Association of Emphysema, Gout, and Inflammatory Markers With Long-term Incidence of Age-Related Maculopathy FREE

INFLAMMATION HAS been hypothesized to be a pathogenetic mechanism in several age-related conditions such as atherosclerosis, ¹ Alzheimer disease, ² and diabetes.³ It has also been hypothesized that inflammation plays a role in the pathogenesis of age-related maculopathy (ARM).^{4 - 7} Hageman et al⁷ have shown that drusen contain proteins associated with immune-mediated processes and inflammation. In addition, chronic inflammatory cells have been observed on the outer surface of Bruch's membrane in eyes with neovascular macular degeneration.⁶ The presence of these cells may cause atherogenesis and microvascular injury by direct release of long-acting oxidants, toxic oxygen compounds, and proteolytic enzymes that may also damage Bruch's membrane.^{8 - 9}

Epidemiological studies to date have not shown a consistent association of systemic inflammatory disease and its markers with ARM.^{10 - 20} Furthermore, there has been no demonstrated protective effect of anti-inflammatory drugs on the incidence of ARM.^{21 - 23} We examined whether 2 diseases associated with inflammatory response, emphysema and gout, and markers of systemic inflammation (eg, white blood cell count, platelet count, and serum albumin level) were related to the incidence and progression of ARM in the large population-based Beaver Dam Eye Study.²⁴

Methods used to identify and describe the population have appeared in previous reports.^{24 - 32} In brief, a private census of the population of Beaver Dam, Wis, was performed from September 15, 1987, to May 4, 1988, to identify all residents in the city or township of Beaver Dam who were aged 43 to 84 years. The tenets of the Declaration of Helsinki were followed, the approval of the institutional review board was granted, and informed consent was obtained from each subject. Of the 5924 eligible individuals, 4926 participated in the baseline examination between March 1, 1988, and September 14, 1990.²⁴ Ninety-nine percent of the population was white. Of those subjects who were still alive at follow-up, 3684 (81.1%) participated in the 5-year follow-up examinations from March 1, 1993, through June 14, 1995. Comparisons between participants and nonparticipants at the time of the baseline and 5-year follow-up examinations have appeared elsewhere.²⁵

Prior to the start of the 10-year follow-up examinations on March 1, 1998, 350 (9.5%) of the participants from the 5-year examination had died. Of the 3334 surviving subjects in the baseline and second examination, 2764(82.9%) participated in the second follow-up examination between March 1, 1998, and June 9, 2000. One participant could not be located, 42 (1.3%) permitted an interview only, 38 (1.1%) had moved out of the area and did not participate, 337 (10.1%) refused to participate, and 152 (4.6%) died prior to being examined. The mean and median times between the baseline and 10-year follow-up examinations were 10.1 years and 10.0 years, respectively, and the SD was 0.4 years.

Comparisons between participants and nonparticipants at the 10-year follow-up have been presented elsewhere.²⁶ Subjects who died before their scheduled examination for the 10-year follow-up (n = 502) were older at baseline than those who participated (69.1 years vs 58.7 years; P<.001). Subjects who were alive but did not participate in the 10-year follow-up (n = 418) were also older at baseline than those who did (61.1 years vs 58.7 years; P<.001). After adjusting for age, those who were alive during the study period and did not participate were more likely to have fewer years of education, a lower income, poorer visual acuity, a history of cardiovascular disease, a history of never drinking alcohol, more pack-years smoked, a higher serum cholesterol level, higher systolic and diastolic blood pressures, and a higher white blood cell count than participants; they were also more likely to be retired at baseline. After adjusting for age and sex, participants with early ARM at baseline were as likely to participate as those without ARM (data not shown). While controlling for age, there were no differences in participation at the follow-up examinations for men and women with a history of emphysema or gout and early ARM compared with those who had a history of these conditions without early ARM (data not shown).

Similar procedures were used at both the baseline and follow-up examinations and are described in detail elsewhere.^{28 - 29} Informed consent was obtained from each participant. The examinations at baseline and follow-up included measuring weight, height, pulse rate, and blood pressure(using a random-zero sphygmomanometer following the Hypertension Detection and Follow-up Program protocol).²⁷ We administered a standardized questionnaire that included specific questions regarding history of gout, emphysema, cigarette smoking, and vitamin use. Casual blood specimens were obtained. White blood cell and platelet counts were determined using a Coulter counter method. Serum albumin and uric acid levels were determined by Technicon, Inc (RA 1000 Analyzer; Bayer Diagnostics, Tarrytown, NY). We obtained stereoscopic 30° color fundus photographs centered on the optic disc (Diabetic Retinopathy Study [DRS] standard field 1) and macula (DRS standard field 2) and nonstereoscopic color fundus photographs temporal to but including the fovea of each eye.²⁷ For purposes of this article, the 2663 people (3570 at the first 2 examinations) with at least 1 eye free of confounding lesions (eg, retinal detachment or non–age-related chorioretinal scarring) at all 3 examinations (right eye: n = 2592 [3475 at the first 2 examinations]; left eye: n = 2600 [3501 at the first 2 examinations]; both eyes: n = 2529 [3406 at the first 2 examinations]) are included in the analyses.^{29 - 32}

The Wisconsin Age-Related Maculopathy Grading System^{29 - 30} was used to assess the presence and severity of lesions associated with ARM. Grading procedures, lesion descriptions, and detailed definitions for the presence and severity of specific lesions as well as the 5-year incidence have appeared elsewhere.^{29 - 32} Incidence implies the appearance of a lesion at follow-up that was absent at baseline and that could be graded at both the baseline and follow-up examinations. Progression implies the presence of a lesion at baseline with a worsening at follow-up.

Incidence was determined for maximum size and type of each specific drusen class, increased retinal pigment, retinal pigment epithelial (RPE) depigmentation, pigmentary abnormalities (defined as RPE depigmentation or increased retinal pigment), signs of exudative macular degeneration, and pure geographic atrophy. For example, if none of the subfields had soft indistinct drusen at baseline and these drusen were present in 1 or more subfields at the 5- or 10-year follow-up examination, the eye would be considered to have"incident" soft indistinct drusen.

Early ARM was defined as the presence of either soft indistinct drusen or any type of drusen associated with RPE depigmentation or increased retinal pigment. Late ARM was defined as either exudative macular degeneration or pure geographic atrophy.

A 6-level severity scale for ARM was defined as follows:

For participants, progression was defined as an increase in maculopathy severity in either eye by 2 or more steps from levels 10 through 30 and 1 or more steps from level 40 or 50 from baseline to either the 5-year or 10-year follow-up examination.

Age was defined as the age at the time of baseline examination. People were defined as having a history of emphysema or gout if at baseline they responded affirmatively to questions regarding the presence of these conditions. Subjects were classified as nonsmokers if they had smoked fewer than 100 cigarettes in their lifetime, as ex-smokers if they had smoked more than this number of cigarettes in their lifetime but had stopped smoking before the baseline examination, and as current smokers if they had not stopped smoking. A current heavy drinker was defined as a person consuming 4 or more servings of alcoholic beverages daily; a former heavy drinker, as someone who had consumed 4 or more servings daily in the past but not the previous year; and a nonheavy drinker, as a person who had never consumed 4 or more servings daily on a regular basis. Participants were classified as current vitamin users if they took at least 1 vitamin per week within a month prior to the baseline examination, past vitamin users if they had ever regularly taken vitamins at least once per week but not within the last month, and as never using vitamins if they had never regularly taken vitamins at least once a week.

For these analyses, we examined the associations of white blood cell count, serum albumin level, serum uric acid level, platelet count, and history of emphysema and gout at baseline with the incidence of each of the specific maculopathy lesions, incidence of 2 end points of disease severity (early and late ARM), and progression of ARM. White blood cell count, serum albumin level, serum uric acid level, and platelet count were treated as continuous variables. To analyze the data, we used SAS statistical software (SAS Institute Inc, Cary, NC). The analytical approaches used allowed subjects who were right-censored(not seen after the 5-year examination because of death or nonparticipation) to contribute information to the estimates. Cumulative events were estimated using the Kaplan-Meier (product limit) survival approach.³³ Multivariate risk ratios and 95% confidence intervals were calculated from the discrete linear logistic model.³⁴ All risk factors of interest that were continuous were treated as such in the analyses. Age- and sex-adjusted models were constructed by outcome for each of the potential risk factors. Final models were then built according to outcome for each risk factor by adding vitamin use, systolic blood pressure, and history of smoking or heavy drinking into the model. Tests of trend were done treating categorical risk factors as continuous variables in the discrete linear logistic model and computing the χ² statistic for the parameter estimate. In these models, smoking status, heavy drinking status, and vitamin use were each assessed using 2 indicator variables.

The mean serum uric acid level increased with age, whereas the serum albumin level and platelet count decreased with age (Table 1). There was no relationship between white blood cell count and age, but the prevalence of emphysema and gout increased with age (Table 1). The 10-year incidence and progression of ARM, soft indistinct drusen, drusen size 125 µm or greater in diameter, RPE depigmentation, increased retinal pigment, exudative macular degeneration, and geographic atrophy increased with age (Table 2).

While controlling first for age and sex (data not shown) and then for age, sex, a history of heavy drinking, smoking status, systolic blood pressure, and vitamin use at baseline, we found that a higher white blood cell count at baseline was associated with an increased 10-year incidence of large retinal drusen, RPE depigmentation, and progression of ARM; that a lower serum albumin level was associated with an increased incidence of exudative macular degeneration; that a history of emphysema at baseline was associated with a higher incidence of RPE depigmentation, increased retinal pigment, and exudative macular degeneration; and that a history of gout was associated with a higher incidence of pure geographic atrophy (Table 3 and Table 4). The fully adjusted models were similar to those adjusted only for age and sex. Higher platelet count and higher serum uric acid level were not statistically significantly associated with ARM (data not shown).

In Beaver Dam, while controlling for age, cigarette smoking, and other risk factors, a higher white blood cell count was related to an increased 10-year risk of developing large drusen, pigmentary abnormalities, and progression of ARM. In addition, another sign associated with systemic inflammation, lower serum albumin level, was related to the 10-year incidence of exudative macular degeneration.³⁵ Furthermore, in Beaver Dam a history of emphysema, independent of smoking and age, was associated with the incidence of pigmentary abnormalities and exudative macular degeneration, and gout was associated with the incidence of geographic atrophy. The local destructive pathologic process in gout and emphysema is thought to be inflammation.^{36 - 40} These conditions may be associated with systemic inflammation caused by the release of cytokines, such as interleukin 1 and interleukin 8, and by increased circulating levels of tumor necrosis factor α and the increased release of this hormone from circulating cells.^{38 ,41 - 42} These factors have been hypothesized to play a role in the pathogenesis of exudative macular degeneration.⁷ However, it is possible that the associations reported in this article may be due in part to noninflammatory processes, such as low oxygen tension in persons with emphysema, rather than inflammatory disease.

Epidemiological data, most of which are cross-sectional, have not been consistent regarding the association of white blood cell count and other inflammatory factors with ARM.^{10 - 20} In a small case-control study, ²¹ an association was found between higher white blood cell count and exudative macular degeneration, but no association was found in the Cardiovascular Health Study¹⁷ (CHS), National Health and Nutrition Examination Survey III¹⁶ (NHANES III), or Atherosclerosis Risk in Communities Study.¹⁴ Another marker of systemic inflammation, high plasma fibrinogen level, was found to be associated with prevalent late but not early ARM in the Blue Mountains Eye Study¹² and with exudative macular degeneration in the NHANES III. However, the plasma fibrinogen level was not associated with ARM in the Rotterdam Study, ¹³ CHS, or Eye Disease Case-Control Study.¹⁰ Furthermore, the CHS showed no association of C-reactive protein, another marker of systemic inflammation, with ARM.

There are several strengths to this study including its high participation rate, length of follow-up, and use of standardized protocols to measure ARM end points. However, any conclusions or explanations in this article regarding associations or lack of them must be made with caution for several reasons. First, the concomitant low frequency of certain risk factors (eg, emphysema) and of the incidence of some lesions (eg, pure geographic atrophy), evident in the large 95% confidence intervals around the estimated risk ratios, limits our ability to detect (or reject) meaningful relationships. For example, in Beaver Dam, with 3470 participants, 71 of whom had a history of emphysema at baseline and 23 of whom had an incidence of pure geographic atrophy by the 10-year examination, we would be able to detect an odds ratio of about 8.2 with a power of 0.80 (α = .05) for this association. Second, some findings (eg, gout and the incidence of geographic atrophy) of potential biological significance may be entirely due to chance given the large number of associations examined. Third, it is possible that no relationship was found between some risk factors and ARM because subjects with these factors who developed this disease did not live to participate in the follow-up examination. However, nonparticipation as a result of death is unlikely to bias our findings because ARM was not shown to be associated with mortality.⁴³

In summary, the 10-year incidence data from Beaver Dam show a modest association of 2 diseases, gout and pulmonary emphysema, and 2 signs of inflammation, higher white blood cell count and lower serum albumin level, with the 10-year incidence of ARM independent of smoking and other risk factors. Further prospective study is needed that will examine the associations of inflammatory disease and markers of acute and chronic inflammation, such as interleukins and C-reactive protein, with ARM.

Submitted for publication June 21, 2002; final revision received September 18, 2002; accepted January 22, 2003.

This study was supported by grant EY06594 (Drs R. Klein and B. Klein) from the National Institutes of Health, Bethesda, Md, and in part by Research to Prevent Blindness (Dr R. Klein, Senior Scientific Investigator Award), New York, NY.

We thank the Beaver Dam Scientific Advisory Board (Mae Gordon, PhD, Lee Jampol, MD, Mary Frances Cotch, PhD, Natalie Kurinij, PhD, Daniel Seigel, PhD, and Robert Wallace, MD) and George Davis, MD, Alan Ehrhardt, MD, and Thomas Castillo, MD, for their contributions.

Corresponding author: Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, 610 N Walnut St, 450 WARF, Madison, WI 53726-2397 (e-mail: kleinr@epi.ophth.wisc.edu).