Periodontitis and Subsequent Risk of Cataract: Results From Real-World Practice

Background Periodontitis can lead to systemic inflammation and oxidative stress, contributing to the development of various diseases. Periodontitis could also be associated with several ocular diseases. Methods We conducted a retrospective population-based cohort study using the National Health Insurance Research Database of Taiwan to evaluate the risk of cataract in people with and without periodontitis. We established a periodontitis cohort and a non-periodontitis cohort, which included 359,254 individuals between 2000 and 2012. Age, gender, and enrolled year were matched. All participants were monitored until the end of 2013. Cox proportional hazard models were applied to estimate hazard ratios (HRs) and confidence intervals (CIs). Results Patients with periodontitis had a significantly higher risk to develop cataract than those without periodontitis [10.7 vs. 7.91 per 1,000 person-years, crude HR = 1.35 (95% CI = 1.32–1.39), and adjusted HR = 1.33 (95% CI = 1.30–1.36)]. The significant levels remained the same after stratifying by age, gender, presence of comorbidity, and use of corticosteroid. In addition, we found that diabetes mellitus and hyperlipidemia had a synergistic effect in the interaction of periodontitis and cataract development. Conclusion Patients with periodontitis have a higher risk of cataract development than those without periodontitis. Such patients may request frequent ocular health check-up. Further studies should be performed to confirm the association and to understand the mechanisms.

Cataract is caused by a build-up of protein that clouds the lens, which can lead to blurred vision and blindness (14). Around 95 million people worldwide are affected by cataract, which remains the leading cause of blindness in middle-and lowincome countries (15). Many causative factors could promote the development of cataract, which include old age, female gender, smoking, sunlight exposure, family history, diabetes mellitus, cardiovascular disease, chronic airway disease, corticosteroid use, and ocular infection or inflammation (16,17).
The association between periodontitis and cataract remains largely unknown. As we know, periodontitis may increase the systemic inflammatory reaction, and cataract could be initiated and exacerbated by the result of chronic inflammation (18)(19)(20). Furthermore, periodontitis-induced oxidative stress may also play a crucial role in the development of cataract (21)(22)(23). In a cross-sectional study, Gervasio et al. (24) examined many institutionalized geriatric residents and reported that the prevalence of periodontitis and cataract were both predominant. However, the exact relationship between these two common diseases is not well-established to date. Therefore, we aimed to conduct a retrospective population-based cohort study based on the National Health Insurance Research Database (NHIRD) in Taiwan to evaluate the association of periodontitis and subsequent development of cataract.

Data Source
The National Health Insurance (NHI) program operated since 1995, with more than 99.9% of Taiwan citizens enrolled. The NHIRD is managed and updated by the National Health Research Institutes between 1995 and 2013. We applied the Longitudinal Health Insurance Database 2000 (LHID2000), a subset of NHIRD, to complete the study. The database included detailed medical information of 1,000,000 people randomly selected in 2000, such as demographic status, diagnostic code, medication, and procedure claims was available. The study was approved by the Research Ethics Committee of the China Medical University and Hospital (CMUH-104-REC2-115). Informed consent was unnecessary for the de-identified data and waived by the Research Ethics Committee.

Study Population
We selected newly diagnosed adult patients with periodontitis [International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes 523.3 and 523.4] between 2000 and 2012 as the periodontitis group (n = 179,627). The date of diagnosis was defined as the index date. We excluded those with incomplete demographic data and those with cataract before the index date. Thus, we selected the same number of adult individuals without periodontitis as the comparison group. Age, gender, and index year were matched between the periodontitis and the non-periodontitis groups. The exclusion criteria were the same as the periodontitis group. All participants were monitored until (1) the development of cataract, (2)

Study Outcome and Confounders
The primary outcome of the study was the diagnosis of cataract (ICD-9-CM code 366). We further identified several comorbidities that may be potential risk factors for cataract and the most related medication, corticosteroid, as confounders.

Statistical Analysis
We applied chi-squared test and t-test to compare the distribution of baseline characteristics for categorical and continuous variables. We have drawn the Kaplan-Meier curves followed by testing inter-group differences with a log-rank test to evaluate the cumulative incidence of cataract in both groups. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariate Cox models were used to estimate the adjusted HRs (aHRs) and 95% CIs after controlling age, sex, comorbidities, and corticosteroid use, which were significant in the univariate model. All the analyses were performed using STATA statistical software (StataCorp. 2015, R 14, StataCorp LP). The level of significance was set at 0.05 using a two-tailed test.

RESULTS
This study included 179,627 periodontitis patients and 179,627 non-periodontitis individuals that displayed similar distributions of age and gender ( Table 1). The mean age of the periodontitis group was 40.3 (standard deviation = 13.5) years, 51.0% of whom were women. The prevalence rates of hypertension, diabetes mellitus, hyperlipidemia, asthma/COPD, CLD, rheumatic diseases, and corticosteroid use were all greater in patients with periodontitis than those without periodontitis (p < 0.001). Figure 1 shows that the cumulative incidence of cataract was higher in the periodontitis group than in the non-periodontitis group (p < 0.001) after a 14-year follow-up.

DISCUSSION
This retrospective population-based cohort study analyzed the incidence of cataract in individuals with and without periodontitis. Results showed that periodontitis patients were associated with a higher risk of cataract development than non-periodontitis individuals. As expected, the incidences of cataract were higher in older people than in younger people, in women than in men, in those with comorbidity than in those without comorbidity, and in corticosteroid users than in noncorticosteroid users. Furthermore, cataract risk was significantly higher in the periodontitis group than in the comparison group even after stratifying by age, gender, the presence of comorbidity, or corticosteroid use. Moreover, we found that diabetes mellitus and hyperlipidemia had a synergistic effect in the interaction of periodontitis and cataract development.
In the present study, we have evaluated several potential risk factors and their impacts on cataract development. Overall, diabetes mellitus played the most important role in the development of cataract, followed by hypertension, hyperlipidemia, CKD, CLD, corticosteroid use, rheumatic diseases, and asthma/COPD. Triple H (hypertension, hyperglycemia, and hyperlipidemia), metabolic syndrome, atherosclerosis, and cardiovascular diseases would have the most impact to cataract development; these findings correlated with previous studies (14,15). However, the association between chronic liver disease and cataract or rheumatic diseases and cataract needs further investigations.
The potential mechanisms of the association between periodontitis and cataract remained unclear, but several hypotheses have been suggested. First, odontogenic ocular infections may directly influence the development of cataract. Both mouth and teeth are known reservoirs for many pathogens; therefore, periodontitis may contribute to repeated or chronic ocular infections (25). In a large-scale cohort study, Chau et al. (11). have reported that patients with periodontal disease (n = 467,170) are at a higher risk of infectious scleritis (aHR = 1.270, 95% CI = 1.114-1.449), uveitis (aHR = 1.144, 95% CI = 1.074-1.218), and infectious keratitis (aHR = 1.094, 95% CI = 1.030-1.161) than those without periodontal disease (n = 467,170). These infectious conditions have shown to be risk factors of cataract (15). Second, oral microbiome from periodontitis can cause immune responses to exacerbate cataractogenesis. Some observations implied periodontitisinduced systemic inflammation and oxidative stress in the pathogenesis of eye diseases (15,26,27). That is, periodontal microbiota may trigger immune dysfunction in the oro-opticnetwork and promote the development of cataract. Third, the impact of periodontitis in the induction and progression of ocular diseases such as diabetic retinopathy, glaucoma, and age-related macular degeneration has been identified (12,13,27,28). The pathophysiology between periodontitis and these ocular complications may be similar to that of cataract. Finally, smoking, lower socioeconomic status, and shared comorbidities, such as diabetes mellitus, hypertension, hyperlipidemia, cardiovascular disease, and chronic airway disease, may also contribute to the development of cataract in periodontitis patients.
The primary strength of the study is the use of populationbased data that are highly representative of the general population. No difference was found in the demographic distribution between LHID2000 and the original NHIRD. In addition, the universal coverage in the insurance system ensures that all citizens can have no access barriers to health care (29). Moreover, the NHIRD reflected a real-world scenario and the results of clinical practices.
Certain limitations should be considered in the study. First, the diagnosis is only based on ICD code, but the NHIRD has been validated and the results showed the data was reliable (30). Second, the NHIRD does not contain detailed information on smoking habits, occupational or environmental exposure, body mass index, and family history, which may be confounding factors. Third, the database did not contain clinical variables such as dental and ocular findings, disease severity and subtype, laboratory data, culture reports, and imaging findings. Fourth, the treatment effects of periodontitis could not be well-evaluated in the database. Fifth, the follow-up period may be short for cataract development. Finally, the study could be biased because of possible unmeasured or unknown confounding variables.

CONCLUSION
Patients with periodontitis are at a higher risk of cataract development than those without periodontitis. Such patients may request frequent ocular health check-up. Further studies should be performed to confirm the association and to understand the mechanisms.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by CMUH-104-REC2-115. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.