]. Neurological complications of the central nervous system, such as cognitive dysfunction and dementia, are widely reported, with prevalence rates ranging from 8% to 49% in patients with pSS [3].

Dementia has emerged as the most common neurodegenerative disease that threatens health, with a high incidence rate, serious socioeconomic burden, and irreversible neuronal damage to the brain [4]. However, the role of neuroinflammation in dementia remains controversial. Vasculitis, autoantibodies, immune complex deposition, and cellular inflammation are potential mechanisms through which pSS increases the likelihood of developing dementia, leading to nerve damage, cognitive decline, and dementia onset. A recent meta-analysis revealed a significant increase in the risk of dementia in individuals with pSS [5]. Nevertheless, four of the five studies were conducted in only one country, raising the need for research in diverse settings.

Hydroxychloroquine (HCQ) is commonly used in patients with pSS. Recently, Varma et al. showed that the initiation of HCQ was associated with a reduced risk of developing Alzheimer’s disease (AD) compared with methotrexate initiation in patients with rheumatoid arthritis (RA) [6]. This finding was consistent across four distinct analysis schemes designed to address specific types of bias, including informative censoring, reverse causality, and outcome misclassification. They also showed that HCQ rescued impaired hippocampal synaptic plasticity in an APP/PS1 transgenic mouse model of AD and corrected multiple molecular abnormalities [6]. In contrast, a cohort study utilizing a UK primary care database found no association between HCQ exposure in patients with connective tissue disease (CTD) and the risk of AD; however, only a limited number of patients with pSS were included [7]. The association between HCQ and the primary prevention of dementia in patients with pSS has not been well established.

Hence, this nationwide population-based cohort study aimed to investigate (1) whether pSS can contribute to the development of dementia and (2) whether the use of HCQ can decrease the incidence of dementia in patients with pSS, using the Health Insurance Review and Assessment (HIRA) database.

In the present population-based cohort study, the incidence rate for dementia in patients with pSS was 0.68 per 100 person-years, and pSS was significantly associated with an increased risk of dementia. Early exposure to HCQ is associated with a lower risk of dementia in patients with pSS.

Several epidemiological studies have evaluated the association between pSS and the risk of developing dementia. A recent meta-analysis demonstrated that the risk of dementia was 1.24 times higher in SS (95% CI: 1.15–1.33) [5]. Nevertheless, four of the five studies included in the analysis were conducted in Taiwan, potentially introducing geographical bias and a relatively significant overlap in the study samples [13–16]. Therefore, we analyzed the association between pSS and dementia using HIRA data, which was consistent with the results of previous studies conducted in Taiwan. We added a prescription code for anti-dementia medication to the operational definition of dementia to increase the reliability of the diagnosis. In South Korea’s Health Insurance System, hospitals can receive medical expenses for anti-dementia drugs after evaluation of medical records, including the Mini-Mental State Examination and Global Deterioration Scale score or Clinical Dementia Rating score, and approval of the HIRA. Therefore, it was considered that the possibility of falsely coding dementia would be low, and that patients with moderate to high degrees of dementia would be included more often than those with mild cognitive impairment. Recent studies have demonstrated that the upregulation of proinflammatory cytokines plays multiple roles in neurodegeneration [17]. However, the risk for dementia does not appear to increase in all autoimmune diseases. A recent meta-analysis showed that pSS (pooled relative risk, 1.26; 95% CI, 1.14–1.39) and systemic lupus erythematosus (pooled relative risk, 1.43; 95% CI, 1.19–1.73) were related to elevated risk of dementia, but no relationship between RA and risk of dementia was found [18]. A Mendelian randomization study showed an association between pSS, multiple sclerosis, and AD among seven autoimmune diseases [19]. Therefore, further studies are required to understand how disease-specific pathogenesis contributes to dementia development.

Research on the pathophysiology of AD has revealed that autophagy disruption plays a role in the build-up of protein aggregates [20]. One possible mechanism by which HCQ lowers the risk of dementia is as follows. Experimental findings indicate that the degradation of amyloid plaques is inhibited by autophagy-blocking substances such as HCQ [7,20]. In the Drug Repurposing for Effective Alzheimer’s Medicines study, the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway was identified as a potential drug target for pharmacoepidemiological analysis due to its involvement in cytokine signaling [21]. Varma et al. [6] showed that HCQ initiation was associated with a lower risk of incident AD than methotrexate initiation in patients with RA.

Moreover, they demonstrated that HCQ rescues impaired hippocampal synaptic plasticity in APP/PS1 transgenic mice and corrects multiple molecular abnormalities underlying AD, such as neuroinflammation, Aβ clearance, and tau phosphorylation underlying AD through inactivation of STAT3 [6]. However, contradictory results have been previously reported. In 2001, an 18-month randomized, placebo-controlled trial, and the results of the study showed no effect of HCQ against placebo on the progression of dementia in patients with early AD [22]. The Taiwanese National Health Insurance Research Database found that HCQ, methotrexate, and sulfasalazine increased the risk of AD in patients with RA, rather than providing protection. A cohort study conducted in the UK reported that the long-term use of HCQ in patients with CTD was not associated with a decreased risk of AD compared to non-use of HCQ [7]. Although our study showed a preventive effect of HCQ against dementia in patients with pSS, caution should be exercised. To date, no randomized controlled trials have assessed the effect of HCQ on the primary prevention of dementia. The absence of trials is due to the requirement for extended study durations spanning several years and the necessity of recruiting a substantial number of participants to yield significant and meaningful outcomes. In the absence of such evidence, larger observational studies are needed to explore the effect of HCQ on dementia prevention, considering the timing and duration of HCQ use for each specific disease rather than all CTDs.

In this study, 48% of patients with pSS used HCQ within 6 months of diagnosis, a figure that was higher than expected. The European Alliance of Associations for Rheumatology recommendations for the management of Sjögren’s syndrome suggest the use of HCQ only for frequent episodes of acute musculoskeletal pain [23]. However, Fauchais et al. [24] reported that HCQ is used by more than half of patients with arthralgia in real-life settings. Similarly, a Chinese multicenter registration study reported that HCQ, the most frequently prescribed drug for pSS, was used by 67.5% of patients [25]. No disease-modifying drugs are currently available for pSS. Among the available therapeutic options, HCQ stands out for its good safety profile and minimal side effects [26]. Therefore, the high prescription rate of HCQ in clinical practice deviates from the recommendations.

We also found that patients with pSS were more likely to have cardiovascular (CV) comorbidities and risk factors than those without pSS. We included patients with mixed dementia because autopsy studies have reported prevalence of mixed Vascular-Alzheimer Dementia as 20–22%. Moreover, in clinical practice, the distinction between AD and vascular dementia is complex owing to their overlapping clinical presentation [27]. Therefore, evaluation and management of CV risk factors should be considered in patients with pSS. HCQ has been shown to exert beneficial effects on the metabolic and CV outcomes in patients with RA [28]. This effect is achieved through the reduction of modifiable risk factors for CV disease, such as the decreased incidence of diabetes. A UK cohort study demonstrated that chronic exposure to HCQ is associated with a lower mortality risk in patients with CTD [7]. However, whether HCQ can reduce vascular dementia through metabolic and CV improvements remains unclear.

This study has some limitations. First, because this retrospective study was based on a claims database, medical chart review was not possible. Other factors, such as disease activity and severity of pSS, laboratory findings such as inflammatory markers, autoantibody profiles, and risk factors for dementia, such as family history, smoking, alcohol use, or level of education, could not be considered. Secondly, the dose, duration, and adherence to HCQ were not investigated. All individuals were classified as HCQ users or non-users based on their HCQ use within 6 months after the diagnosis of pSS. Finally, drug-related effects other than those of HCQ, including those of non-steroidal anti-inflammatory drugs, steroids, and immunosuppressive agents, were not evaluated.

Numerous brain regions exhibit a high density of glucocorticoid receptors, and the prolonged elevation of endogenous glucocorticoid levels may induce neurotoxicity, thereby increasing the risk of cognitive decline and dementia. However, a recent systematic review revealed that individuals on long-term glucocorticoids tended to exhibit notably poorer executive function, particularly working memory and global cognitive function. Nevertheless, most studies of dementia (both all-cause dementia and AD) indicated either null or negative associations with glucocorticoid use, suggesting a potential protective effect. Therefore, although glucocorticoid therapy in individuals with inflammatory conditions may adversely affect their specific cognitive function and brain structures, it could also substantially decrease the risk of dementia [29]. Considering the pivotal role of the immune/inflammatory response in the development of AD, preclinical studies suggest that immunomodulatory agents such as calcineurin inhibitors could potentially modify dementia progression [30]. Therefore, owing to the lack of information on various risk factors for dementia, including education, physical activity, smoking, and the use of medications such as glucocorticoids and immunosuppressants, these limitations could impact the results, particularly the potential for bias. Thus, further studies that include more detailed data on risk factors and medications are needed to validate our findings.

In conclusion, using nationwide claims data, we found that pSS is independently associated with the development of dementia. Thus, HCQ may prevent dementia in patients with pSS.