Introduction
Periodontitis is a destructive inflammatory disease, causing loss of supporting bone and soft tissue surrounding the teeth, and may lead to tooth loss if left untreated. Periodontitis has been reported in 40% of the US adult population [
1], and severe periodontitis in 7.4% worldwide [
2]. In a recent cross-sectional study based on the 2017 Classification, Stage III and Stage IV periodontitis combined was observed in 17% of adults in a Norwegian population [
3].
Periodontitis is associated with several non-communicable diseases (NCDs) [
4‐
6]. Shared immunological and inflammatory reactions in the host or bacteremia caused by pathogens of periodontal origin are suggested mechanisms of these associations. Disease activity is modulated through production of inflammatory factors, including interleukins, prostaglandins, and matrix metalloproteinases [
7].
The supporting evidence of an association between periodontitis and systemic diseases includes several mechanisms. It is suggested that elevated systemic inflammation, observed through acute-phase proteins and oxidative stress biomarkers is a result of organisms entering the circulation. AGE-RAGE interactions are central in the plausible mechanistic links between periodontitis and diabetes, and leads to the exaggerated inflammatory response and periodontal tissue destruction seen in diabetics. Moreover, diabetes is associated with elevated levels of several cytokines and other mediators in saliva and gingival crevicular fluid (GCF) [
4]. Translocated circulating oral microbiota is also thought to impact on development of atherothrombogenesis through induction of systemic inflammation [
5].
P. gingivalis has been shown to accelerate atherosclerosis in animal models, and to induce aorta fatty streaks after bacteremia [
8,
9]. Further mechanistic evidence includes elevated levels of antibodies that have been shown to cross-react with antigens in cardiovascular tissues and increased production of reactive oxygen species (ROS) in peripheral neutrophils in periodontitis patients [
8,
10].
The 2017 Classification redefines the outline of case criteria and disease severities. The aim of this cross-sectional study was to reproduce associations between periodontitis with the use of the 2017 Classification and several prevalent NCDs.
Discussion
This cross-sectional study of 4933 adult participants assessed associations between self-reported NCDs and periodontitis stages based on the 2017 Classification. The results suggest that periodontitis is associated with CVD, hyperglycemia in participants with diabetes and with COPD/emphysema related to the severity of periodontal disease. The associations were generally stronger with increasing stage severity. No association was observed between periodontitis and rheumatoid disorders.
The observed associations between periodontitis and CVD in the present investigation are consistent with other previous studies [
28,
29]. The most recent study [
28] used NHANES data to investigate associations between coronary heart disease/stroke (CVD) and periodontitis by the 2017 Classification of Periodontal and Peri-Implant Diseases and Conditions. The authors assessed clinical periodontal attachment loss and reported that Stage III and IV periodontitis were associated with 3.59 times greater occurrence of CVD compared to Stage I periodontitis. This is higher, but comparable to the present study (OR 1.73 (95% CI 1.04–2.89). Further, the increasing effect sizes of periodontitis stages and CVD in the present study confirm findings by Ngamdu and coworkers with OR 2.58 (95% CI 0.97–6.89) and 3.59 (95% CI 1.12–11.54), for Stage II and Stage III/IV, respectively. Studies with different design are also supportive of these findings. A large longitudinal study of Korean individuals older than 40 years [
30], showed that periodontitis assessed from medical records was associated with future cardiac events in individuals without previous cardiac disease and that this association was reduced with good oral hygiene and more frequent dental visits. Improved oral hygiene behavior was suggested as a modifier of the association between periodontitis and CVD. Another follow-up study reported adverse cardiovascular events in individuals who had been treated for severe periodontitis [
31]. This association was observed in individuals older than 60 years, only.
Neither sensitivity analyses of participants below 75 years nor analyses of non-diabetics produced results that differed vastly from the main analyses in the present study. The associations between CVD and periodontitis Stage II (OR 1.65, 95% CI 0.99–2.73) and Stage III/IV (OR 1.82, 95% CI 1.03–3.21) in participants younger than 75 years, are in line with a report from the PAROKRANK case–control study [
29], despite the differences in study design. In PAROKRANK the association between myocardial infarction and radiologically assessed periodontal bone loss (OR 1.28 (95% CI 1.03–1.60) was assessed in patients < 75 years only, to avoid disturbance from accumulation of concomitant disorders.
There is abundant literature on the relationship between periodontitis and diabetes. It has been stated that diabetic patients in general have higher severity of periodontal disease compared to non-diabetics
, while other studies report comparable periodontal status in patients with controlled diabetes to that of the general population [
32]. A systematic review by Graziani and coworkers [
33] concluded that due to heterogeneity among publications, there is still some conflicting evidence, and stated that several studies are unable to confirm periodontitis’ impact on diabetes control, incidence and complications, or that type 2 diabetes in individuals with periodontitis is associated with higher levels of HbA1c. The present observations are in line with the aforementioned statements. Stage II and Stage III/IV periodontitis were associated with hyperglycemia in self-reported diabetics in the total population. This association was also observed with Stage III/IV in the subpopulation of participants less than 75 years. When self-reported diabetes was assessed alone without consideration of glycemic control, no association was observed.
Periodontitis was not associated with rheumatoid disorders in the present study, which is in contrast to a recent systematic review and meta-analysis [
34]. Hussain and co-workers emphasized that rheumatoid arthritis did not affect periodontal attachment level, but that there is moderate evidence to suggest that individuals with periodontitis have more swollen or tender joints, report more pain on visual analogue scales and have higher erythrocyte sedimentation rates, assessed by a disease activity score tool in 28 joints (DAS28). In the present analysis of rheumatoid disorders, information about joint pain and -motion, functionality, duration of symtoms and use of medication were not assessed, hence the present model design may have inflicted the contrasting findings.
The present analysis of COPD/emphysema is supportive of a Japanese 5-year cohort study [
35]. The authors reported an association between severe periodontitis and COPD. Similarly, a systematic review and meta-analysis have validated associations between periodontitis and asthma, COPD and pneumonia [
36]. The biological plausibility for such associations include epithelial damage to lower respiratory tract caused by periodontal pathogens and cytokine release, and neutrophilic inflammation with subsequent proteolytic destruction of connective tissue [
6,
37]. It has been suggested that smoking should be considered a modifier of associations between COPD and periodontitis as smoking plays an important role in etiology in both diseases [
38]. When analyzing never-smokers in the present investigation, no association with NCDs were observed with the exception of COPD/emphysema. The wide confidence intervals in the present analysis indicates uncertainty of the relationship with COPD/emphysema. Only 2.1% (
n = 104) of the total population reported COPD/emphysema, and 51 of these 104 individuals (49%) were classified with periodontitis Stage III/IV.
The stages of the 2017 classification reflect severity of periodontitis. Accordingly, it may be used to explore a dose-dependent relationship between periodontitis stages and associated conditions, and perhaps more easily identify if there are certain stages or individuals with increased likelihood of coincident diseases. This is of relevance for patients and dental professionals and may be important in risk factor modification as part of periodontal therapy. Conversely, individuals with systemic diseases may present more severe stages of periodontitis, and awareness of this association for patients and medical doctors is encouraged. The latest staging and grading system may facilitate research on how established and potential risk indicators or determinants of periodontitis are distributed between the different stages of disease. Nevertheless, the suitability of the new classification system in epidemiological research, and its potential benefits for patients’ periodontal health has yet to be explored. The cross-sectional design of the present study will not fully reflect disadvantages of the classification in this respect.
The investigated population is representative of smaller cities and rural areas in Norway [
11,
13] and the results from the present study may only be generalized to similar populations. Previous findings from the HUNT Study have shown that non-participants had lower socioeconomic status and higher prevalence of chronic diseases and mortality than those who participated [
39]. This was confirmed in the latest cohort profile [
13] who reported a less healthy lifestyle and inferior self-reported health and higher proportion of cardiovascular diseases, chronic obstructive pulmonary disease, diabetes and antihypertensive medication use, in non-participants. In the present analysis, total household income had a modest effect on the observed associations. Low socioeconomic status has been presented as a risk factor for periodontal disease [
40], however, the magnitude may be masked in the present investigation due to inclusion of younger, healthy individuals in a generally healthy, high-income population. There was a tendency of a protective relationship between higher income and NCDs (Supplementary Table
5).
Moreover, the magnitude of the crude ORs compared to the adjusted ORs of the statistical estimates suggests that some of the independent variables have a significant effect as determinants of the outcomes, together with periodontitis stages. This should be taken into consideration when interpreting the results.
Self-reported systemic illness is a limitation in the present investigation. HUNT cohort profiles [
13] indicate that when compared to hospital journal charts and registries, the sensitivity, specificity and predictive values of the self-reported information varies across diagnoses. In-depth validity studies have been conducted. For self-reported diabetes, Midthjell and co-workers [
41] found that patient administered questionnaires regarding a well-defined disease, was highly reliable for epidemiological purposes. The modest inter-examiner reliability of the clinical examiners is also a limitation. On the other hand, the clinical measurements and biological samples are considered strengths. The large sample size of nearly 5000 individuals and full mouth clinical and radiographical periodontal examination and assessment by the 2017 Classification are also strengths of this study.
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