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Purpose: To study the effect of potential risk factors on the development of open-angle glaucoma (OAG) in a population in which pseudoexfoliation (PEX) is a common finding.
Methods: In 1984–1986, a population-based survey of 760 people aged 65–74 years was conducted in the municipality of Tierp, Sweden. From 1988 to 2006, a follow-up study of the 530 people with normal visual fields has been in progress. To increase the cohort, 273 ophthalmic outpatients were enroled. Reliable visual fields were available for 679 people, representing 6 126 person-years at risk. A time-weighted mean intraocular pressure (IOP) for all visits was calculated.
Results: Sixty-four subjects developed definite OAG, 29 of whom were exposed to PEX. Risk factors associated with OAG were higher age, a positive family history, increased IOP and PEX. The age-standardized rate ratio (SRR) was 14.8 times (95% confidence interval [CI] 7.92–27.8) greater in subjects with mean IOP ≥20 mmHg than in those with mean IOP <20 mmHg. When subjects with IOP <20 mmHg at baseline were affected by PEX, the SRR increased 5.01-fold (95% CI 1.97–12.8), compared with the unaffected group. However, when mean IOP at follow-up was taken into account, there was no relationship between OAG and PEX as a distinct risk factor. Among participants in the population survey, 69% of all cases were attributable to a mean IOP ≥20 mmHg.
Conclusion: Increased IOP and PEX were serious risk factors for incident OAG. The effect of PEX was mediated by increased IOP.
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Pseudoexfoliation (PEX) is an age-related disorder, characterized by the production and accumulation of a fibrillar material in the anterior segment of the eye (Ritch & Schlötzer-Schrehardt 2001). Common sequence variants in the LOXL1 gene, involved in elastin formation, have been found to confer susceptibility to OAG (Thorleifsson et al. 2007). Although PEX is attracting increasing attention, longitudinal data regarding PEX and OAG are scarce. In a previous report from Tierp (Ekström 1993), PEX was identified, for the first time, as an independent risk factor for the development of OAG. In the Visual Impairment Project, Le et al. (2003) found an increased risk for subjects with PEX. Finally, in a long-term follow-up of a cohort in northern Sweden, Åström et al. (2007) demonstrated a fourfold increased risk for participants exposed to PEX.
In the present investigation, potential risk factors for OAG were studied. The significance of optic disc haemorrhages was also evaluated. The investigation took the form of a population-based 20-year follow-up study.
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By the end of the study, 64 cases of OAG had been detected, 34 with capsular and 30 with chronic simple glaucoma, all of whom were ultimately classified as definite cases. Five of the capsular glaucomas were not exposed to PEX at baseline. Three cases of capsular and 10 of chronic simple glaucoma were diagnosed as NTG. Table 2 provides SRRs for OAG at baseline. Increased IOP, PEX and a positive family history were associated with OAG. People aged ≥70 years experienced a 1.97-fold (95% confidence interval [CI] 1.21–3.22) increased risk, compared with those <70 years.
Table 2. Associations of potential risk factors and incident open-angle glaucoma.
|Baseline characteristics||SRR (95% CI)|
|Female gender||0.77 (0.46–1.30)|
|Positive family history of OAG||2.04 (1.04–4.00)|
|Medical history factors|
| Smoking, ≥35 years||1.16 (0.63–2.14)|
| Diabetes mellitus (E10–E14)||0.63 (0.23–1.74)|
| Blood-pressure-lowering treatment||0.96 (0.57–1.62)|
| Ischaemic heart disease (I20–I25)||0.85 (0.42–1.73)|
| Arteriosclerosis (I70–I72)||1.59 (0.50–5.09)|
| Obstructive lung disease (J42–J45)||0.49 (0.12–2.00)|
|Ocular factors, any eye|
| IOP ≥20 mmHg||6.83 (3.99–11.7)|
| Pseudoexfoliation||5.68 (3.47–9.31)|
| Myopia (≤−1 dioptre)*||0.87 (0.27–2.76)|
The results presented in Table 3 suggested interaction between increased IOP and PEX at baseline, i.e. the joint effect of increased IOP and PEX was greater than the sum of their individual effects. A chi-square test supported a significant difference in incidence rates across IOP categories (χ2df=2 = 6.21; p = 0.04). In subjects with IOP <20 mmHg, PEX was associated with a fivefold excess risk of OAG, compared with the reference (no exposure) group. In Table 4, baseline IOP is replaced by mean IOP at follow-up visits. In this case, PEX alone was not associated with OAG. When excluding subjects in the intermediate pressure category, interaction between mean IOP ≥25 mmHg and PEX was evident (χ2df=1 = 5.71; p = 0.02). In the whole cohort, a mean IOP ≥20 mmHg increased the SRR for OAG 14.8-fold (95% CI 7.92–27.8). In the part of the cohort that participated in the population survey, 69% of all cases were attributable to a mean IOP ≥20 mmHg.
Table 3. Age-standardized rate ratios for open-angle glaucoma (OAG) associated with increased intraocular pressure (IOP) and pseudoexfoliation (PEX) at baseline.
|≥25 mmHg||41.1 (16.6–102)||10.6 (3.96–28.2)|
|20–24 mmHg||19.4 (8.97–41.9)||5.49 (2.60–11.6)|
|<20 mmHg||5.01 (1.97–12.8)||1.00*|
Table 4. Age-standardized rate ratios for open-angle glaucoma (OAG) associated with increased mean intraocular pressure (IOP) at follow-up and pseudoexfoliation (PEX) at baseline.
|≥25 mmHg||55.9 (25.9–121)||25.8 (11.3–59.0)|
|20–24.99 mmHg||9.90 (3.38–29.0)||6.76 (2.91–15.7)|
|<20 mmHg||2.27 (0.497–10.4)||1.00*|
Cox proportional hazards models included age, mean IOP, an interaction term, PEX and gender. The final model is shown in Table 5. Consistent with results of the standardized analysis, interaction between mean IOP ≥25 mmHg and PEX more than doubled the relative hazard. Inclusion of PEX in a model containing mean IOP and the interaction term did not add any further information.
Table 5. Cox regression model relating fixed and time-dependent covariates to development of open-angle glaucoma.
|Covariate||HR (95% CI)|
| Age (per year)*||1.15 (1.05–1.26)|
| Mean IOP ≥25 mmHg, PEX†||2.38 (1.87–3.03)|
|Time-dependent (per 10 years)|
| Mean IOP <20 mmHg‡||1.00|
| Mean IOP 20–24.99 mmHg||3.92 (2.13–7.22)|
| Mean IOP ≥25 mmHg||15.4 (4.52–52.1)|
Optic disc haemorrhages were found in 22 subjects, 12 of whom developed OAG. Haemorrhages were associated with a 15.0-fold (95% CI 6.05–37.1) increased risk in men and a 2.55-fold (95% CI 1.01–6.49) increased risk in women; men with haemorrhages were 3.41 (95% CI 1.08–10.7) times more likely to be diagnosed with OAG, than were women. A marked covariation between increased IOP, haemorrhages and OAG was demonstrated; the SRR in subjects exposed to haemorrhages and mean IOP ≥20 mmHg increased 25.3-fold (95% CI 10.3–62.4), compared with the no exposure group.
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Spanning over 20 years, this study is the longest follow-up study on risk factors for OAG based on automated perimetry to be reported so far. It is the second study of its kind conducted in a population in which PEX is a common finding. Higher age, a positive family history, increased IOP and PEX were associated with incident OAG. At baseline, IOP ≥20 mmHg increased the risk sevenfold, while PEX increased the risk sixfold.
The significance of increased IOP has been documented in other studies. In the Barbados Eye Studies, every increase of baseline IOP by 1 mmHg was associated with a 12% increased risk (Leske et al. 2008). Follow-up of the Visual Impairment Project in Australia revealed an excess risk of ‘at least probable’ OAG of 10% for each 1 mmHg increase at baseline (Le et al. 2003). Whereas PEX is extremely uncommon in Barbados (Leske et al. 2002), PEX increased the risk 11-fold in the Australian study.
In general, cohort studies on risk factors for OAG report an effect of increased IOP at baseline. At rescreening, a substantial proportion of subjects classified as exposed may actually have an IOP within the normal range, while subjects with normal IOP at baseline have increased IOP (Ekström 1993). To avoid this misclassification of exposure, mean IOP at every visit was used in the analyses. In addition, mean values were adjusted to account for the effect of aggregated pressure readings within a short period of time.
Total attributable fraction is the proportion of cases in the population attributable to a specific exposure: the larger the proportion of exposed cases, the greater the attributable fraction. In the absence of bias, attributable fraction is the proportion of disease burden caused by the exposure. When excluding those recruited to the original cohort, the proportion of OAG cases attributed to a mean IOP ≥20 mmHg was estimated to 69%.
Pseudoexfoliation at baseline was identified as an independent risk factor for OAG. When subjects with IOP <20 mmHg were affected by PEX, the risk increased fivefold, compared with the unaffected group. However, when mean IOP at follow-up was taken into account, there was no association between PEX as a separate risk factor and OAG. This finding indicates that the effect of PEX was mediated by increased IOP, as suggested in a previous report (Ekström 2000). The result concurs with the understanding of PEX as a disorder obstructing the outflow of aqueous humour.
Interaction between PEX and increased IOP was established. Exposure to PEX and a mean IOP ≥25 mmHg increased the risk of OAG 56-fold, compared with the reference group. The finding in Tierp is of great public health importance. An intensified effect of increased IOP in the presence of PEX is a likely explanation for the high prevalence of OAG, reported from Nordic countries (Jonasson et al. 2003; Ekström & Alm 2008).
Multivariate analyses using Cox hazards models identified high age, increased IOP and interaction between increased IOP and PEX as risk factors for OAG. In agreement with the results of the stratified analysis, interaction explained more of the variation in the data than PEX as a distinct risk factor. Unfortunately, competing risks affected the analyses. In particular, data on subjects who received pressure-reducing treatment were strongly correlated to OAG data. Therefore, conclusions based on Cox hazards models should be interpreted with some caution.
To increase the statistical power of the study, the original cohort of people participating in the population survey was enlarged by adding patients seeking medical attention at the Eye Department in Tierp. These measures will never bias the result as long as the identification of OAG was independent of the exposure under study, which was the case in this study. In fact, OAG incidence in people exposed to increased IOP and PEX was somewhat lower among those recruited to the cohort (data not shown).
Apart from the already established risk factors, this study failed to identify any association between baseline characteristics and OAG. None of the medical diagnoses increased the incidence. However, exposed cases were generally few in numbers, limiting the ability to reveal unknown risk factors. Similarly, there was insufficient power to study the effect of myopia. Smoking did not increase the risk.
Optic disc haemorrhages found at ophthalmoscopy were closely associated with OAG. In view of all the unanswered questions regarding haemorrhages, they should be conceived of as a sign of the disease rather than a risk factor for the disease. Notably, men with a haemorrhage were 3 times more likely to develop OAG than women with haemorrhage. To the best of our knowledge, such a finding has not been reported elsewhere. The result seems to be in conflict with that reported by Bengtsson et al. (2008), which suggested lower odds ratios for the presence of disc haemorrhages for men with manifest glaucoma. Bearing in mind the relatively small numbers of subjects with haemorrhages, the finding in Tierp should be regarded with a certain reservation.
The strengths of this study include the community-based approach, the long follow-up time, the high participation and the use of computerized perimetry to identify cases. The classification of OAG was based on the decision of ‘masked’ observers. The limitations are the tolerably small size of the cohort and the lack of optic disc photography at study visits. Only people in the age range 65–74 years were included.
To sum up, the cohort study in Tierp provides estimates of risk factors for OAG over a 20-year period. Increased IOP and PEX were the only risk factors of importance. A mean IOP ≥20 mmHg accounted for approximately 70% of OAG morbidity in the population. The effect of PEX was mediated by increased IOP.