Systemic lupus erythematosus (SLE) is an autoimmune-mediated diffuse connective tissue disease characterized by systemic autoimmune inflammation (1). SLE involves multiple organ systems with complex clinical manifestations and repeated disease courses. It often occurs in women of childbearing age (1–3). The etiology of SLE remains unclear, but genetic and environmental factors may play a role in the pathogenesis of the condition. A population-based study in Taiwan found that the average annual incidence of SLE was 4.87 per 100,000 persons between 2003 and 2008 (4). Additionally, an epidemiological study of SLE patients in the Thrace region of Turkey reported that the mean annual incidence of SLE was 4.44 per 100,000 persons, which was similar to the results of the Taiwanese study (5).

Retinal vasculitis (RV) is a type of inflammatory disease involving retinal blood vessels that is often accompanied by choroidal and vitreous inflammation. In severe cases, it can cause complications such as macular edema, which can significantly impair vision and even cause blindness. The pathogenesis of RV includes immune complex deposition and cellular immune response, causing a series of vascular damages and inflammatory responses (6). In addition to local retinal vascular inflammation, patients with RV can often have systemic vasculitis. The causes of RV are infectious and non-infectious, and most of the non-infectious causes are autoimmune diseases, including SLE.

Approximately 40% of SLE patients can have fundus changes (7). A previous cross-sectional study found that 2/69 (3%) of SLE patients had RV (6). RV can occur in the early or late stages of different SLE patients. Some patients have RV as the initial manifestation, and some patients develop severe RV when SLE disease progresses, even involving the optic nerve or causing retinal hemorrhage and severely impairing the patient's visual function (8–10). At present, compared with non-SLE individuals, the increase in the incidence of RV in SLE patients and the correlation between SLE and the risk of RV are unclear. Therefore, in this study, we explored the correlation between SLE and the risk of RV through a retrospective cohort study based on a population-based database.

The baseline characteristics of the SLE and non-SLE groups are shown in Table 1. We matched the two groups for sex, age, and year of the index date at a 1:20 ratio. Ultimately, there were 231,720 matched individuals in the non-SLE group and 11,586 patients in the SLE group (Figure 1). By comparing the urbanization and low income proportions of the two groups, we found that the proportion of suburban and rural patients in the SLE group and the proportion of low income patients were higher than those in the non-SLE group. The incidence of comorbidities in the SLE group was higher among the sex-matched and age-matched populations (Table 1). The mean follow-up periods in the SLE and non-SLE groups were 6.43 and 7.04 years, respectively.

The cumulative incidence of RV was significantly higher in the SLE group than in the non-SLE group (p < 0.001) at the end of the follow-up period, and the Kaplan–Meier curves are shown in Figure 2. The incidence rates of RV were 56.39 per 100,000 person-years (95% CI, 56.33–56.44) and 2.45 per 100,000 person-years (95% CI, 2.45–2.45) in the SLE and non-SLE groups, respectively, and the incidence rate ratio of RV was 22.99 (95% CI, 14.91–35.45) (Table 2). The results revealed that there was an increased risk of RV in the SLE group.

The adjusted HRs for RV was estimated via Cox proportional hazard regressions, which are provided in Table 3. In all three models, SLE patients were found to have a significantly higher risk of developing RV with consistency. From model 1 to model 3, the HRs under SLE exposure were 22.43 (95% CI, 14.55–34.59), 22.67 (95% CI, 14.70–34.96), and 23.61 (95% CI, 14.94–37.32), respectively. Additionally, in all models, we did not find that differences in sex, age, urbanization, low income, and comorbidity affected the relative risk of RV.

Table 4 shows the results of the RV risk estimation under SLE exposure using sensitivity analysis. Owing to the lack of relevant laboratory test results in the database, we divided the analysis into three scenarios based on different definitions of RV events. Detailed scenarios are shown in Table 4. The RV aHRs of SLE patients in scenarios 1–3 were 23.61 (95% CI, 14.94–37.32), 81.34 (95% CI, 42.05–157.34), and 434.78 (95% CI, 103.95–1,818.63), respectively. We found a high correlation between SLE exposure and severe RV requiring treatment with DMARDs or immunosuppressants. It also suggested that SLE patients were at markedly increased risk of RV development.

To our knowledge, this is the first retrospective cohort study to use nationwide population-based data to assess the correlation between SLE and RV risk. In the current study, we found that patients with SLE had an increased risk of RV compared with individuals without SLE. Moreover, according to different Cox regression models, we concluded that all SLE patients had a high risk of RV. Better understanding of the correlation between SLE and RV could facilitate the early diagnosis of RV in SLE patients.

The ocular manifestations of SLE include skin diseases involving the eyelids, secondary Sjogren's syndrome, scleritis, RV, and neuro-ophthalmological diseases. Although ocular manifestations are not part of the SLE classification criteria, as many as one-third of SLE patients can be observed to have ocular manifestations (14). RV and SLE are both autoimmune diseases with a common immunological basis and produce a common immunological damaging effect. RV and SLE can occur concomitantly or alternately. There have been reports of a case with acute necrotizing RV as the primary manifestation of SLE (15) and a case of SLE patients with optic neuritis and RV as the main manifestations (16). The similarity between the cases was that the patients were all young women. In addition, studies have shown that the degree of fundus lesions is closely associated with the course of SLE, which can reflect the pathological status and degree of other organs (17). When SLE patients have central nervous system involvement, they are more likely to involve the eyes, causing active retinopathy, optic neuropathy, and retinal vascular occlusive diseases (7, 18). Therefore, it is recommended that clinicians perform regular fundus examinations on SLE patients to assess the patient's disease progression and treatment.

The mechanism of RV in patients with SLE has not been fully elucidated. It is currently believed that SLE can cause RV through a variety of mechanisms, including immune complex deposition and other antibody-related mechanisms, vasculitis, and thrombosis (19). RV and non-ocular systemic manifestations of SLE can occur concomitantly or alternately. Ushiyama et al. found that retinopathy was associated with anticardiolipin antibodies and central nervous system lupus (6). SLE patients with retinopathy had higher serum creatinine levels and maximum SLE disease activity index (SLEDAI) than those without retinopathy (6). In a prospective study of 550 SLE patients, Stafford-Brady et al. found that 88% of patients with active SLE were associated with lupus retinopathy, and retinopathy was a marker of poor survival in SLE patients (7). These studies all suggested that the presence of anticardiolipin antibodies, vasculitis, nervous system diseases, and urinary system diseases in SLE was associated with the occurrence of retinopathy, which was consistent with our research results. These antibodies and systemic diseases may be the reasons why SLE patients are more likely to develop RV.

This study had several upsides. First, the database that we used comprised nationwide longitudinal population-based data. Second, the study was supported by a large-scale sample to avoid selection and recall bias. This allowed our hypothesis to proceed smoothly, and the result can be considered more comprehensive and complete. However, this study also had several limitations. First, the NHID lacks data on some clinical characteristics, such as smoking habits, lifestyle, and family history, which may all be risk factors for the development of RV. Although we did undertake some measures to deal with some confounders, such as the diagnosis of chronic obstructive pulmonary disease due to a history of smoking, residual confounders may still have existed and increased the risk of bias. Second, because the data in the NHID are anonymous, we could not obtain laboratory data to confirm the diagnosis of patients, such as laboratory indices of blood and urine samples, fundus photograph results, fluorescein angiography, and imaging results. The laboratory data of some patients suggested viral infections such as CMV infection, but the doctor missed the diagnosis, which may have caused errors in our results. Nevertheless, we explored consistency in the results under different definitions of RV in the sensitivity analysis, and the cohort analysis of Taiwan NHID has also shown high levels of quality and validity in other studies (20, 21). Third, unless SLE patients have eye discomfort, rheumatologists rarely perform eye-related examinations, which results in many patients failing to receive timely RV diagnosis, causing errors in the results. In addition, the study lacks data from people from other countries and races, and whether the results can be extrapolated to other regions requires further investigation. Therefore, these limitations need to be addressed through further research to confirm our conclusions.

In conclusion, this nationwide population-based cohort study demonstrated that SLE patients are at a very high risk of incidental RV. Clinicians should provide appropriate monitoring and education for SLE patients for the risk of RV. If necessary, early intervention can be provided to reduce the risk of blindness and other disabilities. Further research is needed in the future to identify the possible mechanisms of these correlations.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

This study was approved by the Institutional Review Board of Taichung Veterans General Hospital in Taiwan (approval number: CE17100B). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

X-HC and J-CS wrote the manuscript. JW and H-HC conducted bioinformatics analysis, analyzed the data, and drew diagrams. H-YM made a lot of contributions to the design of the research, conducted data analysis, graph generation, and wrote the manuscript. All authors read and approved the final manuscript.

This work was supported by a grant from the National Natural Science Foundation of China Grants [81760298] and the 139 Program for the High-Level Medical Talents in Guangxi Province.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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