Current Knowledge on Correlations Between Highly Prevalent Dental Conditions and Chronic Diseases

An Umbrella Review

Max W. Seitz, MSc; Stefan Listl, PhD, Dr Med Dent; Andreas Bartols, Dr Med Dent; Ingrid Schubert, Dr Rer Soc; Katja Blaschke, MSc; Christian Haux, MSc; Marieke M. Van Der Zande, PhD

Disclosures

Prev Chronic Dis. 2019;16(9):e132

Abstract and Introduction

Abstract

Introduction: Studies have investigated the relationships between chronic systemic and dental conditions, but it remains unclear how such knowledge can be used in clinical practice. In this article, we provide an overview of existing systematic reviews, identifying and evaluating the most frequently reported dental–chronic disease correlations and common risk factors.

Methods: We conducted a systematic review of existing systematic reviews (umbrella review) published between 1995 and 2017 and indexed in 4 databases. We focused on the 3 most prevalent dental conditions and 10 chronic systemic diseases with the highest burden of disease in Germany. Two independent reviewers assessed all articles for eligibility and methodologic quality using the AMSTAR criteria and extracted data from the included studies.

Results: Of the initially identified 1,249 systematic reviews, 32 were included for qualitative synthesis. The dental condition with most frequently observed correlations to chronic systemic diseases was periodontitis. The chronic systemic disease with the most frequently observed correlations with a dental condition was type 2 diabetes mellitus (T2DM). Most dental–chronic disease correlations were found between periodontitis and T2DM and periodontitis and cardiovascular disease. Frequently reported common risk factors were smoking, age, sex, and overweight. Using the AMSTAR criteria, 2 studies were assessed as low quality, 26 studies as moderate quality, and 4 studies as high quality.

Conclusion: The quality of included systematic reviews was heterogeneous. The most frequently reported correlations were found for periodontitis with T2DM and for periodontitis with cardiovascular disease. However, the strength of evidence for these and other disease correlations is limited, and the evidence to assess the causality of these disease correlations remains unclear. Future research should focus on the causality of disease links in order to provide more decisive evidence with respect to the design of intersectoral care processes.

Introduction

Human life expectancy has been increasing for many years.^[1] However, as life expectancy increases, so does the prevalence of chronic diseases within the population.^[2] Treatment of chronic diseases frequently takes place in highly specialized disciplines.^[3] However, chronic conditions often emerge, develop, and occur in parallel with other illnesses,^[4] and with each chronic condition life expectancy again decreases.^[5] Because of the high likelihood of patients with chronic conditions developing additional diseases, scientific study of the correlations between diseases is necessary.

The medical scope of such correlations often exceeds the boundaries of medical disciplines. An example of this is the correlation between dental conditions and other noncommunicable diseases, which have been investigated in many scientific publications and in previous empirical literature.^[6] In the past decades, however, dental care and primary medical care have largely evolved separately. Addressing the links between dental and other chronic conditions can improve health care and prevention of chronic conditions,^[7] in particular identifying appropriate and necessary areas for inter-professional cooperation between general medical and dental professionals.^[7]

Many systematic reviews (SRs) to estimate the extent of dental–chronic disease correlations have been conducted for specific dental conditions and chronic systemic diseases, but a systematic overview to provide information about the extent to which there is decisive evidence with respect to the design of intersectoral care processes does not exist so far. The aim of this study was to conduct an umbrella review to provide an overview of the most recent evidence from SRs about interdependencies between dental conditions and chronic systemic diseases. The underlying research question was, "What is the current state of knowledge concerning possible relationships between dental conditions and chronic systemic diseases?" The umbrella review aimed to identify potential intervention points for inter-professional cooperation, including evidence on 1) correlations between highly prevalent dental conditions and chronic systemic diseases, 2) common risk factors, and 3) how dental conditions cause chronic diseases and vice versa.

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Abstract and Introduction
Methods
Results
Discussion
References
Sidebar

Table 1. Results of the Quality Assessment for Included Systematic Reviews Using AMSTAR Checklist, Systematic Umbrella Review of Correlation Between Prevalent Dental Conditions and Chronic Diseases, 1995–2017
Study (year)	1. A Priori Design	2. Duplicate Selection	3. Literature Search	4. Status of Publication	5. List of Studies	6. Characteristics of Studies	7. Quality of Studies	8. Scientific Quality	9. Appropriate Methods	10. Likelihood of Bias	11. Conflict of Interest	Score
Abduljabbar, Javed et al (2017) (19)	0	1	1	0	1	1	1	1	1	0	0	7
Abduljabbar, Vohra et al (2017) (20)	1	1	1	1	1	1	1	1	1	0	0	9
Al-Hamoudi (2017) (21)	0	0	1	0	0	1	1	0	1	0	0	4
Azarpazhooh and Leake (2006) (22)	0	0	1	0	1	1	1	0	0	0	0	4
Batista et al (2011) (23)	0	0	1	1	1	1	0	0	0	0	0	4
Botero et al (2016) (24)	1	1	1	1	0	1	1	1	1	1	0	9
Dai et al (2015) (25)	0	1	1	0	1	1	1	0	1	1	0	7
D'Aiuto et al (2017) (26)	0	1	1	0	0	1	0	0	1	0	0	4
D'Aiuto et al (2013) (27)	0	1	1	0	0	1	1	0	0	0	1	5
Dietrich et al (2017) (28)	0	0	1	0	0	1	1	0	0	0	0	3
Faggion et al (2016) (29)	0	1	1	0	1	1	1	1	1	1	1	9
Hasuike et al (2017) (30)	1	0	1	0	0	1	1	1	1	0	1	7
Kelly et al (2013) (31)	0	1	1	0	1	0	1	1	1	0	1	7
Kothari et al (2017) (32)	0	1	1	1	0	1	0	0	1	0	0	5
Lafon et al (2014) (33)	0	1	1	0	0	1	1	0	1	0	0	5
Lam et al (2011) (34)	0	1	1	0	0	1	0	0	0	0	0	3
Leira et al (2017) (35)	1	1	1	0	0	1	1	1	1	0	0	7
Leng et al (2015) (36)	1	0	1	0	0	1	0	0	1	1	0	5
Li et al (2014) (37)	1	1	1	1	1	1	1	1	0	1	1	10
Lira et al (2017) (38)	0	1	1	1	1	1	1	0	1	0	0	7
Martin-Cabezas et al (2016) (39)	0	1	1	0	0	1	0	0	1	0	0	4
Mauri-Obradors et al (2017) (40)	0	1	1	0	0	1	1	0	0	0	0	4
Orlandi et al (2014) (41)	0	1	1	1	0	1	1	0	1	1	0	7
Sanchez et al (2017) (42)	0	0	1	1	0	1	1	0	0	0	0	4
Schmitt et al (2015) (43)	0	1	1	1	1	1	1	0	1	0	0	7
Teeuw et al (2014) (44)	0	0	1	0	0	1	1	0	1	1	0	5
Tonsekar et al (2017) (45)	0	1	1	0	1	1	1	1	0	0	0	6
Ungprasert et al (2017) (46)	0	1	1	0	0	1	1	1	1	1	0	7
Xu et al (2017) (47)	0	1	1	0	0	1	1	0	1	1	0	6
Zeng, Leng et al (2016) (48)	0	1	1	0	1	1	0	0	1	1	0	6
Zeng et al (2012) (49)	0	1	1	0	0	1	0	0	1	1	0	5
Zeng, Xia et al (2016) (50)	0	1	1	0	1	1	0	0	1	1	0	6

Abbreviation: AMSTAR, Assessing the Methodological Quality of Systematic Reviews.

Table 2. Characteristics of Included Systematic Reviews, Systematic Umbrella Review of Correlation Between Prevalent Dental Conditions and Chronic Diseases, 1995–2017
Study	Years Searched	Study Type(s)	Population	Chronic Systemic Disease	Dental Disease	Interventions	Outcome	Common Risk Factors/Confounders	Quality Assessment Tool Used	Conclusions
Abdul-jabbar, Javed et al (2017) (19)	Up to March 2016	RCTs	6 Studies, 18–64 patients per study	T2DM	Chronic periodontitis	Laser therapy or antimicrobial photodynamic therapy after SRP	Clinical periodontal outcomes and glycemic outcomes	NA	Jadad	LT alone or aPDT showed significant improvement in the clinical periodontal parameters and glycemic levels in T2DM patients. Future RCTs are warranted to confirm these findings.
Abdul-jabbar, Vohra et al (2017) (20)	Up to October 2016	RCTs	4 Studies, 53–75 patients per study	DM	Chronic periodontitis	aPDT plus SRP/control SRP only	Clinical periodontal outcomes and glycemic outcomes	NA	Jadad	aPDT improved clinical periodontal and glycemic parameters in DM patients. When compared with SRP alone, none of the studies showed additional benefits of aPDT.
Al-Hamoudi (2017) (21)	Up to May 2017	RCTs	6 Studies in Brazil and Saudi Arabia. Number of participants, 20–30; 4 studies of patients with T2DM, 3 studies with cigarette smokers	T2DM	Chronic periodontitis	SRP plus aPDT, (control SRP only)	Clinical (PD reduction and CAL gain): microbiological (bacterial count) and immunological (cytokine profile) outcomes	Smoking	Modified Jadad quality scale for reporting randomized controlled trials	SRP plus aPDT improved clinical periodontal and immunological parameters in T2DM and cigarette smokers, no benefits of aPDT compared with SRP alone.
Azarpazhooh and Leake (2006) (22)	Up to July 2005	Case-control and cross-sectional for COPD	Periodontal disease and COPD: 2 cross-sectional studies and 2 case-control studies; 46 to 13,792 participants	COPD	Periodontal disease, tooth loss (dentulous and edentulous patients): dental plaque	Tooth brushing, decontamination/rinsing	Risk of pneumonia/risk of COPD	NA	NA	Fair evidence of an association of pneumonia with oral health, poor evidence supporting a weak association (OR <2.0) between COPD and oral health, good evidence (I, grade A recommendation) that oropharyngeal decontamination with different antimicrobial interventions reduces the progression or occurrence of respiratory diseases.
Batista et al (2011) (23)	Up to May 2010	Longitudinal, cross-sectional, and case-control studies, measuring PD and atherosclerosis clinically	Longitudinal, cross-sectional, and case-control studies, measuring PD and atherosclerosis clinically	Atherosclerosis	Periodontal disease: measures not standardized	NA	Intima-media thickness (atherosclerosis measure)	See Table 3 per study, no confounders assessed in all studies (mostly age and smoking)	NA	Although most studies reviewed found a positive association between PD and atherosclerosis, methodological limitations raise doubts on the validity. All included studies found a significant association.
Botero et al (2016) (24)	1995 to July 2015	Systematic reviews, with or without meta-analysis	13 Systematic reviews, ranging from 2 studies with 143 participants to 35 studies with 2,565 participants (mostly included RCTs, some also non-RCTs)	DM type 1 and T2DM	Periodontitis	Nonsurgical periodontal treatment, with/without antibiotics (2 studies, flap surgery)	Glycemic control: HbA1c or fasting glucose levels	NA	AMSTAR	Periodontal treatment could help improve glycemic control in patients with T2DM and periodontitis (10/12 systematic reviews with meta-analysis). Whether reduction in HbA1c values (0.23 to 1.03 percentage points) is significant for T2DM treatment and control is unclear. Impact of PT in patients with type 1 diabetes and adjunctive antimicrobials is inconclusive. Eight Reviews were of high quality, 5 moderate, 1 low. Three reviews had low risk of bias, 6 were unclear, and 5 high.
Dai et al (2015) (25)	Up to November 2013	Observational studies (clinical trials were excluded)	23 Observational studies: 6 tooth loss, 4 caries, 3 oral hygiene, 4 periodontal health, with 20−706 patients per study	Stroke	Tooth loss, periodontitis, caries experience	NA	Oral health outcomes and oral health–related behaviors	Oral health behaviors	MORE	Poorer oral health status among patients with a stroke diagnosis compared with healthy controls, greater tooth loss, higher dental caries experience, and poorer periodontal status.
D'Aiuto et al (2017) (26)	2005–2015	Systematic reviews/meta-analyses	30 Systematic reviews: 5–78 studies included per review. Number of participants unclear. Various types of studies included in systematic reviews.	DM	Periodontal disease, tooth loss, caries	NA	Bidirectional relationship, oral health–diabetes	NA	AMSTAR	Strong evidence of T2DM being a risk factor for periodontal diseases, weak evidence in relation to type 1 diabetes. Weak evidence in relation to dental caries experience in children. Limited evidence of periodontitis being a risk factor for diabetes, but evidence of periodontal treatment leading to modest short-term improvement in glycemic control (not sustained beyond 3 months).
D'Aiuto et al (2013) (27)	Up to July 2012	RCT for meta-analysis	14 Studies: 32–160 participants per study	CVD	Periodontal disease	SRP or surgical treatment, tooth extraction, antibiotics	CVD risk factors	Biomarkers subject to methodological and environmental confounders	NA	Main consistent finding after periodontal therapy was a reduction of serum levels of CRP (stable measure of systemic inflammation) and an improvement of measures of endothelial function (which represents a surrogate marker of CVD).
Dietrich et al (2017) (28)	2005–2015	Systematic reviews and/or meta-analyses	22 Systematic reviews. 3–89 studies per systematic review of various types. Number of participants not reported	CVD	Oral health: periodontitis, caries, tooth loss	Oral health promotion, periodontal treatment	NA	NA	AMSTAR and PRISMA	High quality evidence of association between CVD and oral health. Mainly association between chronic periodontitis and atherosclerotic heart disease and is independent of confounding factors. No causal relationship has been established. Firm association between oral health (periodontitis, caries and tooth loss) and atherosclerotic cardiovascular disease, that is, coronary heart disease, stroke, and peripheral vascular disease. Little or no evidence to support any links between oral health and other forms of cardiovascular disease that are non-atherosclerotic such as HT, arrhythmias, and heart failure. Periodontal therapy is associated with reductions in surrogate markers of atherosclerotic CVD.
Faggion et al (2016) (29)	Up to March 2015	Systematic reviews with meta-analysis	11 Meta-analyses, original studies based on 12–514 patients	DM type 1 and T2DM	Periodontal disease	Periodontal treatment	HbA1c levels	NA	AMSTAR and OQAQ	SRs showing an average decrease of 0.46% (median, 0.40%) of HbA1c levels. These values, nevertheless, are not significant when meta-analyses of longer follow-ups (up to 6 mos) are evaluated. Furthermore, most primary studies included in those SRs had several methodological limitations.
Hasuike et al (2017) (30)	Up to July 2015	Systematic reviews with meta-analysis	9 Studies, 60–1,135 participants	DM type 1 and T2DM	Periodontal disease	Periodontal treatment with or without adjunctive use of local drug delivery and systemic antibiotics.	Changes in HbA1c	NA	AMSTAR	Significant effect of periodontal treatment on improvement of HbA1c levels in diabetes patients, although effect size is extremely small. In addition to this small effect size, the supporting evidence cannot be regarded as high quality.
Kelly et al (2013) (31)	Up to May 2012	Systematic reviews	13 Systematic reviews, 9 with meta-analyses. Not reported how many studies were included in each systematic review	Chronic heart disease	Periodontal disease	NA	Quality appraisal	NA	AMSTAR and Glenny et al (51)	Apart from analyzing the methodological and structural quality of the selected systematic reviews and meta-analyses, we did not attempt to perform any outcome analyses. There was substantial heterogeneity in the types of articles included in the 13 reviews, with varying study designs including cohort, cross-sectional, case-control, and RCTs.
Kothari et al (2017) (32)	Through January 2016	Observational studies, case-control studies, and 1 mixed-methods study	27 Studies; no information on number of participants per study	Acquired brain injury, including cerebrovascular diseases	Tooth loss, periodontal status, caries	Professional oral health care or oral hygiene instruction (in some studies)	NA	NA	NA	Currently low level of interest in topic. All included studies reported poor oral health in patients with brain injury. Studies also showed significant improvements in oral health if appropriate measures were implemented at rehabilitation settings. Stroke patients seemed to present with higher incidence of missing teeth and tooth mobility.
Lafon et al (2014) (33)	Up to April 2012	Cohort studies	9 Studies: 5 in North America, started during 1970–1980. Participants ranged from 1,137–51,529. Length of follow-up from 12–57 years	Stroke	Periodontal disease	NA	Periodontitis and tooth loss	NA	Evaluation grid	Results suggested a link between stroke and periodontal diseases. The association was significant for periodontitis and tooth loss. The risk of ischemic or hemorrhagic stroke was higher in people with periodontitis (estimated adjusted risk, 1.63 [1.25–2.00]). Tooth loss was also a significant risk factor for stroke (estimated adjusted risk, 1.39 [1.13–1.65]). In this review, gingivitis did not significantly influence the occurrence of stroke.
Lam et al (2011) (34)	NA	3 RCTs, 3 pre–post interventions, 1 split-mouth, 1 quasi-experimental	8 Studies, ranging from 6–303 patients	CVD	Oral health: periodontal health	Oral health instruction, extractions, periodontal treatment	Periodontal health and changes in systemic blood marker levels	NA	NA	Periodontal interventions were found to be capable of modifying numerous surrogate markers of cardiovascular outcomes including CRP, Ox-LDL, WBC, fibrinogen, IL-6, and endothelial dysfunction. It must be accepted, however, that neither a cause-and-effect relationship, nor the exact mechanism whereby periodontal disease may affect cardiovascular disease risk has been established. Whether the reduction of systemic inflammatory markers can truly decrease the risk of secondary cardiovascular events remains to be shown by studies of longer duration. Interventions aimed at improving periodontal parameters such as plaque and gingival bleeding were successful in patients with HT, CHD, and previous heart transplantation. Periodontal interventions were less successful at effecting changes in CsA-induced gingival overgrowth in heart transplantation patients. None of the effective articles included assessments on the effect of oral promotion interventions on oral microflora.
Leira et al (2017) (35)	Up to March 2015	3 cohort (retrospective and prospective), 5 case-control studies	8 Studies, 95–9,962 patients. Europe, North America, and Asia. Data collected between 1968 and 2012	Ischemic stroke (assessed as acute ischemic lesion on brain imaging and/or neurological deficit, TOAST and ICD)	Periodontitis (assessed with CAL, PPD, and radiographic bone loss)	NA	Risk of ischemic stroke	Most commonly adjusted vascular risk factors were: age, sex, DM, HT, smoking status, hypercholesterolemia, and BMI	GRADE	Suggested a positive association between ischemic stroke and prevalence of periodontitis. The risk of cerebral ischemia was higher in subjects with periodontitis (RR, 2.88 [95% CI, 1.53–5.41]).
Leng et al (2015) (36)	Up to May 2015	Prospective cohort studies	15 Studies enrolling 230–406 participants	Coronary heart disease	Periodontal disease	NA	CHD-related morbidity (fatal and nonfatal) or mortality, evaluated using relative risk or hazard ratio	Sex, BMI, smoking, age, family history of heart disease, education, blood pressure (most common confounders)	NA	Patients with periodontal disease were at a significantly increased risk of developing CHD (RR, 1.19; 95% CI, 1.13–1.26; P < .001). Subgroup analyses according to the effect measure, adjustment for confounding factors, median follow-up time, country of study origin, assessment method of periodontal disease, and sex all indicated significant associations between periodontal disease and CHD.
Li et al (2014) (37)	Up to April 2014	RCT and quasi-RCT	1 RCT, 303 participants	CVD	Chronic periodontitis	SRP and community care	Cardiovascular events	NA	Cochrane's RoB assessment tool, GRADE	The study recorded 12 cardiovascular events, but results were not significant. Also, serum high sensitivity CRP: who had high CRP, and adverse events all reported nonsignificant results. Because only 1 was study eligible for inclusion, which was also judged to be at high risk of bias, the results should be interpreted with caution.
Lira et al (2017) (38)	Up to September 2016	Clinical trials	12 Studies qualitative analysis; 8 meta-analyses, 30–70 patients per study	DM	Periodontal disease	Adjunctive use of systemic antibiotics in nonsurgical periodontal treatment, compared with nonsurgical periodontal treatment alone.	Changes in HbA1c	NA	Cochrane's RoB assessment tool	Shows no additional benefit of associating systemic antibiotics to nonsurgical periodontal treatment versus SRP alone in improving HbA1c levels 3–4 months after treatment.
Martin-Cabezas et al (2016) (39)	2000 to June 2016	Longitudinal studies or case-control studies and cross-sectional studies	25 Studies in review; 18 in meta-analysis: 20 cross-sectional, 3 case-control, and 2 longitudinal studies, across Asia, Europe, United States, and Africa. Ranging from 8,124–1,025,340 participants.	HT	Periodontal disease	NA	HT	Age, sex, smoking, BMI, binge drinking	NOS	Results from the present meta-analysis support the association between HT and periodontal diseases with a range of ORs from 1.15 to 1.67. Highest OR was calculated when severe form of periodontitis with secure diagnosis criteria was considered (OR, 1.64).
Mauri-Obradors et al (2017) (40)	1998 to January 2016	Primary studies	19 Studies: 4× longitudinal studies; 15× cross-sectional studies. A total of 3,712 patients, of whom 2,084 had diabetes.	DM type 1 and T2DM	Caries, periodontal disease, BMS, oral mucosa alterations	NA	Oral manifestations	NA	Recommendations made by OCEBM	DM leads to multiple complications, which increase when glycemic control of the patient is inadequate. The main oral complication attributed to diabetes is periodontal disease: considered the sixth complication of DM. Higher prevalence of periapical lesions in patients with poorly controlled diabetes. Information presented in the literature about the relationship between the DM and tooth decay is inconsistent.
Orlandi et al (2014) (41)	Through January 2014	Cross-sectional studies, case-control studies, population surveys, cohort studies, pilot studies, controlled trials, RCTs	35 Studies for systematic review, 22 studies for meta-analysis; 2,021 cases, 3,431 control	c-IMT; FMD	Periodontitis	Periodontal intervention	Increase in c-IMT. Effects of periodontal treatment on FMD.	CVD (age, sex, systolic blood pressure, HDL-C, smoking, diabetes, HT treatment, and total cholesterol). Athero-sclerosis	Newcastle-Ottawa Quality Assessment Scale	Diagnosis of PD was associated with a mean increase in c-IMT of 0.08 mm (95% CI, 0.07–0.09 mm) and a mean difference in FMD of 5.1% compared with controls (95% CI, 2.08%–8.11%). A meta-analysis of the effects of periodontal treatment on FMD showed a mean improvement of 6.64% between test and control (95% CI, 2.83%–10.44%). Periodontal disease is associated with greater subclinical atherosclerosis as assessed by increased c-IMT and an independent predictor of cardiovascular events in high-risk populations. There is evidence of an impaired FMD, which is restored by periodontal treatment in individuals having periodontal disease.
Sanchez et al (2017) (42)	NA	3 MA/SR of RCT, 1 MA/SR of RCT and single cohort studies, 1 SR of oral health promotion interventions, 1x SR of RCT/quasi-RCT, 1 MA/SR, 1 MA/SR of intervention trials, 1 MA of pilot trials, 1 MA/SR of intervention and nonintervention trials, SR of intervention trials; 2 SR, 1 LR, 1x pre–post mixed design, 1 pilot of an oral health program, 1 oral health guidelines for prenatal care, 1x best practice recommendations; 1 RCT, 1 pre–post test design, 1 pilot of an education program, 1 pre–post mixed design, 1 pilot of an oral health education model, 2 cross-sectional studies, 3 pilots of a screening tool, 1 best practice recommendations	34 Studies included from Australia, Europe, United States, France, Italy, United Kingdom, Turkey, Sweden, England	CVD	Periodontal disease	Periodontal treatment	CVD	NA	AMSTAR	Strong association between periodontal disease and CVD. Although a causal link has not been confirmed between periodontal disease and CVD, the general consensus is that cardiovascular patients need to be made aware of this association and its potential implications.
Schmitt et al (2015) (43)	Up to September 2014	RCTs: case-control studies, cross-sectional studies, prospective cohort pilot study	Studies included in qualitative synthesis = 10; studies included in quantitative synthesis =7; sample size in total 2,257 (range, 26–814)	Arterial stiffness	Periodontitis	Periodontal treatment	Primary outcome had to be the measure of arterial stiffness by means of pulse wave velocity assessment.	Age, sex, smoking, or diabetes	GRADE system	The present systematic review and meta-analysis support an association between severe periodontitis and increased pulse wave velocity. The measurement of arterial stiffness provides a cardiovascular marker of the cumulative impact of both known and unknown risk factors, which may include periodontitis.
Teeuw et al (2014) (44)	Up to June 2013	RCTs, CCTs	Studies included n = 20; cases in total n = 865 (11–212 patients per study)/control in total n = 657 (11–105 patients per study). Cases and control in total n = 1522.	Atherosclerosis	Periodontitis	Treatment of periodontitis	Clinical CVD parameters (ie, clinical event, such as angina pectoris, MI, stroke, death) and/or markers related to atherosclerosis and CVD risk, including markers of systemic inflammation and thrombosis, lipid and glucose metabolism, and vascular function.	Overweight and smoking	GRADE	PT reduces the risk for CVD by improving plasma levels of inflammatory (CRP, IL-6, TNF-a), thrombotic (fibrinogen), and metabolic (triglycerides, TC, HDL-C, HbA1c) markers and endothelial function. This improvement is sustained well more than 6 months after therapy, and it is greater in those individuals having both periodontitis and co-morbidities like CVD and/or DM. Our findings emphasize the effectiveness and need for periodontal diagnosis and periodontal therapy in atherosclerotic and diabetic individuals to improve their systemic health.
Tonsekar et al (2017) (45)	Up to April 2016	4x retrospective cohort, 3x prospective cohort, 1x case-control study nested in a longitudinal study	Studies included n = 8; 4,075 participants; number of participants 144 to 911; countries: United States, South Korea, France, Sweden.	Dementia	Periodontal disease, tooth loss	NA	Outcome measured was assessed by verified cognitive tests such as Mini-Mental State Examination: Delayed Word Recall and Digit Symbol Substitution Test.	Apolipoprotein E (ApoE) allele, considered a major genetic risk factor for Alzheimer disease and a possible confounding factor in the association between periodontitis and dementia.	Newcastle-Ottawa Scale	Association between subsequent dementia, periodontal disease and tooth loss was inconclusive.
Ungprasert et al (2017) (46)	Up to July 2016	Case-control or cohort study	Studies included n = 5; number of subjects (cases/comparators) 1) 115,365/115,365; 2) 1,358/70,020; 3) 100/100; 4) 50/121; 5) 60/45. The 5 studies included 312,584 subjects. Countries: Taiwan, United States, Greece, Norway, Italy.	Psoriasis	Periodontitis	NA	Periodontitis and risk of psoriasis	Confounders: smoking, obesity, and DM	Newcastle–Ottawa quality assessment scale	Patients with periodontitis have a significantly increased risk of psoriasis.
Xu et al (2017) (47)	Up to July 2016	6x cross-sectional, 12x case control, 4x cohort studies	Studies included n = 22; 129,630 participants; countries: United States, Sweden, Japan, India, Spain, Iran, China, Germany, Greece.	MI	Periodontal disease	NA	Periodontal disease (including pocket probing depth, attachment loss, bleeding on probing, plaque index, gingival index, X-ray, and microbiological results) and the risk of myocardial infarction	Risk factors including age, smoking, and diabetes are common in both PD and MI	Newcastle-Ottawa Scale	Significant association between periodontal disease and MI. Subgroup analyses also confirmed the elevated risk for MI in periodontal disease subjects.
Zeng, Leng et al (2016) (48)	Up to February 20, 2015	10x cross-sectional, 5x case control	Studies included n = 15; 17,330 participants; countries: United States, Sweden, Germany, Austria, Italy, Spain, Japan, Portugal, Poland, South Korea, China.	Carotid atherosclerosis	Periodontal disease	NA	Risk of carotid atherosclerosis as diagnosed by c-IMT (by ultrasound) or carotid plaque thickness (by panoramic radiographs)	Common risk factor: smoking; confounder: DM	NA	Periodontal disease was associated with carotid atherosclerosis, although available evidence is insufficient to confirm the causal relationship of periodontal disease and carotid atherosclerosis.
Zeng et al (2012) (49)	Up to January 10, 2012	Observational studies (cross-sectional, case-control, or cohort design)	Studies included n = 14; subjects (case/control): between 28/30 and 810/12,982. Countries: United States, Poland, Norway, Iran, China, India.	COPD	Periodontal disease	NA	Relationship between PD and COPD	NA	NA	Periodontal disease significantly increases the risk of COPD, with the increase being likely independent of conventional COPD risk factors. Dental plaque that contains bacteria may be responsible for COPD, therefore, good attention to teeth brushing and general oral hygiene care may reduce the risk of COPD.
Zeng, Xia et al (2016) (50)	Up to June 10, 2015	Cohort and nested case-control studies	Studies included n = 5; subjects: (lung cancer/sample): 1)191/11,328; 2)236/48,375; 3) 225/30,666; 4) 243/153,566; 5) 754/77,485. Countries: United States, Sweden, China.	Lung Cancer	Periodontal disease	NA	Risk of lung cancer in patients with periodontal disease	Smoking	NA	Periodontal disease is associated with a significant and increased risk of lung cancer.

Abbreviations: AMSTAR, Assessing the Methodological Quality of Systematic Reviews; aPDT, antimicrobial PhotoDynamic Therapy; BMI, body mass index; BMS, burning mouth syndrome; CAL, clinical attachment level (14); CAL, clinical attachment loss (29); CCT, controlled clinical trial; CHD, coronary heart disease; CI, confidence interval; c-IMT, carotid intima-media thickness; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; CsA, cyclosporin A; CVD, cardiovascular disease; DM, diabetes mellitus; FMD, flow-mediated dilation; GRADE Grading of Recommendations, Assessment, Development and Evaluations; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HT, hypertension; ICD, International Classification of Diseases; IL, interleukin; LT, laser therapy; MA, meta-analysis; MI, myocardial infarction; MORE, Methodological Evaluation of Observational Research; NA, not applicable; NOS, Newcastle-Ottowa Scale; OCEBM, Centre for Evidence-Based Medicine, Oxford; OQAQ, Overview Quality Assessment Questionnaire; PD, probing depth; PPD, probing pocket depth; PT, periodontal therapy; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; OR, odds ratio; Ox-LDL, oxidized low-density lipoprotein; RCT, randomized controlled trial; SR, systematic review; SRP, scaling and root planing; T2DM, type 2 diabetes mellitus; TC, total cholesterol; TOAST, Trial of Org 10172 in Acute Stroke Treatment; WBC, white blood cell.

Table 3. Number of Systematic Reviews Observing Disease Correlations, Systematic Umbrella Review of Correlation Between Prevalent Dental Conditions and Chronic Diseases, 1995–2017 ^a
Dental or Chronic Disease	Periodontitis	Tooth Loss	Dental Caries
Diabetes mellitus	46 (41/5)	1 (1/0)	4 (1/3)	51
Cardiovascular disease	33 (22/11)	6 (6/0)	2 (1/1)	41
Cerebrovascular disease	4 (0/4)	2 (0/2)	2 (0/2)	8
Chronic obstructive pulmonary disease	2 (0/2)	1 (0/1)	—	3
Dementia	1 (0/1)	1 (0/1)	—	2
Psoriasis	1 (0/1)	—	—	1
Lung cancer	1 (0/1)	—	—	1
Total	88	11	8	107

Abbreviation: — , not applicable.
^aThe first number in the parentheses indicates the number of systematic reviews included in the umbrella review; the second number indicates the number of reviews that were individually included in the systematic reviews.