Are Rheumatoid Arthritis and Periodontitis Linked?
—A new large cohort study called into question a bidirectional relationship between rheumatoid arthritis and periodontitis.
An analysis of over 3 million residents of Denmark challenges previous reports of a bidirectional relationship between rheumatoid arthritis (RA) and periodontitis.1,2
“The dental research community has shown significant interest in the connections between periodontitis and RA, and other systemic conditions such as cardiovascular diseases and diabetes mellitus,” said Eero Raittio, DDS, PhD, of Aarhus University in Aarhus, Denmark, and the University of Eastern Finland in Kuopio, Finland, in an interview with 鶹ý. “Our study sought to address some of the methodological limitations and provide more credible insights into this area of research.”
“Unfortunately, research in this area appears to have been strongly influenced by the desire to promote the status of dental care in society, leading to biased, overly optimistic findings and inadequate methodological quality,” said Dr. Raittio, who is also the lead author of the new study.
For the research, the investigators evaluated the relationship between incident periodontitis and RA, using causal inference analysis with nationwide data from Denmark.
Study design
The study cohort consisted of permanent residents of Denmark aged 20 or older between 1990 and 2018 who were registered with the Danish Civil Registration System, the National Patient Register, and the National Health Insurance Service Register.
Individuals who died or left Denmark before 2000 were excluded as were those for whom no corresponding income or socioeconomic data were available. All individuals born before 1920 were excluded because education data were unavailable.
The investigators included a washout period between 1990 and 1999 to identify only incident RA or periodontitis cases. Individuals with RA or periodontitis before 2000 were excluded. Those with incident RA and periodontitis in the same year were also excluded because the authors could not determine which occurred first.
Incident RA was defined as two or more hospital encounters (outpatient, inpatient, or emergency) in the National Patient Register with RA diagnostic codes. Individuals were classified as having incident RA in the year of their first encounter that had an RA diagnostic code or during which they received subgingival or surgical periodontal treatments.
Incident periodontitis was defined by treatment codes because the National Health Insurance Service Register does not contain diagnostic codes. Subgingival or surgical periodontal treatments in two different years were deemed a diagnosis of periodontitis, with the year of the first periodontitis treatment recorded as the year of incidence. The investigators included dental service use as a variable because their definition of periodontitis was based on treatment codes. Dental service covariates were dental services other than periodontitis treatment in each calendar year and the number of years these other services were used during the washout period.
The investigators used survival analysis with marginal structural survival models to estimate the effect of periodontitis on incidence of RA and vice versa for new cases between 2000 and 2017. To account for covariates, they modeled time-varying exposure for factors including age, sex, birth country, municipality, education, socioeconomic variables, diabetes, and variables related to use of dental services.
To evaluate a bidirectional association, the investigators performed a cross-sectional association analysis using data from 2017 and included a simulation of smoking prevalence, which was not available in the register data.
Study population
Of 6,564,086 individuals aged 20 or older between 1990 and 2018, the investigators identified 3,308,635 individuals aged 20 to 79 years in 2000 who met inclusion criteria and were represented in the survival analysis. The cross-sectional analysis included 2,574,536 individuals who were alive and living in Denmark during 2017.
The median (interquartile range) age in 2000 was 43 years (31-57) and half were male. The majority (93%) were born in Denmark.
The effect of periodontitis on risk of incident RA was analyzed from a sample that included 20,348 cases of incident RA and 740,799 cases of incident periodontitis. For the effect of RA on the risk of incident periodontitis, the sample included 17,297 cases of incident RA and 742,562 cases of incident periodontitis.
Incident RA in individuals with periodontitis
Using the marginal structural model with adjustment for covariates, the investigators estimated a hazard ratio (HR) of 1.05 (95% confidence interval [CI], 0.88-1.25) for the effect of periodontitis on incident RA.
The investigators calculated the restricted mean survival time (RMST) for incident diagnosis of RA over 18-year follow-up for individuals with or without periodontitis and found nearly identical results. For both groups, the RMST was 16.94 years (95% CI, 16.93-16.95) and the investigators calculated that the difference between them was 0.003 years, equivalent to only 1 day.
Incident periodontitis in individuals with RA
The marginal structural model with adjustment for covariates yielded an HR of 0.84 (95% CI, 0.80-0.88) for the effect of RA on incident periodontitis, indicating that RA reduces risk of periodontitis.
RMST analysis, however, suggested that this effect was not strong over 18-year follow-up. For individuals without RA, the RMST for incident periodontitis was estimated to be 14.11 years (95% CI, 14.08-14.14). For individuals with RA, the estimated RMST for incident periodontitis was similar at 14.52 years (95% CI, 14.41-14.64). This difference was 0.41 years or approximately 151 days.
Cross-sectional association
For the cross-sectional analysis to evaluate a bidirectional relationship between RA and periodontitis in the 2017 cohort, investigators adjusted for age, sex, birth country, and number of years with a dental visit during the washout period. With these adjustments for covariates, the prevalence ratio (PR) for the association of RA with periodontitis was 1.05 (95% CI, 1.01-1.09).
However, when the PR was adjusted by simulating smoking confounding, RA and periodontitis were no longer associated (PR, 0.99; 95% simulation interval, 0.93-1.04).
Common risk factors
In their paper, the investigators concluded that their findings suggested that positive findings for associations between RA and periodontitis were likely caused by residual confounding. “The study suggests that these diseases are not necessarily more likely to occur together or increase the likelihood of developing each other if the common risk factors are taken into account,” Dr. Raittio told 鶹ý.
In his estimation, “It is important for physicians and dentists treating patients with or without RA or periodontitis to consider the common risk factors for both diseases, such as smoking. For instance, there is room for improvement in [encouraging] smoking cessation.”
The investigators wrote that limitations of the study included the use of an unvalidated definition of periodontitis based on treatment codes, which could cause underestimation of prevalence and incidence of mild cases, and possible missing cases treated outside the health system. They did not control for all potential confounders, including smoking, disease severity, or type. The results also may not be generalizable to other countries or health care systems.
Regarding the future, Dr. Raittio said, “One potential next step could be to explore the impact of dental or medical care on improving important patient outcomes, like arthritis symptoms or tooth loss, in patients with RA or periodontitis.”
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