PERIODONTAL DISEASE AND AGE-RELATED MACULAR DEGENERATION Results From the National Health and Nutrition Examination Survey III SUSHANT WAGLEY, AB,* KYLE V. MARRA, BS,† RAMA A. SALHI, MHS,* SHIVA GAUTAM, PHD,‡ RAFAEL CAMPO, MD,‡ PETER VEALE, DMD,§ JOHN VEALE, DMD, MPH,§ JORGE G. ARROYO, MD, MPH† Purpose: To study the association between periodontal disease (PD) and age-related macular degeneration (AMD). Methods: For this cross-sectional analysis, 8,208 adults aged 40 years or older with retinal photographs graded for AMD were used from the National Health and Nutrition Examination Survey III. National Health and Nutrition Examination Survey III standardized dental measurements of PD status (defined as loss of .3 mm of attachment between the gum and tooth in at least 10% of sites measured). Participants were stratified into 60 years or younger and older than 60 years of age groups. Association between PD and AMD was assessed while controlling for sex, race, education, poverty income ratio, smoking, hypertension, body mass index, cardiovascular disease, and C-reactive protein. Results: In this population, a total of 52.30% had PD, and the prevalence of AMD was 11.45%. Logistic regression model controlled for confounders and stratified by age 60 years or younger versus older than 60 years showed PD to be independently associated with an increased risk for AMD (odds ratio = 1.96, 95% confidence interval = 1.22–3.14, P = 0.006) for those aged 60 years or younger but not for subjects older than 60 years (odds ratio = 1.32, confidence interval = 0.93–1.90, P = 0.120). Conclusion: In this population-based study, PD is independently associated with AMD in those aged 60 years or younger. RETINA 35:982–988, 2015
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treatment options for AMD further emphasize the importance of managing risk factors in the aging population. Age-related macular degeneration has been shown to be associated with age,4 higher body mass index (BMI),5 race,4 cigarette smoking,6,7 hypertension,4 low antioxidant levels,8,9 and systemic inflammation.10,11 It has been suggested that age-associated changes and oxidative stress resulting in cellular damage act as the triggering factors in AMD.2 This cellular damage is further aggravated by the subsequent immune and inflammatory response. A chronic aberrant inflammatory response may result in the progression of AMD into advanced stages, resulting in severe decrease in vision.1 Periodontal disease (PD) is a common chronic infectious/inflammatory disease that peaks in prevalence in late middle age.12 Periodontal disease has
ge-related macular degeneration (AMD) is a major cause of irreversible vision loss in the elderly population,1,2 and the prevalence of AMD is projected to drastically increase because of the growing number of aging adults.3 Despite recent advances in our understanding of the pathophysiology behind AMD, the limited From the *College of Human Medicine, Michigan State University, East Lansing, Michigan; †Division of Ophthalmology, Beth Israel Deaconess Medical Center, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; ‡Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and §Veale and Veale Dentistry, Dartmouth, Massachusetts. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Jorge G. Arroyo, MD, MPH, Division of Ophthalmology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue CC-5, Boston, MA 02215; e-mail: jarroyo@ bidmc.harvard.edu
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already been shown to be independently associated with atherosclerotic vascular disease, with studies identifying oral pathogens and their components in atherosclerotic plaques.13 Similarly, oral pathogens have also been identified in neovascular membranes excised from patients with AMD.14 In PD, the accumulation of bacterial biofilm (dental plaque) adjacent to the gums results in damage to the periodontal tissue from bacterially induced inflammation.13 This loss of tissue results in the formation of periodontal pockets that allow for the introduction of pathogens and their biologically active components into the circulation, potentially leading to infection and systemic inflammation.15 It has been proposed that these sequences of events underlie the link between PD and atherosclerotic vascular disease.13 Atherosclerotic vascular disease and AMD share many common risk factors.16 Although there is evidence linking the association between atherosclerotic vascular disease and AMD, we do not understand the relationship between PD and AMD. Although there is emerging evidence about the association between PD and AMD,17 further studies are necessary. We hypothesized that infection and inflammation of gum tissue may play a role in the development of AMD. To test our hypothesis, we examined whether PD is independently associated with AMD in participants from the National Health and Nutrition Examination Survey 1988 to 1994 (NHANES III). Methods
Fig. 1. Selection guideline used to obtain the final 5,887 participants with PD and AMD.
Study Design This cross-sectional analysis was conducted using NHANES data, a study designed to provide health statistics on the U.S. population through interviews, physical examination, and ancillary testing. Details about the NHANES study design, sampling, and methodology have been extensively described elsewhere.18 For this analysis, we used the NHANES III survey, as it measured oral health status, inflammatory markers, and AMD across 6 years, from 1988 to 1994. Figure 1 outlines the selection guideline used to obtain the final 5,887 participants with PD and AMD who were included for analysis in this study. All NHANES protocols were reviewed and approved by the National Center for Health Statistics Ethics Board, and informed consent was collected from all participating subjects. This analysis of NHANES III data was reviewed and declared exempt by Institutional Review Board for Research Involving Human Subjects at the Beth Israel Deaconess Medical Center, and this study adhered to the Declaration of Helsinki.
Periodontal Examination All NHANES III periodontal examinations were conducted at the Mobile Examination Center by a licensed dentist trained in the use of epidemiological indices for oral health.19 Buccal and mesial-buccal aspects of each tooth from one randomly assigned upper quadrant and one randomly assigned lower quadrant were scored for loss of attachment. The maximum number of teeth that could be measured in each subject was 14. The parameter used for this study was the level of periodontal attachment, which was reported in millimeters (mm) and calculated by measuring the distance from the cementoenamel junction to the bottom of the sulcus. We used level of periodontal attachment for this analysis because while gingival bleeding and pocket depth reveal current disease activity, attachment loss provides a cumulative indication of loss of support from aggregate effects of pathologic factors.13 The National Institute of Dental and Craniofacial Research defines PD as loss of attachment .3 mm at least 1 site.20 Although a single site with
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.3 mm attachment loss would be considered pathological, in this study, PD was defined as .10% of sites with .3 mm of loss of attachment to increase the likelihood that we identify true pathology. Our more conservative definition of PD is adapted from a previously published study examining the association between PD and heart disease.21 Fundus Photographs, Grading, and Age-Related Macular Degeneration Detailed description of procedures used for retinal photographs have been described under the NHANES III protocol.19 Briefly, a retinal photograph of 1 randomly selected eye was taken at the Mobile Examination Center for adults aged 40 years and older. Ocular fundus photographs were then graded for AMD using standardized protocols as defined by the Wisconsin Age-Related Maculopathy Grading System. In NHANES III, those coded as having early AMD met at least 1 of the 3 following sets of conditions: 1) degeneration of retinal pigment epithelium and presence of hard drusen and/or presence of soft drusen, 2) hyperpigmentation and presence of hard drusen and/or presence of soft drusen, 3) presence of soft drusen with covering grid area greater than or equal to a circle of 95 mm in diameter. Those coded as having late AMD met at least 1 of the following conditions: 1) geographic atrophy, 2) subretinal hemorrhage, 3) subretinal fibrous scar, 4) sensory serous (subretinal) detachment.19,22 We combined early and late AMD (prevalence of 10.78 and 0.67%, respectively) to create a global variable “Any AMD” for this analysis because of the low prevalence of late AMD in the population. Covariables Established risk factors for AMD alongside demographic indicators were selected as covariates. Early signs of AMD may develop in patients in their middle age but is predominantly seen in the elderly. In our study, only subjects aged 40 years or older were used in the analysis. Demographic data included age, sex, race (white vs. non-white), education level (high school or greater vs. less than high school), and poverty index—measured as poverty income ratio (PIR). Behavioral data included smoking status (current or previous smoker vs. never smoked). Medical data consisted of information obtained from both a physical examination and a questionnaire. We included BMI, hypertension (yes vs. no) defined as systolic blood pressure of $140 mmHg or diastolic pressure of $90 mmHg or selfreported physician diagnosis of hypertension, and history of cardiovascular disease (CVD) that was
coded as a binary (yes vs. no) from combining self-reported physician diagnosis of myocardial infarction, stroke, and congestive heart failure. The medical examination portion of the NHANES survey also consisted of a laboratory section. Blood drawn at the Mobile Examination Center was analyzed for C-reactive protein (CRP), which has been previously shown to be associated with PD and AMD.23 Given the strong relationship between age and AMD, age was controlled for in our primary analysis of all of the patients in this study. As PD peaks in the late middle ages, we decided to stratify age into 2 groups: 60 years or younger versus older than 60 years as a secondary analysis of the data. The decision to divide age into two groups was also based on stratification patterns in the model that existed whether age was stratified as a binary or as deciles. Statistical Analysis Weighted statistical analysis was conducted because of the complex sampling design of NHANES III. Weighted means and distributions were estimated for selected variables using STATA (Stata Statistical Software: Release 12; StataCorp LP, College Station, TX) through t-test and chi-squared test procedures. Stratified univariate and multivariate logistic regressions were used to estimate the odds ratios (ORs). Multivariate regression models were stratified by age (60 years or younger vs. older than 60 years) and controlled for sex, race, education, PIR, smoking status, BMI, hypertension, CVD, and CRP. Results Overall, of the 8,208 participants with graded fundus photographs, 11.45% (940) were identified as having AMD—10.78% (885) early AMD and 0.67% (55) late AMD. To understand how the risk factors for AMD differed between age groups, distributions were age stratified to compare participants 60 years or younger with those older than 60 years. In participants aged 60 years or younger, only 5.31% had fundoscopic findings consistent with AMD, whereas 18.32% of those older than 60 years in age were found to have AMD. The majority of subjects (68.25%) older than 60 years and only 42.08% of subjects aged 60 years or younger met our criteria for PD. Table 1 presents the baseline characteristics of the study population by age, unadjusted for other variables. The overall multivariate model controlled for sex, race, education, PIR, smoking, hypertension, BMI, CVD, and CRP. In this model, PD was significantly associated with an increased risk for “Any AMD” with
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Table 1. Characteristics of NHANES III Participants Stratified by Age Age Characteristic AMD Yes No Sex Female Male Race White Non-white Education Less than high school High school or higher Smoking status Current or past smoker Never smoked Hypertension Yes No CVD Yes No PD Yes No Mean (SD) PIR BMI, kg/m2 CRP, mg/L
#60 years (n = 4,432)
.60 years (n = 3,876)
Total (n = 8,208)
230 (5.31) 4,102 (94.69)
710 (18.32) 3,166 (81.68)
940 (11.45) 7,268 (88.55)
2,291 (52.89) 2,041 (47.11)
1,984 (51.19) 1,892 (48.81)
4,275 (52.08) 3,933 (47.92)
2,885 (66.60) 1,147 (33.40)
3,036 (78.35) 839 (21.65)
5,921 (72.15) 2,286 (27.85)
1,566 (36.38) 2,738 (63.62)
2,123 (55.13) 1,728 (44.87)
3,689 (45.24) 4,466 (54.76)
2,503 (57.78) 1,829 (42.22)
2,079 (53.64) 1,797 (46.36)
4,582 (55.82) 3,626 (44.18)
948 (22.07) 3,348 (77.93)
1,938 (50.00) 1,938 (50.00)
2,886 (30.19) 5,286 (69.81)
192 (4.43) 4,140 (95.57)
593 (15.30) 3,283 (84.70)
785 (9.56) 7,423 (90.44)
1,510 (42.08) 2,078 (57.92)
1,569 (68.25) 730 (31.75)
3,079 (52.30) 2,808 (47.70)
2.84 (1.93) 28.31 (6.01) 4.9 (8.3)
2.43 (1.79) 27.06 (5.14) 5.7 (9.9)
Cardiovascular disease includes myocardial infarction, stroke, and congestive heart failure. Values are presented as n (%).
an OR = 2.00 (95% confidence interval = 1.43–2.77, P , 0.001). This significant was lost once age was added to the model as a continuous variable (OR = 1.36, 95% confidence interval = 0.98–1.90, P = 0.065). However, in the age-stratified multivariate regression model adjusted for sex, race, education, PIR, smoking, hypertension, BMI, CVD, and CRP, PD showed significance in the younger age group compared with the older age group. In the agestratified model, PD was significantly associated with AMD in the 60 years or younger age group (OR = 1.96, 95% confidence interval = 1.22–3.14, P = 0.006) but not in the .60 years age group (OR = 1.32, confidence interval = 0.93–1.90, P = 0.120). Table 2 summarizes these findings. Discussion In this study, NHANES participants who were 60 years or younger and those who met our definition of PD were almost 2 times as likely to have any AMD compared with those who did not have PD, after
controlling for sex, race, education, PIR, smoking, hypertension, BMI, CVD, and CRP. There has been limited work examining the association between oral health and AMD. One study by Brzozowska and Puchalska-Neidbal reported on 56 persons with AMD. The authors noted that most of the 56 persons had lesions in the oral cavity, with the majority of these lesions in the periodontium. This study’s small sample size and inability to control
Table 2. Association of Any AMD With PD
PD—overall* PD stratified by age† #60 years .60 years
OR (95% CI)
P
1.36 (0.98–1.90)
0.065
1.96 (1.22–3.14) 1.32 (0.93–1.90)
0.006 0.120
*Overall analysis adjusted for age, sex, race, poverty income ratio, smoking, hypertension, BMI, CVD. †Age-stratified analysis adjusted for sex, race, poverty income ratio, smoking, hypertension, BMI, CVD. CI, confidence interval.
education, CRP, and education, CRP, and
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possible cofounders limited the conclusiveness of its findings.24 Karesvuo et al have also reported on the relationship between oral health parameters and AMD. Using a population-based survey in Finland, they noted an independent relationship between alveolar bone loss and AMD. However, they identified a significant association between AMD and PD, as measured by alveolar bone loss analyzed from radiographic findings, only in males. Our study differs from the one conducted by Karesvuo et al in many ways. One important difference is that we quantified AMD through graded retinal photographs obtained during the NHANES examination, whereas Karesvuo et al used self-reported “degenerative fundus changes” to identify and quantify AMD. Furthermore, we used a larger sample size compared with the study from Finland, 5,887 versus 1,751, respectively.17 Periodontal disease is a complex infectious/inflammatory disease resulting in the loss of connective tissue and bone support.25 Periodontal infections can cause molecular mimicry between foreign and selfpeptides to produce cross activation of autoreactive B cells and T cells that can lead to tissue pathology or autoimmunity in atherosclerotic vascular disease.26 Similar molecular mimicry mechanisms have been proposed as a potential initial event triggering an immune response that leads to an inflammatory response, which may play a part in the pathogenesis of AMD.27 Findings from this study support this hypothesis linking PD with AMD in certain age groups. The proposal of an infectious mechanism for AMD is further supported by the fact that periodontal pockets place bacterial biofilm in proximity to the circulation15 and regularly introduce pathogens into the circulation. Some of these organisms have been identified in human atheromatous plaques suggesting that they may play a role in the pathophysiology of atherosclerotic vascular disease.13 Similarly, Chlamydia pneumoniae has been identified in excised human choroidal neovascular membranes from patients with wet AMD.14 It is not known how many other microorganisms of the 500+ that constitute our oral flora may also be spread endogenously. Each of these potential organisms has unique pathogenassociated molecular patterns that are known to activate the lytic and opsonic complement pathways. Although it is conceivable that endogenously spread oral pathogens may be “innocent bystanders” in AMD, an infectious mechanism of action in the pathophysiology of AMD is plausible and may potentially explain the independent association between PD and AMD. Changes in the oral flora may be a factor exacerbating the rise in PD. The “normal” human oral flora
has changed significantly with the incorporation of highly refined carbohydrates into the Western diet. The microbiome of western oral flora is significantly more diverse and virulent than that of indigenous, hunter-gatherer, Amerindian tribes.28 These changes in our oral flora may also play a role in local PD as well as systemic inflammation and disease processes related to atherosclerotic vascular disease and AMD. In addition to the changes in oral flora, it is also important to note the effects of diet on PD and AMD. There is emerging evidence showing how certain dietary patterns may be associated with increased risk for AMD. Chiu et al29 report that an Oriental pattern, characterized by a higher consumption of vegetables, legumes, fruit, whole grains, etc., is independently associated with lower odds of AMD than a Western pattern, characterized by higher intake of red meat, processed meat, refined grains, etc. Similarly, certain dietary patterns have been shown to be associated with improved overall oral health.30 In both diseases, evidence points to the role of macronutrients and micronutrients that modulate proinflammatory and antiinflammatory cascades in mediating the progression of disease.31,32 Residual confounding is a concern with any epidemiological study.23 We addressed this by controlling for known AMD risk factors. For example, smokinginduced oxidative stress can potentially activate inflammatory responses.33 Similarly, already present CVD can also cause a patient to have an elevated inflammatory state. In our model, PD was still significantly associated with AMD in those aged 60 years of younger even after controlling for smoking, CVD, and CRP. This significant association was lost in with those older than 60 years. The loss of a significant association between PD and AMD at ages older than 60 years may be due to an increasing influence from the covariates with age that dilutes the effect of PD on AMD. Previous studies on the association between PD and CVD have reported similar trends showing a more prominent risk for PD in younger populations.34,35 It should be noted that a previous study by Klein et al36 using NHANES III data reported a 9.4% prevalence rate of AMD, as compared with this study’s higher prevalence of 11.45%. Where the study by Klein et al only excluded retinal images marked as ungradable, our study eliminated all participants coded as blank in addition to those with ungradable fundus photographs in the NHANES III. An important limitation of this study was our inability to analyze participants’ genetic information, specifically the complement factor H gene. Mutations in the CFH gene are known to inhibit regulation of the complement system and independently increase the risk for AMD. Furthermore, recall bias may be
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applicable in some variables that relied on selfreporting to measure history of disease. Because of inadequate power, subgroup analysis for early and late AMD was not possible. As is always the case with epidemiologic studies in general, there may exist other confounding variables that were not controlled for in this study, which may also play a role in the development of AMD. Nevertheless, we find a significant association between PD and AMD for those subjects aged 60 years or younger after controlling for many of the currently known risk factors for AMD. Finally, because of the cross-sectional nature of this study, causality between PD and AMD cannot be proven. However, there are strengths in our study, including a large sample size, standardized data collection through the NHANES protocol, standardized AMD detection and grading protocol, standardized oral health measurements from epidemiologically trained dental professionals, and the generalizability of the study to the U.S. population. An understanding of the influence of oral health on AMD may aid in limiting the disease’s visual manifestations in the growing elderly population. Improving oral care to reduce PD warrants further study, as PD prevention may also lead to reduced risk for other age-related diseases. These preliminary results lay the important foundation for further research examining the relationship between PD and AMD. Key words: periodontal disease, age-related macular degeneration, oral health. Acknowledgments The authors acknowledge the Grimshaw-Gudewicz Charitable Foundation for their continued support of our clinic’s success in patient care and research. References 1. Jager RD, Mieler WF, Miller JW. Age-Related macular degeneration. N Engl J Med 2008;358:2606–2617. 2. Arroyo JG. A 76-year-old man with macular degeneration. JAMA 2006;295:2394–2406. 3. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564–572. 4. Age-Related Eye Disease Study Research G. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: age-Related Eye Disease Study Report Number 3. Ophthalmology 2000;107: 2224–2232. 5. Seddon JM, Cote J, Davis N, et al. Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio. Arch Ophthalmol 2003; 121:785–792.
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6. Tan JS, Mitchell P, Kifley A, et al. Smoking and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Arch Ophthalmol 2007;125:1089–1095. 7. Klein R, Knudtson MD, Cruickshanks KJ, et al. Further observations on the association between smoking and the long-term incidence and progression of age-related macular degeneration: the Beaver Dam Eye Study. Arch Ophthalmol 2008;126:115–121. 8. van Leeuwen R, Boekhoorn S, Vingerling JR, et al. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA 2005;294:3101–3107. 9. Age-Related Eye Disease Study Research G. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119:1417–1436. 10. Seddon JM, George S, Rosner B, et al. Progression of agerelated macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers. Arch Ophthalmol 2005;123:774–782. 11. Shankar A, Mitchell P, Rochtchina E, et al. Association between circulating white blood cell count and long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Am J Epidemiol 2007;165:375–382. 12. Eke PI, Dye BA, Wei L, et al. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res 2012; 91:914–920. 13. Lockhart PB, Bolger AF, Papapanou PN, et al. Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association?: a scientific statement from the American Heart Association. Circulation 2012;125: 2520–2544. 14. Kalayoglu MV, Bula D, Arroyo J, et al. Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2005;243:1080–1090. 15. Hujoel PP, White BA, Garcia RI, et al. The dentogingival epithelial surface area revisited. J Periodontal Res 2001;36: 48–55. 16. Snow KK, Seddon JM. Do age-related macular degeneration and cardiovascular disease share common antecedents? Ophthalmic Epidemiol 1999;6:125–143. 17. Karesvuo P, Gursoy UK, Pussinen PJ, et al. Alveolar bone loss associated with age-related macular degeneration in males. J Periodontol 2013;84:58–67. 18. Ezzati TM, Massey JT, Waksberg J, et al. Sample design: Third National Health and Nutrition Examination Survey. Vital Health Stat 2 1992:1–35. 19. (CDC). CfDCaP. National Health and Nutrition Examination Survey Data Examination File. Hyattsville, MD: Department of Health and Human Services; 1996. 20. Periodontal (Gum) Disease. National Institute of Dental and Craniofacial Research. Bethesda, MD. 2013. 21. Elter JR, Champagne CM, Offenbacher S, et al. Relationship of periodontal disease and tooth loss to prevalence of coronary heart disease. J Periodontol 2004;75:782–790. 22. Klein R, Davis MD, Magli YL, et al. The Wisconsin agerelated maculopathy grading system. Ophthalmology 1991; 98:1128–1134. 23. Seddon JM, Gensler G, Milton RC, et al. Association between C-reactive protein and age-related macular degeneration. JAMA 2004;291:704–710.
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24. Brzozowska A, Puchalska-Niedbal L. Oral status as a potential source of infection in AMD patients–introduction [in Polish]. Klin Oczna 2012;114:29–32. 25. Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet 2005;366:1809–1820. 26. Kohm AP, Fuller KG, Miller SD. Mimicking the way to autoimmunity: an evolving theory of sequence and structural homology. Trends Microbiol 2003;11:101–105. 27. Donoso LA, Vrabec T, Kuivaniemi H. The role of complement Factor H in age-related macular degeneration: a review. Surv Ophthalmol 2010;55:227–246. 28. Contreras M, Costello EK, Hidalgo G, et al. The bacterial microbiota in the oral mucosa of rural Amerindians. Microbiology 2010;156:3282–3287. 29. Chiu CJ, Chang ML, Zhang FF, et al. The relationship of major american dietary patterns to age-related macular degeneration. Am J Ophthalmol 2014;158:118–127.e111. 30. Staufenbiel I, Weinspach K, Forster G, et al. Periodontal conditions in vegetarians: a clinical study. Eur J Clin Nutr 2013; 67:836–840.
31. Chapple IL. Potential mechanisms underpinning the nutritional modulation of periodontal inflammation. J Am Dent Assoc 2009;140:178–184. 32. Chew EY, Clemons TE, Agron E, et al. Long-term effects of vitamins C and E, beta-carotene, and zinc on age-related macular degeneration: AREDS report no. 35. Ophthalmology 2013;120:1604–1611.e1604. 33. Seddon JM, Willett WC, Speizer FE, et al. A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996;276:1141–1146. 34. Janket SJ, Baird AE, Chuang SK, et al. Meta-analysis of periodontal disease and risk of coronary heart disease and stroke. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95: 559–569. 35. DeStefano F, Anda RF, Kahn HS, et al. Dental disease and risk of coronary heart disease and mortality. BMJ 1993;306: 688–691. 36. Klein R, Chou CF, Klein BE, et al. Prevalence of age-related macular degeneration in the US population. Arch Ophthalmol 2011;129:75–80.
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treatment options for AMD further emphasize the importance of managing risk factors in the aging population. Age-related macular degeneration has been shown to be associated with age,4 higher body mass index (BMI),5 race,4 cigarette smoking,6,7 hypertension,4 low antioxidant levels,8,9 and systemic inflammation.10,11 It has been suggested that age-associated changes and oxidative stress resulting in cellular damage act as the triggering factors in AMD.2 This cellular damage is further aggravated by the subsequent immune and inflammatory response. A chronic aberrant inflammatory response may result in the progression of AMD into advanced stages, resulting in severe decrease in vision.1 Periodontal disease (PD) is a common chronic infectious/inflammatory disease that peaks in prevalence in late middle age.12 Periodontal disease has
ge-related macular degeneration (AMD) is a major cause of irreversible vision loss in the elderly population,1,2 and the prevalence of AMD is projected to drastically increase because of the growing number of aging adults.3 Despite recent advances in our understanding of the pathophysiology behind AMD, the limited From the *College of Human Medicine, Michigan State University, East Lansing, Michigan; †Division of Ophthalmology, Beth Israel Deaconess Medical Center, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; ‡Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and §Veale and Veale Dentistry, Dartmouth, Massachusetts. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Jorge G. Arroyo, MD, MPH, Division of Ophthalmology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue CC-5, Boston, MA 02215; e-mail: jarroyo@ bidmc.harvard.edu
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already been shown to be independently associated with atherosclerotic vascular disease, with studies identifying oral pathogens and their components in atherosclerotic plaques.13 Similarly, oral pathogens have also been identified in neovascular membranes excised from patients with AMD.14 In PD, the accumulation of bacterial biofilm (dental plaque) adjacent to the gums results in damage to the periodontal tissue from bacterially induced inflammation.13 This loss of tissue results in the formation of periodontal pockets that allow for the introduction of pathogens and their biologically active components into the circulation, potentially leading to infection and systemic inflammation.15 It has been proposed that these sequences of events underlie the link between PD and atherosclerotic vascular disease.13 Atherosclerotic vascular disease and AMD share many common risk factors.16 Although there is evidence linking the association between atherosclerotic vascular disease and AMD, we do not understand the relationship between PD and AMD. Although there is emerging evidence about the association between PD and AMD,17 further studies are necessary. We hypothesized that infection and inflammation of gum tissue may play a role in the development of AMD. To test our hypothesis, we examined whether PD is independently associated with AMD in participants from the National Health and Nutrition Examination Survey 1988 to 1994 (NHANES III). Methods
Fig. 1. Selection guideline used to obtain the final 5,887 participants with PD and AMD.
Study Design This cross-sectional analysis was conducted using NHANES data, a study designed to provide health statistics on the U.S. population through interviews, physical examination, and ancillary testing. Details about the NHANES study design, sampling, and methodology have been extensively described elsewhere.18 For this analysis, we used the NHANES III survey, as it measured oral health status, inflammatory markers, and AMD across 6 years, from 1988 to 1994. Figure 1 outlines the selection guideline used to obtain the final 5,887 participants with PD and AMD who were included for analysis in this study. All NHANES protocols were reviewed and approved by the National Center for Health Statistics Ethics Board, and informed consent was collected from all participating subjects. This analysis of NHANES III data was reviewed and declared exempt by Institutional Review Board for Research Involving Human Subjects at the Beth Israel Deaconess Medical Center, and this study adhered to the Declaration of Helsinki.
Periodontal Examination All NHANES III periodontal examinations were conducted at the Mobile Examination Center by a licensed dentist trained in the use of epidemiological indices for oral health.19 Buccal and mesial-buccal aspects of each tooth from one randomly assigned upper quadrant and one randomly assigned lower quadrant were scored for loss of attachment. The maximum number of teeth that could be measured in each subject was 14. The parameter used for this study was the level of periodontal attachment, which was reported in millimeters (mm) and calculated by measuring the distance from the cementoenamel junction to the bottom of the sulcus. We used level of periodontal attachment for this analysis because while gingival bleeding and pocket depth reveal current disease activity, attachment loss provides a cumulative indication of loss of support from aggregate effects of pathologic factors.13 The National Institute of Dental and Craniofacial Research defines PD as loss of attachment .3 mm at least 1 site.20 Although a single site with
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.3 mm attachment loss would be considered pathological, in this study, PD was defined as .10% of sites with .3 mm of loss of attachment to increase the likelihood that we identify true pathology. Our more conservative definition of PD is adapted from a previously published study examining the association between PD and heart disease.21 Fundus Photographs, Grading, and Age-Related Macular Degeneration Detailed description of procedures used for retinal photographs have been described under the NHANES III protocol.19 Briefly, a retinal photograph of 1 randomly selected eye was taken at the Mobile Examination Center for adults aged 40 years and older. Ocular fundus photographs were then graded for AMD using standardized protocols as defined by the Wisconsin Age-Related Maculopathy Grading System. In NHANES III, those coded as having early AMD met at least 1 of the 3 following sets of conditions: 1) degeneration of retinal pigment epithelium and presence of hard drusen and/or presence of soft drusen, 2) hyperpigmentation and presence of hard drusen and/or presence of soft drusen, 3) presence of soft drusen with covering grid area greater than or equal to a circle of 95 mm in diameter. Those coded as having late AMD met at least 1 of the following conditions: 1) geographic atrophy, 2) subretinal hemorrhage, 3) subretinal fibrous scar, 4) sensory serous (subretinal) detachment.19,22 We combined early and late AMD (prevalence of 10.78 and 0.67%, respectively) to create a global variable “Any AMD” for this analysis because of the low prevalence of late AMD in the population. Covariables Established risk factors for AMD alongside demographic indicators were selected as covariates. Early signs of AMD may develop in patients in their middle age but is predominantly seen in the elderly. In our study, only subjects aged 40 years or older were used in the analysis. Demographic data included age, sex, race (white vs. non-white), education level (high school or greater vs. less than high school), and poverty index—measured as poverty income ratio (PIR). Behavioral data included smoking status (current or previous smoker vs. never smoked). Medical data consisted of information obtained from both a physical examination and a questionnaire. We included BMI, hypertension (yes vs. no) defined as systolic blood pressure of $140 mmHg or diastolic pressure of $90 mmHg or selfreported physician diagnosis of hypertension, and history of cardiovascular disease (CVD) that was
coded as a binary (yes vs. no) from combining self-reported physician diagnosis of myocardial infarction, stroke, and congestive heart failure. The medical examination portion of the NHANES survey also consisted of a laboratory section. Blood drawn at the Mobile Examination Center was analyzed for C-reactive protein (CRP), which has been previously shown to be associated with PD and AMD.23 Given the strong relationship between age and AMD, age was controlled for in our primary analysis of all of the patients in this study. As PD peaks in the late middle ages, we decided to stratify age into 2 groups: 60 years or younger versus older than 60 years as a secondary analysis of the data. The decision to divide age into two groups was also based on stratification patterns in the model that existed whether age was stratified as a binary or as deciles. Statistical Analysis Weighted statistical analysis was conducted because of the complex sampling design of NHANES III. Weighted means and distributions were estimated for selected variables using STATA (Stata Statistical Software: Release 12; StataCorp LP, College Station, TX) through t-test and chi-squared test procedures. Stratified univariate and multivariate logistic regressions were used to estimate the odds ratios (ORs). Multivariate regression models were stratified by age (60 years or younger vs. older than 60 years) and controlled for sex, race, education, PIR, smoking status, BMI, hypertension, CVD, and CRP. Results Overall, of the 8,208 participants with graded fundus photographs, 11.45% (940) were identified as having AMD—10.78% (885) early AMD and 0.67% (55) late AMD. To understand how the risk factors for AMD differed between age groups, distributions were age stratified to compare participants 60 years or younger with those older than 60 years. In participants aged 60 years or younger, only 5.31% had fundoscopic findings consistent with AMD, whereas 18.32% of those older than 60 years in age were found to have AMD. The majority of subjects (68.25%) older than 60 years and only 42.08% of subjects aged 60 years or younger met our criteria for PD. Table 1 presents the baseline characteristics of the study population by age, unadjusted for other variables. The overall multivariate model controlled for sex, race, education, PIR, smoking, hypertension, BMI, CVD, and CRP. In this model, PD was significantly associated with an increased risk for “Any AMD” with
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Table 1. Characteristics of NHANES III Participants Stratified by Age Age Characteristic AMD Yes No Sex Female Male Race White Non-white Education Less than high school High school or higher Smoking status Current or past smoker Never smoked Hypertension Yes No CVD Yes No PD Yes No Mean (SD) PIR BMI, kg/m2 CRP, mg/L
#60 years (n = 4,432)
.60 years (n = 3,876)
Total (n = 8,208)
230 (5.31) 4,102 (94.69)
710 (18.32) 3,166 (81.68)
940 (11.45) 7,268 (88.55)
2,291 (52.89) 2,041 (47.11)
1,984 (51.19) 1,892 (48.81)
4,275 (52.08) 3,933 (47.92)
2,885 (66.60) 1,147 (33.40)
3,036 (78.35) 839 (21.65)
5,921 (72.15) 2,286 (27.85)
1,566 (36.38) 2,738 (63.62)
2,123 (55.13) 1,728 (44.87)
3,689 (45.24) 4,466 (54.76)
2,503 (57.78) 1,829 (42.22)
2,079 (53.64) 1,797 (46.36)
4,582 (55.82) 3,626 (44.18)
948 (22.07) 3,348 (77.93)
1,938 (50.00) 1,938 (50.00)
2,886 (30.19) 5,286 (69.81)
192 (4.43) 4,140 (95.57)
593 (15.30) 3,283 (84.70)
785 (9.56) 7,423 (90.44)
1,510 (42.08) 2,078 (57.92)
1,569 (68.25) 730 (31.75)
3,079 (52.30) 2,808 (47.70)
2.84 (1.93) 28.31 (6.01) 4.9 (8.3)
2.43 (1.79) 27.06 (5.14) 5.7 (9.9)
Cardiovascular disease includes myocardial infarction, stroke, and congestive heart failure. Values are presented as n (%).
an OR = 2.00 (95% confidence interval = 1.43–2.77, P , 0.001). This significant was lost once age was added to the model as a continuous variable (OR = 1.36, 95% confidence interval = 0.98–1.90, P = 0.065). However, in the age-stratified multivariate regression model adjusted for sex, race, education, PIR, smoking, hypertension, BMI, CVD, and CRP, PD showed significance in the younger age group compared with the older age group. In the agestratified model, PD was significantly associated with AMD in the 60 years or younger age group (OR = 1.96, 95% confidence interval = 1.22–3.14, P = 0.006) but not in the .60 years age group (OR = 1.32, confidence interval = 0.93–1.90, P = 0.120). Table 2 summarizes these findings. Discussion In this study, NHANES participants who were 60 years or younger and those who met our definition of PD were almost 2 times as likely to have any AMD compared with those who did not have PD, after
controlling for sex, race, education, PIR, smoking, hypertension, BMI, CVD, and CRP. There has been limited work examining the association between oral health and AMD. One study by Brzozowska and Puchalska-Neidbal reported on 56 persons with AMD. The authors noted that most of the 56 persons had lesions in the oral cavity, with the majority of these lesions in the periodontium. This study’s small sample size and inability to control
Table 2. Association of Any AMD With PD
PD—overall* PD stratified by age† #60 years .60 years
OR (95% CI)
P
1.36 (0.98–1.90)
0.065
1.96 (1.22–3.14) 1.32 (0.93–1.90)
0.006 0.120
*Overall analysis adjusted for age, sex, race, poverty income ratio, smoking, hypertension, BMI, CVD. †Age-stratified analysis adjusted for sex, race, poverty income ratio, smoking, hypertension, BMI, CVD. CI, confidence interval.
education, CRP, and education, CRP, and
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possible cofounders limited the conclusiveness of its findings.24 Karesvuo et al have also reported on the relationship between oral health parameters and AMD. Using a population-based survey in Finland, they noted an independent relationship between alveolar bone loss and AMD. However, they identified a significant association between AMD and PD, as measured by alveolar bone loss analyzed from radiographic findings, only in males. Our study differs from the one conducted by Karesvuo et al in many ways. One important difference is that we quantified AMD through graded retinal photographs obtained during the NHANES examination, whereas Karesvuo et al used self-reported “degenerative fundus changes” to identify and quantify AMD. Furthermore, we used a larger sample size compared with the study from Finland, 5,887 versus 1,751, respectively.17 Periodontal disease is a complex infectious/inflammatory disease resulting in the loss of connective tissue and bone support.25 Periodontal infections can cause molecular mimicry between foreign and selfpeptides to produce cross activation of autoreactive B cells and T cells that can lead to tissue pathology or autoimmunity in atherosclerotic vascular disease.26 Similar molecular mimicry mechanisms have been proposed as a potential initial event triggering an immune response that leads to an inflammatory response, which may play a part in the pathogenesis of AMD.27 Findings from this study support this hypothesis linking PD with AMD in certain age groups. The proposal of an infectious mechanism for AMD is further supported by the fact that periodontal pockets place bacterial biofilm in proximity to the circulation15 and regularly introduce pathogens into the circulation. Some of these organisms have been identified in human atheromatous plaques suggesting that they may play a role in the pathophysiology of atherosclerotic vascular disease.13 Similarly, Chlamydia pneumoniae has been identified in excised human choroidal neovascular membranes from patients with wet AMD.14 It is not known how many other microorganisms of the 500+ that constitute our oral flora may also be spread endogenously. Each of these potential organisms has unique pathogenassociated molecular patterns that are known to activate the lytic and opsonic complement pathways. Although it is conceivable that endogenously spread oral pathogens may be “innocent bystanders” in AMD, an infectious mechanism of action in the pathophysiology of AMD is plausible and may potentially explain the independent association between PD and AMD. Changes in the oral flora may be a factor exacerbating the rise in PD. The “normal” human oral flora
has changed significantly with the incorporation of highly refined carbohydrates into the Western diet. The microbiome of western oral flora is significantly more diverse and virulent than that of indigenous, hunter-gatherer, Amerindian tribes.28 These changes in our oral flora may also play a role in local PD as well as systemic inflammation and disease processes related to atherosclerotic vascular disease and AMD. In addition to the changes in oral flora, it is also important to note the effects of diet on PD and AMD. There is emerging evidence showing how certain dietary patterns may be associated with increased risk for AMD. Chiu et al29 report that an Oriental pattern, characterized by a higher consumption of vegetables, legumes, fruit, whole grains, etc., is independently associated with lower odds of AMD than a Western pattern, characterized by higher intake of red meat, processed meat, refined grains, etc. Similarly, certain dietary patterns have been shown to be associated with improved overall oral health.30 In both diseases, evidence points to the role of macronutrients and micronutrients that modulate proinflammatory and antiinflammatory cascades in mediating the progression of disease.31,32 Residual confounding is a concern with any epidemiological study.23 We addressed this by controlling for known AMD risk factors. For example, smokinginduced oxidative stress can potentially activate inflammatory responses.33 Similarly, already present CVD can also cause a patient to have an elevated inflammatory state. In our model, PD was still significantly associated with AMD in those aged 60 years of younger even after controlling for smoking, CVD, and CRP. This significant association was lost in with those older than 60 years. The loss of a significant association between PD and AMD at ages older than 60 years may be due to an increasing influence from the covariates with age that dilutes the effect of PD on AMD. Previous studies on the association between PD and CVD have reported similar trends showing a more prominent risk for PD in younger populations.34,35 It should be noted that a previous study by Klein et al36 using NHANES III data reported a 9.4% prevalence rate of AMD, as compared with this study’s higher prevalence of 11.45%. Where the study by Klein et al only excluded retinal images marked as ungradable, our study eliminated all participants coded as blank in addition to those with ungradable fundus photographs in the NHANES III. An important limitation of this study was our inability to analyze participants’ genetic information, specifically the complement factor H gene. Mutations in the CFH gene are known to inhibit regulation of the complement system and independently increase the risk for AMD. Furthermore, recall bias may be
GUM DISEASE AND MACULAR DEGENERATION WAGLEY ET AL
applicable in some variables that relied on selfreporting to measure history of disease. Because of inadequate power, subgroup analysis for early and late AMD was not possible. As is always the case with epidemiologic studies in general, there may exist other confounding variables that were not controlled for in this study, which may also play a role in the development of AMD. Nevertheless, we find a significant association between PD and AMD for those subjects aged 60 years or younger after controlling for many of the currently known risk factors for AMD. Finally, because of the cross-sectional nature of this study, causality between PD and AMD cannot be proven. However, there are strengths in our study, including a large sample size, standardized data collection through the NHANES protocol, standardized AMD detection and grading protocol, standardized oral health measurements from epidemiologically trained dental professionals, and the generalizability of the study to the U.S. population. An understanding of the influence of oral health on AMD may aid in limiting the disease’s visual manifestations in the growing elderly population. Improving oral care to reduce PD warrants further study, as PD prevention may also lead to reduced risk for other age-related diseases. These preliminary results lay the important foundation for further research examining the relationship between PD and AMD. Key words: periodontal disease, age-related macular degeneration, oral health. Acknowledgments The authors acknowledge the Grimshaw-Gudewicz Charitable Foundation for their continued support of our clinic’s success in patient care and research. References 1. Jager RD, Mieler WF, Miller JW. Age-Related macular degeneration. N Engl J Med 2008;358:2606–2617. 2. Arroyo JG. A 76-year-old man with macular degeneration. JAMA 2006;295:2394–2406. 3. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564–572. 4. Age-Related Eye Disease Study Research G. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: age-Related Eye Disease Study Report Number 3. Ophthalmology 2000;107: 2224–2232. 5. Seddon JM, Cote J, Davis N, et al. Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio. Arch Ophthalmol 2003; 121:785–792.
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6. Tan JS, Mitchell P, Kifley A, et al. Smoking and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Arch Ophthalmol 2007;125:1089–1095. 7. Klein R, Knudtson MD, Cruickshanks KJ, et al. Further observations on the association between smoking and the long-term incidence and progression of age-related macular degeneration: the Beaver Dam Eye Study. Arch Ophthalmol 2008;126:115–121. 8. van Leeuwen R, Boekhoorn S, Vingerling JR, et al. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA 2005;294:3101–3107. 9. Age-Related Eye Disease Study Research G. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119:1417–1436. 10. Seddon JM, George S, Rosner B, et al. Progression of agerelated macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers. Arch Ophthalmol 2005;123:774–782. 11. Shankar A, Mitchell P, Rochtchina E, et al. Association between circulating white blood cell count and long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Am J Epidemiol 2007;165:375–382. 12. Eke PI, Dye BA, Wei L, et al. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res 2012; 91:914–920. 13. Lockhart PB, Bolger AF, Papapanou PN, et al. Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association?: a scientific statement from the American Heart Association. Circulation 2012;125: 2520–2544. 14. Kalayoglu MV, Bula D, Arroyo J, et al. Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2005;243:1080–1090. 15. Hujoel PP, White BA, Garcia RI, et al. The dentogingival epithelial surface area revisited. J Periodontal Res 2001;36: 48–55. 16. Snow KK, Seddon JM. Do age-related macular degeneration and cardiovascular disease share common antecedents? Ophthalmic Epidemiol 1999;6:125–143. 17. Karesvuo P, Gursoy UK, Pussinen PJ, et al. Alveolar bone loss associated with age-related macular degeneration in males. J Periodontol 2013;84:58–67. 18. Ezzati TM, Massey JT, Waksberg J, et al. Sample design: Third National Health and Nutrition Examination Survey. Vital Health Stat 2 1992:1–35. 19. (CDC). CfDCaP. National Health and Nutrition Examination Survey Data Examination File. Hyattsville, MD: Department of Health and Human Services; 1996. 20. Periodontal (Gum) Disease. National Institute of Dental and Craniofacial Research. Bethesda, MD. 2013. 21. Elter JR, Champagne CM, Offenbacher S, et al. Relationship of periodontal disease and tooth loss to prevalence of coronary heart disease. J Periodontol 2004;75:782–790. 22. Klein R, Davis MD, Magli YL, et al. The Wisconsin agerelated maculopathy grading system. Ophthalmology 1991; 98:1128–1134. 23. Seddon JM, Gensler G, Milton RC, et al. Association between C-reactive protein and age-related macular degeneration. JAMA 2004;291:704–710.
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24. Brzozowska A, Puchalska-Niedbal L. Oral status as a potential source of infection in AMD patients–introduction [in Polish]. Klin Oczna 2012;114:29–32. 25. Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet 2005;366:1809–1820. 26. Kohm AP, Fuller KG, Miller SD. Mimicking the way to autoimmunity: an evolving theory of sequence and structural homology. Trends Microbiol 2003;11:101–105. 27. Donoso LA, Vrabec T, Kuivaniemi H. The role of complement Factor H in age-related macular degeneration: a review. Surv Ophthalmol 2010;55:227–246. 28. Contreras M, Costello EK, Hidalgo G, et al. The bacterial microbiota in the oral mucosa of rural Amerindians. Microbiology 2010;156:3282–3287. 29. Chiu CJ, Chang ML, Zhang FF, et al. The relationship of major american dietary patterns to age-related macular degeneration. Am J Ophthalmol 2014;158:118–127.e111. 30. Staufenbiel I, Weinspach K, Forster G, et al. Periodontal conditions in vegetarians: a clinical study. Eur J Clin Nutr 2013; 67:836–840.
31. Chapple IL. Potential mechanisms underpinning the nutritional modulation of periodontal inflammation. J Am Dent Assoc 2009;140:178–184. 32. Chew EY, Clemons TE, Agron E, et al. Long-term effects of vitamins C and E, beta-carotene, and zinc on age-related macular degeneration: AREDS report no. 35. Ophthalmology 2013;120:1604–1611.e1604. 33. Seddon JM, Willett WC, Speizer FE, et al. A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 1996;276:1141–1146. 34. Janket SJ, Baird AE, Chuang SK, et al. Meta-analysis of periodontal disease and risk of coronary heart disease and stroke. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95: 559–569. 35. DeStefano F, Anda RF, Kahn HS, et al. Dental disease and risk of coronary heart disease and mortality. BMJ 1993;306: 688–691. 36. Klein R, Chou CF, Klein BE, et al. Prevalence of age-related macular degeneration in the US population. Arch Ophthalmol 2011;129:75–80.
