Sjögren’s disease (SjD) is known to be associated with subclinical atherosclerosis and arterial hypertension [1]. This study investigates premature stroke in SjD and compares clinical characteristics of SjD patients with and without cerebrovascular accidents (CVA) and those of younger (<50 years) and older (≥50 years) stroke patients. In this retrospective, single-center case-control study, we included 548 patients with confirmed SjD from Hannover Medical School between August 2018 and September 2023. Among them, 37 (6.8%) had a history of CVA (SjD+CVA). The study design includes two control groups (CGs): SjD patients without any previous CVA (SjD-CG) and patients with CVA without any systemic rheumatic disease (Neuro-CG). For this Neuro-CG, an additional 560 patients from the neurological clinic, admitted with at least one cerebral infarction, were enrolled in this study. The study protocol was approved by the local ethics committee (8179_BO_S_2018) and declaration of consent was received from all the subjects.

After age matching at baseline in a 3:1 ratio, 111 patients with a mean age of 62.3 years were included in both control groups. The cohorts differed significantly only with regard to arterial hypertension and sex distribution. The usual sex distribution among SjD patients was altered in the SjD+CVA group, with a higher proportion of male patients (35%), whereas it remained typical in the SjD-CG (17%) (Table 1).

The median age at the occurrence of stroke was significantly lower in the SjD+CVA cohort compared to patients in the Neuro-CG (53 vs. 60 years, P=0.042) (Figure 1).

A comparison of traditional cardiovascular risk (CVR) factors within the three cohorts revealed similarities between SjD+CVA and Neuro-CG, whereas SjD-CG demonstrated lower prevalence in nearly all CVR factors.

The concept of atherosclerosis as an auto-inflammatory process has yielded numerous evidence-based findings in recent years [2]. It is evident that traditional CVR factors continue to play a pivotal role in atherogenesis, as reflected in our data set when examining the CVR profiles of the individual cohorts [3].

In addition to the traditional CVR factors, it has been demonstrated that atherogenesis can be accelerated by systemic inflammation even in the initial stages, namely endothelial dysfunction. While Łuczak et al. [4] demonstrated this association in patients with SjD, Zehrfeld et al. [1] also observed a higher prevalence of subclinical atherosclerosis in SjD patients, which is unlikely to be attributed to traditional CVR factors.

This is consistent with the data presented by Zippel et al. [5], which demonstrated an elevated prevalence of atherosclerotic end-stage disease, particularly cerebrovascular events, in patients with SjD.

Our multivariate analysis identified male sex (odds ratio [OR]=5.05, 95% confidence interval [CI] 1.79-14.24, P=0.001), disease activity with a European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) at or above five points (OR=3.68, 95% CI 1.09-12.42, P=0.012), and presence of vasculitis (OR=7.41, 95% CI 1.52-36.16, P=0.029) as independent predictors of CVA in the SjD cohort. There is a direct and logical link between vasculitis and disease activity, which are both linearly connected to the atherogenetic process described above. In the context of higher disease activity, there are more proinflammatory cytokines circulating in the blood. Additionally, more immune cells are recruited [6]. This proinflammatory milieu may, therefore, facilitate the progression of already induced vascular wall or endothelial damage, as previously elucidated by Fernández-Gallego et al. [7].

The proportionately more frequent manifestation of arthritis, vasculitis, interstitial lung disease, polyneuropathies, and lymphomas in male SjD patients also results in an increased ESSDAI, and subsequently, an increased disease activity, which can then promote an acceleration of atherogenesis, as previously described [8].

There is no clear definition of “premature stroke.” Potter et al. [9] describe age limits typically ranging between 45 and 55 years. In our SjD+CVA cohort, stroke occurred in individuals below the age of 40 in 18.9% (7/37), compared to only 5.4% (6/111) of patients in the Neuro-CG (P=0.041). Additionally, 21.6% (8/37) of strokes occurred in patients aged between 40 and 50 years, compared to only 15.3% (17/111) in the Neuro-CG.

A recently published analysis of Taiwanese insurance data revealed an incidence of young stroke in 0.39% of the SjD cohort, in comparison to 0.30% in the healthy cohort [10]. Our findings corroborate the observation of a significantly higher incidence of young stroke in our cohort. Of the 548 SjD patients, 15 patients ultimately experienced such an event at an age below 50 years, resulting in a frequency of 2.74% in our cohort.

Dividing SjD+CVA patients into young (<50 years) and old (≥50 years) groups at the time of stroke, no predictors of stroke occurrence can be found in young SjD patients (Table 2). The two groups did not differ significantly in terms of serological parameters, comorbidities, and disease activity. Due to the retrospective nature of our study, we could not exclude all potential confounders such as lifestyle factors or positive family history, which may explain the unpredictability.

It is noteworthy that 48.6% (18/37) of SjD+CVA patients experienced a stroke prior to the diagnosis of SjD, the majority of them (66.7%) experienced a stroke at young age. However, all patients exhibited sicca symptoms at the time of their CVA. The interval between the initial onset of SjD symptoms and the confirmation of SjD diagnosis was notably prolonged in the younger SjD+CVA subgroup, with a median duration of 4 years (range 1-23.0).

Focusing on the early age at which many patients in our cohort had their ischemic stroke, the available literature generally distinguishes between different etiologies of young stroke: cardioembolic genesis (10%-34%), small vessel disease (12%-26%), cervicospinal dissection (10%-35%), atherosclerosis of the large arteries (4%-29%) [9]. However, the most common classification is cryptogenic (24%-53%), which often shows a persistent foramen ovale in combination with hyperlipidemia, hormonal contraception, and the presence of migraine with aura [9]. Especially in this cryptogenic group, but also in the atherosclerotic strokes in young people, SjD might be one of the additional underlying causes. However, as far as we know, there have been no studies on this.

Our findings reinforce the necessity for more rigorous cerebrovascular risk stratification in patients with SjD. Since SjD-associated strokes may occur cryptogenically or prior to diagnosis, it is essential to explore the implications of these findings for clinical screening and preventive strategies. Given the potential for strokes to arise in patients who may not exhibit traditional risk factors, we propose that early vascular assessments and the evaluation of lipid-lowering therapies should be considered for individuals diagnosed with SjD. Further prospective research is necessary to explore the possible benefit of early cardiovascular treatment strategies.

In our opinion, future discussions should focus not only on the question of preventive lipid-lowering therapy, but also on the development of an adapted CVR score, in particular to identify patients at increased risk of stroke at an early age and thus prevent them more effectively.