RISK OF RETINAL VEIN OCCLUSION IN PATIENTS WITH PSORIASIS A Population-Based Cohort Study YUNG-CHANG YEN, MD, PHD,*† SHIH-FENG WENG, PHD,‡§ FENG-JIE LAI, MD, PHD,¶ YUNG-SONG LIN, MD**††‡‡ Purpose: To investigate the risk of developing retinal vein occlusion (RVO) in patients with psoriasis. Methods: In this retrospective population-based cohort study, 30,198 patients with psoriasis (Psoriasis(+) group) and 30,198 controls without psoriasis (Psoriasis(−) group) between 2001 and 2006 from the Taiwan National Health Insurance Research Database were selected. Results: The incidence of RVO was 1.46 times higher in the Psoriasis(+) group than in the Psoriasis(−) group (3.61 vs. 2.47/10,000 person-years) (adjusted hazard ratio = 1.50; 95% confidence interval = 1.07–2.10) calculated using Cox proportional hazard regression. Age was an independent risk factor for RVO (adjusted hazard ratio: 11.9 for patients 65 years or older vs. 1.00 for those 0–49 years old). In the 65 years or older Psoriasis(+) group, the incidence of developing RVO was 1.97 times higher (95% confidence interval = 1.19–3.26) than in the 65 years or older Psoriasis(−) group. In Psoriasis(+) women, the incidence of developing RVO was 1.82 times higher (95% = 1.05–3.14) than in Psoriasis(−) women. For the subgroup with comorbid hypertension, the incidence of developing RVO was 2.07 times higher (95% confidence interval = 1.22–3.50) in the Psoriasis(+) group than in the Psoriasis(−) group. Conclusion: Psoriasis was significantly associated with a higher risk of developing RVO. RETINA 35:1786–1794, 2015
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prone to have RVO.2 Several studies have identified the systemic risk factors of RVO: hypertension (HTN),3,4 diabetes mellitus (DM),3,4 systemic vascular disease,5 and hypercoagulable states.3,6–8 Because psoriasis is a chronic inflammatory skin disease that involves multiple underlying genetic and environmental factors, the association between psoriasis and other diseases has drawn increasing interest in recent years. Many studies have reported that the prevalences of HTN,9,10 DM,11,12 cardiovascular disease,13,14 and dyslipidemia15–17 are higher in patients with psoriasis than in the general population. Systemic inflammatory mediators generated in psoriasis were hypothesized18,19 to be the underlying mechanism of the associations between these comorbid diseases and psoriasis. The role of systemic inflammation in the pathogenesis and clinical consequences of RVO is a topic of growing interest.20 Autoimmune disease, an immune response caused by systemic inflammation, has long been recognized as a significant risk factor for RVO.20 Moreover, the retinal microangiopathy associated with autoimmune disease is thought to result from
etinal vein occlusion (RVO) is the second most common vascular disease affecting the retina.1,2 In general, middle-aged and elderly people are more From the *Department of Ophthalmology, Chi Mei Medical Center, Liou-Ying, Tainan City, Taiwan; †Department of Nursing, Min Hwei College of Health Care Management, Tainan City, Taiwan; ‡Department of Medical Research, Chi Mei Medical Center, YungKang District, Tainan City, Taiwan; §Department of Hospital and Health Care Administration, Chia-Nan University of Pharmacy and Science, Ren De District, Tainan City, Taiwan; ¶Department of Dermatology, Chi Mei Medical Center, Yung-Kang District, Tainan City, Taiwan; **Center for General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan; ††Department of Otolaryngology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; and ‡‡Department of Otolaryngology, Chi Mei Medical Center, Yung-Kang District, Tainan City, Taiwan. Supported by Taipei Medical University-Chi Mei Medical Center Research Fund, grant number 09909-066. None of the authors have conflicting interests to disclose. Y-C. Yen made substantial contributions to study design and was involved in acquiring data. Y-S. Lin, F-J. Lai, and S-F. Weng made substantial contributions to study conception and design and did data analysis. All authors reviewed and approved the manuscript’s content before submission and jointly agreed to submit the final version. Reprint requests: Yung-Song Lin, MD, Center for General Education, Southern Taiwan University of Science and Technology, 901 Chung Hwa Road, Yung Kan District, Tainan City 710, Taiwan; e-mail: [email protected]
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immune complex–mediated vascular injury and microvascular thrombosis.8,20,21 Psoriasis is recognized as an autoimmune disease22,23 or an immune-mediated inflammatory disease.24,25 Therefore, RVO may be a manifestation of systemic vascular involvement in psoriasis and may have an important effect on health. However, the risk of patients with psoriasis developing RVO has not been systematically examined. We used data from Taiwan’s National Health Insurance Research Database to retrospectively investigate the incidence of RVO in patients with psoriasis. The effects of six comorbidities—DM, HTN, coronary heart disease (CHD), hyperlipidemia, obesity, and chronic obstructive pulmonary disease (COPD)—on the risk of developing RVO were also examined. Materials and Methods Data Sources The Taiwan National Health Insurance program is a universal health-care system that covers 99% of the country’s population of 23.3 million. The data used in this analysis were obtained from the Longitudinal Health Insurance Database 2000, a sub-dataset of National Health Insurance Research Database, which contains all claims data (from 1996 to 2011) of 1 million beneficiaries who were systemic and randomly selected in 2000. There were no significant differences in age, gender, or health-care costs between the sample group and all enrolled residents. The database contains encrypted patient identification numbers, ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes for applied clinical diagnoses and procedures, details of prescribed drugs, dates of admission and discharge, and basic sociodemographic information, including gender and date of birth. Design This was a retrospective cohort study with two study groups: patients with psoriasis (Psoriasis(+) group) and controls without psoriasis (Psoriasis(−) group). The Psoriasis(+) group included patients with an initial diagnosis of psoriasis (ICD-9 codes 690, 696.0, and 696.1). Patients without medical claims for psoriasis who matched the patients in the Psoriasis(+) group in gender, age (±30 days), and index date were randomly selected for the Psoriasis(−) group. The index date for the patients with psoriasis was the date between 2001 and 2006 on which they were first registered as having psoriasis. The index dates for the Psoriasis(−) group were matched based on the index dates of the Psoriasis(+) group. A visit to a physician approximately
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on the index date (±30 days) was required for each patient in the Psoriasis(−) group. Other comorbidities that may have been presented before the index date were defined as follows: DM (ICD-9 code 250.x), HTN (ICD-9 codes 401.x–405.x), CHD (ICD-9 codes 410.x–414.x, A270, and A279), hyperlipidemia (ICD-9 code 272.x), obesity (ICD-9 code 278.x), and COPD (ICD-9 code 496.0). The comorbidities were identified only through a corresponding diagnosis made during admission or by a physician at an outpatient clinic during each of three visits. Controls (Psoriasis(−) group) were matched using a propensity score by age, gender, and comorbid DM, HTN, CHD, hyperlipidemia, obesity, COPD, geographic distribution, and monthly income. Diagnoses of psoriasis and newly developed RVO (ICD-9 codes 362.35 and 362.36) were provided by referral teaching hospitals and tertiary referral medical centers. To investigate the association between the occurrence of RVO and the disease progress of psoriasis, only patients with newly diagnosed psoriasis between 2001 and 2006 were included. The claims data from 1996 to 2000 were used to confirm that none of the enrolled patients had ever been diagnosed with psoriasis or RVO before 2001. The dates of look back were January 1, 1996, to December 31, 2000, before the first index date of January 1, 2001. We assumed that a latent period was necessary for the chronic disease, that is, psoriasis in this case, to have an effect on the occurrence of RVO. Hence, patients were followed-up for a minimum of 6 years (2006–2011) to determine the incidence of RVO until the end of 2011 or until they were censored because of death. Each enrolled patient had to have been registered in this National Health Insurance system since 1996 without termination until the end of 2011, unless they were censored because of death. The identification numbers of all the patients in the National Health Insurance Research Database are encrypted to protect their privacy. The Institutional Review Board of Chi Mei Medical Center approved this study. Statistical Analyses Descriptive statistical analyses using Pearson’s x2 tests were done to compare the differences in sociodemographic characteristics and comorbidities between the Psoriasis(+) and Psoriasis(−) groups. The incidence rate was calculated as the number of RVO cases identified during follow-up divided by the total person-years for each group by gender, age, and comorbidities. The risk of developing RVO was compared by estimating the incidence ratio using a Poisson regression. The risk of developing RVO associated with the comorbidities of DM, HTN, CHD, hyperlipidemia, obesity, and
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COPD was estimated using a Cox proportional hazard models. A Cox proportional hazard regression analysis with propensity score matching was used to estimate the hazard ratio between the Psoriasis(+) and Psoriasis(−) groups. To compare the risk of RVO between two groups, we used propensity score (for diagnosed Psoriasis(+) as the treatment assignment) matching by a greedy algorithm to ensure better comparability among the two groups and minimize possible selection bias in choosing Psoriasis(+) or Psoriasis(−). Propensity score matching, which can bundle many confounding covariates that may be present in an observational study with this number of variables, was used to reduce any selection bias in our hypothesis.26 Score matching identified the predicted probability of obtaining one Psoriasis(+) patient versus one Psoriasis(−) patient from the logistic regression model according to the baseline covariates of age, gender, and the six comorbidities. Afterward, an SAS matching macro, “%OneToManyMTCH,” which was proposed by the Proceedings of the 29th SAS Users Group International,27 was used in this study. It allows propensity score matching from 1-to-1 to 1-to-N based on user specifications using the greedy-matching algorithm (without replacement). The macro makes “best” matches first and “next-best” matches next, in a hierarchical sequence, until no more matches can be made. Each control is selected once at most. The final matched-pair samples contain closely matched individual pairs and balanced Psoriasis(+) and Psoriasis(−) groups (Figure 1). A Cox proportional hazard regression analysis and a Kaplan–Meier survival analysis were used to calculate the cumulative incidence rates of RVO in the two cohorts, and the log-rank test was used to analyze the
Fig. 1. The distribution of propensity scores in patients with psoriasis (Psoriasis(+)) and without (Psoriasis(−)). The distribution of propensity scores in Psoriasis(+) and Psoriasis(−) groups revealed a C statistic value of 0.57 that indicated a big overlap between Psoriasis(+) and Psoriasis(−) groups in our study.
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differences between the survival curves. SAS 9.3 for Windows (SAS Institute, Cary, NC) was used for all statistical analyses. Significance was set at P , 0.05 (two tailed). Results The Incidence of Retinal Vein Occlusion Based on Patient Characteristics Based on the 2001 to 2006 claims data, before the propensity score matching, 30,227 patients (females: 15,395; males: 14,832) with new psoriasis were defined. After the propensity score matching, 30,198 patients (females: 15,373 [50.91%]; males: 14,825) with psoriasis met the eligibility criteria and an additional 30,198 participants without medical claims for psoriasis who were gender, age (±30 days), comorbidity, geographic distribution, monthly income, and index date matched with the patients in the Psoriasis(+) group were selected as controls. The distribution of propensity scores of the Psoriasis(+) and Psoriasis(−) groups were illustrated in Figure 1. The annual incidence of psoriasis in Taiwan averaged 0.13% between 2001 and 2006. There were no significant differences in sociodemographic characteristics (age, gender, monthly income, and geographic distribution) or comorbid medical disorders between the Psoriasis(+) and Psoriasis(−) groups (Table 1). The estimated risks of developing RVO based on gender, age, and the comorbid diseases in the two groups were compared. By the end of the follow-up period, the cumulative incidence rate of RVO was higher in the Psoriasis(+) group than in the Psoriasis(−) group (P = 0.03) (Figure 2). The incidence rates of RVO classified by gender, age, and comorbid diseases were also compared. Psoriasis(+) patients 65 years or older had a significantly (P , 0.01) higher risk and an incidence rate 1.97 times higher (95% confidence interval [CI] = 1.19–3.26) than did their Psoriasis(−) counterparts (Table 2). In both groups, patients 65 years or older had a higher incidence of RVO than did patients 0 to 49 years old (adjusted hazard ratio [AHR]: 11.90; 95% CI = 6.77–20.92) (Table 3). The incidence rate of RVO was significantly (P = 0.03) higher only for women in the Psoriasis(+) group (incidence rate ratio [IRR]: 1.82; P = 0.03) than in the Psoriasis(−) group (Table 2). Association Between Retinal Vein Occlusion and the Comorbidities In general, the risk of developing RVO was higher in the Psoriasis(+) group than in the Psoriasis(−) group
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Table 1. Demographic Characteristics and Comorbid Medical Disorders for Psoriasis(+) Patients and Psoriasis(−) Patients in Taiwan
Age (years) 0–49 50–64 $65 Gender Female Male Baseline comorbidity DM HTN CAD Hyperlipidemia COPD Obesity Geographic distribution North Central South East Monthly income NT$ , 15,840 NT$ 15,841–25,000 NT$ . 25,001
Psoriasis(+)
Controls (Psoriasis(−))
n = 30,198
n = 30,198
21,443 (71.01) 4,392 (14.54) 4,363 (14.45)
21,449 (71.03) 4,492 (14.88) 4,257 (14.10)
15,373 (50.91) 14,825 (49.09)
15,448 (51.16) 14,750 (48.84)
P 0.30
0.54
1,654 3,624 1,255 1,097 892 45
(5.48) (12.00) (4.16) (3.63) (2.95) (0.15)
1,667 3,713 1,238 1,061 857 37
(5.52) (12.30) (4.10) (3.51) (2.84) (0.12)
14,309 5,892 9,109 888
(47.38) (19.51) (30.16) (2.94)
14,273 5,862 9,199 864
(47.26) (19.41) (30.46) (2.86)
12,107 (40.09) 8,441 (27.95) 9,650 (31.96)
12,027 (39.83) 8,460 (28.02) 9,711 (32.16)
0.82 0.27 0.73 0.43 0.40 0.38 0.83
0.79
CAD, coronary artery disease; NT$, New Taiwan dollars (U.S. $1 = ca. NT$ 30).
(AHR: 1.50; 95% CI = 1.07–2.10). The comorbid diseases were matched between the two groups. A multivariate Cox proportional hazard regression analysis, which included gender, age, geographic distribution, monthly income, and comorbidities in the model, revealed no significant differences in the risk of developing RVO between patients with and those without the comorbidities of CHD, hyperlipidemia, obesity, and COPD (Table 3). However, there were significant
differences in the risk of developing RVO between patients with and without the comorbidities of DM (AHR = 1.75; 95% CI = 1.14–2.67) and HTN (AHR = 1.72; 95% CI = 1.17–2.53) (Table 3). Subgroup analysis by comorbid disease showed that the risk of developing RVO was significantly higher only in the subgroup with comorbid HTN (IRR: 2.07; P , 0.01). Methotrexate is used as an alternative or second-line therapy to treat severe psoriasis when first-line creams, ointments, tar products, and phototherapy have not worked or cannot be used. A multivariate Cox proportional hazard regression analysis with gender, age, geographic distribution, monthly income, and comorbidities as variables revealed a significantly higher risk of RVO in Psoriasis(+) patients (AHR = 3.78; 95% CI = 1.18–12.09) who needed methotrexate treatment compared with Psoriasis(+) patients not treated with methotrexate (AHR = 1.47; 95% CI = 1.05–2.06) (Table 4). Discussion Higher Risk of Developing Retinal Vein Occlusion in Patients With Psoriasis
Fig. 2. The cumulative incidence rate in Taiwan (2001–2011) of RVO in patients with psoriasis (Psoriasis(+)) and without (Psoriasis(−)). By the end of 2011, the cumulative incidence rate of RVO was higher in the Psoriasis(+) group than in the Psoriasis(−) group (P = 0.03).
The major finding in this study was that patients diagnosed with psoriasis between the years 2001 and 2006 had a substantially higher incidence of RVO than
0.43 ,0.01 0.67 0.38 0.59 — (0.66–2.67) (1.22–3.50)† (0.50–2.93) (0.20–1.86) (0.46–3.84) — 1.33 2.07 1.21 0.61 1.33
Cohort Psoriasis Yes No Age (years) 0–49 50–64 $65
10 29 45
48 36
18 41 11 5 8 0
21,443 4,392 4,363
14,825 15,373
1,654 3,624 1,255 1,097 892 45
*Rate: per 10,000 person-years. †P , 0.05. BRVO, branch RVO; CAD, coronary artery disease; CRVO, central RVO; PY, person-years.
14 21 9 8 6 0 1,667 3,713 1,238 1,061 857 37 1.60 1.63 1.26 0.64 1.37 — 11,228.74 25,229.21 8,714.15 7,858.30 5,831.56 317.42
84 21 (25.0%) 63 (75.0%) 30,198
All CRVO BRVO Age (years) 0–49 50–64 $65 Gender Male Female Comorbidity DM HTN CAD Hyperlipidemia COPD Obesity
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Table 3. Crude and AHRs of Cox Proportional Hazard Regressions and 95% CIs for the Development of RVO for the Study Cohorts
11,596.82 26,708.13 8,657.63 7,651.22 5,832.08 272.49
1.21 0.79 1.04 1.05 1.03 —
0.28 0.03 1.27 (0.83–1.94) 1.82 (1.05–3.14)† 14,750 15,448 4.25 3.00 112,926.99 119,861.14
38 20
113,554.75 120,885.52
3.35 1.65
0.42 0.21 ,0.01 0.72 (0.32–1.61) 1.43 (0.81–2.50) 1.97 (1.19–3.26)† 21,449 4,492 4,257 0.59 8.71 14.98 169,454.35 33,284.11 30,049.66
14 21 23
169,778.47 34,385.39 30,276.41
0.82 6.11 7.60
0.03 0.03 0.17 1.46 (1.04–2.04)† 2.35 (1.08–5.13)† 1.29 (0.89–1.88) 2.47 0.38 2.09 234,440.27 58 9 (15.5%) 49 (84.5%) 30,198 3.61 0.90 2.71 232,788.12
RVO RVO n Characteristics
n Rate* PY
Controls (Psoriasis(−)) Psoriasis(+) Patients
Table 2. Risk of RVO for Psoriasis(+) Patients and Psoriasis(−) Controls
IRR (95% CI) Rate* PY
P
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Sex Female Male DM Yes No HTN Yes No CAD Yes No Hyperlipidemia Yes No COPD Yes No Obesity Yes No
Crude Hazard Ratio (95% CI)
AHR (95% CI)
1.46 (1.04–2.04)* 1.00
1.50 (1.07–2.10)* 1.00
1.00 1.00 10.54 (6.47–17.14)* 8.96 (5.33–15.05)* 16.02 (10.06–25.52) 11.90 (6.77–20.92) * * 0.61 (0.44–0.86)* 1.00
0.87 (0.62–1.23) 1.00
5.72 (3.86–8.48)* 1.00
1.77 (1.15–2.71)* 1.00
6.25 (4.49–8.72)* 1.00
1.79 (1.21–2.65)* 1.00
4.27 (2.66–6.84)* 1.00
1.00 (0.60–1.65) 1.00
2.97 (1.68–5.26)* 1.00
0.87 (0.48–1.57) 1.00
4.27 (2.46–7.42)* 1.00
1.27 (0.72–2.26) 1.00
— 1.00
— 1.00
Adjusted for age, gender, DM, HTN, CAD, COPD, hyperlipidemia, monthly income, and geographical area of residence. *P , 0.05. CAD, coronary artery disease.
did patients from the general population without psoriasis. To the best of our knowledge, this is the first cohort study to examine the risk of RVO in patients with psoriasis. Hence, we cannot find corresponding literature with which to compare our findings. In the Psoriasis(−) control group, the incidence of RVO increased with the age of the patients: patients 65 years or older had the highest incidence of RVO (7.60 per 10,000 person-years). Our findings agree with other reports.2 Most (53.6%) of the patients in the Psoriasis(+) group who developed RVO were in the 65 years or older group. Compared with the Psoriasis(−) group, patients in the 65 years or older age group had a significantly higher incidence of RVO but patients in the other age groups did not. This discrepancy between different age groups may reflect agerelated differences in the clinical manifestations of psoriasis. This was compatible with our finding in
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Table 4. Crude and AHRs of Cox Proportional Hazard Regressions and 95% CIs for the Development of RVO for the Study Cohorts Variable
Cases
RVO
PY
Rate*
Crude HR (95% CI)
AHR (95% CI)
Psoriasis(−) Psoriasis(+) Psoriasis(+) with methotrexate
30,198 29,855 343
58 81 3
234,440.27 230,040.13 2,747.99
2.47 3.52 10.92
1.00 1.42 (1.02–1.99)† 4.36 (1.37–13.93)†
1.00 1.47 (1.05–2.06)† 3.78 (1.18–12.09)†
*Rate: per 10,000 person-years. †P , 0.05. HR, hazard ratio; PY, person-years.
patients with RVO comorbid with systemic lupus erythematosus, another common autoimmune disease.28 The risk of patients with psoriasis developing central RVO was significantly higher (IRR = 2.35; 95% CI = 1.08–5.13) than for Controls. Psoriasis(+) patients who needed methotrexate treatment had a significantly higher risk for RVO than did Psoriasis(+) patients who were not treated with methotrexate. These findings support our hypothesis that the risk of developing RVO increases with the severity of psoriasis. Hypertension is believed to be one of the major causes of central RVO.29 In addition, we found a synergistic effect for comorbid HTN in the Psoriasis(+) group. The risk of developing RVO was higher in the Psoriasis(+) subgroup with comorbid HTN (IRR = 2.07) than in the overall Psoriasis(+) group (IRR = 1.46) (Table 2). We found a significant difference (IRR = 1.82; 95% CI = 1.05–3.14) between women in the Psoriasis(+) and Psoriasis(−) groups for developing RVO. However, a multivariate Cox proportional hazard regression analysis showed no significant difference in the risk of developing RVO based on gender (AHR = 0.89; 95% CI = 0.63–1.25). Mechanisms Underlying the Higher Risk of Retinal Vein Occlusion in Patients With Psoriasis The underlying mechanism of developing RVO in patients with psoriasis remains unclear. There is growing evidence that patients with psoriasis have a higher prevalence of associated comorbid diseases, such as COPD, obesity, coronary artery disease, hyperlipidemia, DM, and HTN.30 Comorbidities of Chronic Obstructive Pulmonary Disease, Obesity, Coronary Artery Disease, and Hyperlipidemia Patients with psoriasis have a greater risk of developing COPD.31,32 Similarly, patients with branch RVO also showed a greater prevalence of COPD than
did the U.S. white control population.33 For example, psoriasis is characterized by increases in cytokines, such as tumor necrosis factor a, an inflammatory cytokine involved in the pathogenesis of both psoriasis and COPD.34,35 Obesity is considered a chronic low-grade inflammatory condition.36 Adipose tissue may secrete adipocytokines, such as tumor necrosis factor a, interleukin 6, and leptin, which may also be involved in the pathogenesis of psoriasis.37 Patients with psoriasis have higher levels of leptin, and psoriasis itself is an independent risk factor for hyperleptinemia,38 which is associated with increased intimal media thickness of the common carotid artery and with arterial thrombosis.39 Patients with a higher body mass index have a greater risk for RVO.40,41 RVO is also associated with increased intimal media thickness and arterial thrombosis.42,43 Therefore, it is possible for comorbid obesity to be a contributing factor for the increased risk of RVO in patients with psoriasis. Psoriasis is independently associated with cardiovascular disease, and both branch RVO and central RVO are associated with a higher risk of cardiovascular disease compared with the age-standardized risk in the British population.44 Patients with a history of cardiovascular disease have a greater risk of developing central RVO than do those without a history of cardiovascular disease.45,46 Inflammatory cells and pro-inflammatory cytokines are common contributing factors for the development of psoriatic lesions and the breakdown of atherosclerotic plaques.47 For example, tumor necrosis factor a is involved in the pathogenesis of both psoriasis and atherosclerosis.48 Hence, it is possible that a shared mechanism for both psoriasis and RVO in association with cardiovascular diseases accounts for the higher risk of RVO in patients with psoriasis. Psoriasis is associated with a higher risk of dyslipidemia.17 Possible underlying contributing factors include the cytokines interleukin 1, interleukin 6, and tumor necrosis factor a, which mediate psoriasis. Inflammation and a higher level of adhesion and of oxidants in endothelial cells in psoriasis imply early
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atherogenesis.49 These processes might also contribute to the development of RVO because one of the proposed risk factors of RVO is microvascular compromise in the retina.7,29 For these reasons, the comorbidities of COPD, obesity, coronary artery disease, and hyperlipidemia were matched between the Psoriasis(+) and Psoriasis(−) groups in the present study. A multivariate Cox proportional hazard regression analysis, however, showed no significant increase in the risk for RVO in Psoriasis(+) patients with those four comorbidities. Comorbidities of Diabetes Mellitus and HTN Several epidemiological studies11,12,50 have also argued that psoriasis is an independent risk factor for incident type 2 DM. Overproduction of Th1 cytokines in psoriasis is thought to be a possible mechanism underlying the increase of insulin resistance.10,11,51 Furthermore, DM is associated with a higher risk of RVO.3,29 Hence, microangiopathy may be one of the mechanisms shared between psoriasis and RVO in association with DM. Several studies9,52 have reported elevated angiotensin-converting enzyme activity and impairment of the vasodilation mechanism of the endothelium in patients with psoriasis.48 Hypertension is a strong risk factor for all forms of RVO. Endothelin-1, a potent vasoconstrictor, is also elevated in the serum and lesioned skin of Psoriasis(+) patients.53 Hypertension may increase arteriosclerosis, damage endothelial cells, and give rise to abnormalities of intercellular adhesion molecules (ICAM-1) with leukostasis predisposing the patient to RVO.54 Hence, comorbid HTN might be a reason for a higher risk of RVO in patients with psoriasis. In the present study, we found that the comorbidities of DM and HTN were significant for developing RVO in the overall groups. Further subgroup analyses with 6 comorbidities showed that the risk of developing RVO did not increase with comorbid DM but that it did with comorbid HTN (IRR: 2.07; P , 0.01). This implies that comorbid HTN contributes to developing RVO, and the association in the subgroup was more pronounced than it was in the overall group in the present study. Because the baseline comorbidity of HTN was not significantly different between the Psoriasis(+) and Psoriasis(−) groups, we may conclude that there was a synergistic effect between HTN and psoriasis for developing RVO. Strengths and Limitations This study, with its large sample size, indicates that patients with psoriasis have an elevated risk of
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developing RVO. This nationwide population-based dataset, which includes a large sample of psoriasis cases and longitudinal follow-ups, allows researchers to analyze the risk factors for developing RVO with a minimal selection bias. The large sample size also increases the statistical power and precision of risk appraisal. This study has some limitations. Several suspected risk factors for RVO were not available in the insurance database, such as current blood pressure and laboratory data of serum cholesterol and triglyceride levels. The insurance claims data did not include information on the severity of RVO, severity status of the comorbid chronic diseases, or other laboratory test results. The inability to assess these factors may have introduced some bias. Awareness of the elevated risk of developing RVO in patients with psoriasis might prompt the early detection and treatment of RVO. Medications that control autoimmune activity may benefit patients with psoriasis who are at risk for developing RVO. With appropriate and timely medical interventions, the prognosis of RVO in patients diagnosed with psoriasis is good. Additional investigations of the mechanism behind the association between psoriasis and RVO are recommended. Conclusion Psoriasis was associated with a significantly higher risk of developing RVO, especially in patients who were 65 years or older and females. Key words: retinal vein occlusion, psoriasis, autoimmune disease. Acknowledgments This study was based in part on data from the Taiwan National Health Insurance Research Database provided by the Taiwan Bureau of National Health Insurance. The interpretation and conclusions contained herein do not represent those of the Taiwan Bureau of National Health Insurance. References 1. Shahid H, Hossain P, Amoaku WM. The management of retinal vein occlusion: is interventional ophthalmology the way forward? Br J Ophthalmol 2006;90:627–639. 2. Hayreh SS, Zimmerman MB, Podhajsky P. Incidence of various types of retinal vein occlusion and their recurrence and demographic characteristics. Am J Ophthalmol 1994;117:429–441. 3. Shrestha RK, Shrestha JK, Koirala S, Shah DN. Association of systemic diseases with retinal vein occlusive disease. JNMA J Nepal Med Assoc 2006;45:244–248.
PSORIASIS AND RETINAL VEIN OCCLUSION YEN ET AL 4. Bertelsen M, Linneberg A, Rosenberg T, et al. Comorbidity in patients with branch retinal vein occlusion: case-control study. BMJ 2012;345:e7885. 5. Schmidt D. Comorbidities in combined retinal artery and vein occlusions. Eur J Med Res 2013;18:27. 6. Koizumi H, Ferrara DC, Brue C, Spaide RF. Central retinal vein occlusion case-control study. Am J Ophthalmol 2007;144: 858–863. 7. Marcucci R, Bertini L, Giusti B, et al. Thrombophilic risk factors in patients with central retinal vein occlusion. Thromb Haemost 2001;86:772–776. 8. Adamczuk YP, Iglesias Varela ML, Martinuzzo ME, et al. Central retinal vein occlusion and thrombophilia risk factors. Blood Coagul Fibrinolysis 2002;13:623–626. 9. Liu T, Han Y, Lu L. Angiotensin-converting enzyme gene polymorphisms and the risk of psoriasis: a meta-analysis. Clin Exp Dermatol 2013;38:352–358. 10. Qureshi AA, Choi HK, Setty AR, Curhan GC. Psoriasis and the risk of diabetes and hypertension: a prospective study of US female nurses. Arch Dermatol 2009;145:379–382. 11. Brauchli YB, Jick SS, Meier CR. Psoriasis and the risk of incident diabetes mellitus: a population-based study. Br J Dermatol 2008;159:1331–1337. 12. Azfar RS, Seminara NM, Shin DB, et al. Increased risk of diabetes mellitus and likelihood of receiving diabetes mellitus treatment in patients with psoriasis. Arch Dermatol 2012;148:995–1000. 13. Pietrzak A, Bartosinska J, Chodorowska G, et al. Cardiovascular aspects of psoriasis: an updated review. Int J Dermatol 2013;52:153–162. 14. Ahlehoff O, Gislason G, Hansen PR. Cardiovascular aspects of psoriasis: an updated review. Int J Dermatol 2014;53:e337. 15. Ni C, Chiu MW. Psoriasis and comorbidities: links and risks. Clin Cosmet Investig Dermatol 2014;7:119–132. 16. Rocha-Pereira P, Santos-Silva A, Rebelo I, et al. Dislipidemia and oxidative stress in mild and in severe psoriasis as a risk for cardiovascular disease. Clin Chim Acta 2001;303:33–39. 17. Ma C, Harskamp CT, Armstrong EJ, Armstrong AW. The association between psoriasis and dyslipidaemia: a systematic review. Br J Dermatol 2013;168:486–495. 18. Mirshahi A, Hoehn R, Lorenz K, et al. Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts. J Ophthalmic Vis Res 2012;7:39–44. 19. Vergou T, Moustou AE, Maniateas A, et al. Central retinal vein occlusion following infliximab treatment for plaque-type psoriasis. Int J Dermatol 2010;49:1215–1217. 20. Deobhakta A, Chang LK. Inflammation in retinal vein occlusion. Int J Inflam 2013;2013:438412. 21. Montehermoso A, Cervera R, Font J, et al. Association of antiphospholipid antibodies with retinal vascular disease in systemic lupus erythematosus. Semin Arthritis Rheum 1999; 28:326–332. 22. Raychaudhuri SK, Maverakis E, Raychaudhuri SP. Diagnosis and classification of psoriasis. Autoimmun Rev 2014;13: 490–495. 23. Prieto-Perez R, Cabaleiro T, Dauden E, et al. Genetics of psoriasis and pharmacogenetics of biological drugs. Autoimmune Dis 2013;2013:613086. 24. Han R, Rostami-Yazdi M, Gerdes S, Mrowietz U. Triptolide in the treatment of psoriasis and other immune-mediated inflammatory diseases. Br J Clin Pharmacol 2012;74:424–436. 25. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361:496–509. 26. Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127:757–763.
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27. LoriS Parsons. Performing a 1:N case-control Match on propensity score. In: Ovation Research Group, ed. Seattle, Washington: Proceedings of the 29th SAS Users Group International. Montreal, Canada; 2004. 28. Yen YC, Weng SF, Chen HA, Lin YS. Risk of retinal vein occlusion in patients with systemic lupus erythematosus: a population-based cohort study. Br J Ophthalmol 2013;97:1192–1196. 29. Stem MS, Talwar N, Comer GM, Stein JD. A longitudinal analysis of risk factors associated with central retinal vein occlusion. Ophthalmology 2013;120:362–370. 30. Onumah N, Kircik LH. Psoriasis and its comorbidities. J Drugs Dermatol 2012;11:s5–10. 31. Chiang YY, Lin HW. Association between psoriasis and chronic obstructive pulmonary disease: a population-based study in Taiwan. J Eur Acad Dermatol Venereol 2012;26:59–65. 32. Dreiher J, Weitzman D, Shapiro J, et al. Psoriasis and chronic obstructive pulmonary disease: a case-control study. Br J Dermatol 2008;159:956–960. 33. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol 2001;131:61–77. 34. Fabbri LM, Luppi F, Beghe B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204–212. 35. Schon MP, Boehncke WH. Psoriasis. N Engl J Med 2005;352: 1899–1912. 36. Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010;2010: 289645. doi:10.1155/2010/289645. 37. Hamminga EA, van der Lely AJ, Neumann HA, Thio HB. Chronic inflammation in psoriasis and obesity: implications for therapy. Med Hypotheses 2006;67:768–773. 38. Chen YJ, Wu CY, Shen JL, et al. Psoriasis independently associated with hyperleptinemia contributing to metabolic syndrome. Arch Dermatol 2008;144:1571–1575. 39. Ciccone M, Vettor R, Pannacciulli N, et al. Plasma leptin is independently associated with the intima-media thickness of the common carotid artery. Int J Obes Relat Metab Disord 2001;25:805–810. 40. Lam HD, Lahey JM, Kearney JJ, et al. Young patients with branch retinal vein occlusion: a review of 60 cases. Retina 2010;30:1520–1523. 41. Xu L, You QS, Liu W, Jonas JB. Smoking and retinal vein occlusions. The Beijing Eye study. Graefes Arch Clin Exp Ophthalmol 2010;248:1045–1046. 42. Carbone J, Sanchez-Ramon S, Cobo-Soriano R, et al. Antiphospholipid antibodies: a risk factor for occlusive retinal vascular disorders. Comparison with ocular inflammatory diseases. J Rheumatol 2001;28:2437–2441. 43. Levy J, Baumgarten A, Rosenthal G, et al. Consecutive central retinal artery and vein occlusions in primary antiphospholipid syndrome. Retina 2002;22:784–786. 44. Martin SC, Butcher A, Martin N, et al. Cardiovascular risk assessment in patients with retinal vein occlusion. Br J Ophthalmol 2002;86:774–776. 45. Risk factors for central retinal vein occlusion. The Eye disease case-control study group. Arch Ophthalmol 1996;114:545–554. 46. Kohner EM, Cappin JM. Do medical conditions have an influence on central retinal vein occlusions? Proc R Soc Med 1974; 67:1052–1054. 47. Balta I, Balta S, Demirkol S, et al. Aortic arterial stiffness is a moderate predictor of cardiovascular disease in patients with psoriasis vulgaris. Angiology 2014;65:74–78. 48. Costa L, Caso F, D’Elia L, et al. Psoriatic arthritis is associated with increased arterial stiffness in the absence of known
1794 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES cardiovascular risk factors: a case control study. Clin Rheumatol 2012;31:711–715. 49. Tekin NS, Tekin IO, Barut F, Sipahi EY. Accumulation of oxidized low-density lipoprotein in psoriatic skin and changes of plasma lipid levels in psoriatic patients. Mediators Inflamm 2007;2007:78454. 50. Al-Mutairi N, Al-Farag S, Al-Mutairi A, Al-Shiltawy M. Comorbidities associated with psoriasis: an experience from the Middle East. J Dermatol 2010;37:146–155. 51. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005;115:1111–1119.
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52. Ena P, Madeddu P, Glorioso N, et al. High prevalence of cardiovascular diseases and enhanced activity of the reninangiotensin system in psoriatic patients. Acta Cardiol 1985; 40:199–205. 53. Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and hypertension: a systematic review and meta-analysis of observational studies. J Hypertens 2013;31: 433–442; discussion 442–433. 54. Noma H, Funatsu H, Sakata K, et al. Macular microcirculation in hypertensive patients with and without branch retinal vein occlusion. Acta Ophthalmol 2009;87:638–642.
R
prone to have RVO.2 Several studies have identified the systemic risk factors of RVO: hypertension (HTN),3,4 diabetes mellitus (DM),3,4 systemic vascular disease,5 and hypercoagulable states.3,6–8 Because psoriasis is a chronic inflammatory skin disease that involves multiple underlying genetic and environmental factors, the association between psoriasis and other diseases has drawn increasing interest in recent years. Many studies have reported that the prevalences of HTN,9,10 DM,11,12 cardiovascular disease,13,14 and dyslipidemia15–17 are higher in patients with psoriasis than in the general population. Systemic inflammatory mediators generated in psoriasis were hypothesized18,19 to be the underlying mechanism of the associations between these comorbid diseases and psoriasis. The role of systemic inflammation in the pathogenesis and clinical consequences of RVO is a topic of growing interest.20 Autoimmune disease, an immune response caused by systemic inflammation, has long been recognized as a significant risk factor for RVO.20 Moreover, the retinal microangiopathy associated with autoimmune disease is thought to result from
etinal vein occlusion (RVO) is the second most common vascular disease affecting the retina.1,2 In general, middle-aged and elderly people are more From the *Department of Ophthalmology, Chi Mei Medical Center, Liou-Ying, Tainan City, Taiwan; †Department of Nursing, Min Hwei College of Health Care Management, Tainan City, Taiwan; ‡Department of Medical Research, Chi Mei Medical Center, YungKang District, Tainan City, Taiwan; §Department of Hospital and Health Care Administration, Chia-Nan University of Pharmacy and Science, Ren De District, Tainan City, Taiwan; ¶Department of Dermatology, Chi Mei Medical Center, Yung-Kang District, Tainan City, Taiwan; **Center for General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan; ††Department of Otolaryngology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; and ‡‡Department of Otolaryngology, Chi Mei Medical Center, Yung-Kang District, Tainan City, Taiwan. Supported by Taipei Medical University-Chi Mei Medical Center Research Fund, grant number 09909-066. None of the authors have conflicting interests to disclose. Y-C. Yen made substantial contributions to study design and was involved in acquiring data. Y-S. Lin, F-J. Lai, and S-F. Weng made substantial contributions to study conception and design and did data analysis. All authors reviewed and approved the manuscript’s content before submission and jointly agreed to submit the final version. Reprint requests: Yung-Song Lin, MD, Center for General Education, Southern Taiwan University of Science and Technology, 901 Chung Hwa Road, Yung Kan District, Tainan City 710, Taiwan; e-mail: [email protected]
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immune complex–mediated vascular injury and microvascular thrombosis.8,20,21 Psoriasis is recognized as an autoimmune disease22,23 or an immune-mediated inflammatory disease.24,25 Therefore, RVO may be a manifestation of systemic vascular involvement in psoriasis and may have an important effect on health. However, the risk of patients with psoriasis developing RVO has not been systematically examined. We used data from Taiwan’s National Health Insurance Research Database to retrospectively investigate the incidence of RVO in patients with psoriasis. The effects of six comorbidities—DM, HTN, coronary heart disease (CHD), hyperlipidemia, obesity, and chronic obstructive pulmonary disease (COPD)—on the risk of developing RVO were also examined. Materials and Methods Data Sources The Taiwan National Health Insurance program is a universal health-care system that covers 99% of the country’s population of 23.3 million. The data used in this analysis were obtained from the Longitudinal Health Insurance Database 2000, a sub-dataset of National Health Insurance Research Database, which contains all claims data (from 1996 to 2011) of 1 million beneficiaries who were systemic and randomly selected in 2000. There were no significant differences in age, gender, or health-care costs between the sample group and all enrolled residents. The database contains encrypted patient identification numbers, ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes for applied clinical diagnoses and procedures, details of prescribed drugs, dates of admission and discharge, and basic sociodemographic information, including gender and date of birth. Design This was a retrospective cohort study with two study groups: patients with psoriasis (Psoriasis(+) group) and controls without psoriasis (Psoriasis(−) group). The Psoriasis(+) group included patients with an initial diagnosis of psoriasis (ICD-9 codes 690, 696.0, and 696.1). Patients without medical claims for psoriasis who matched the patients in the Psoriasis(+) group in gender, age (±30 days), and index date were randomly selected for the Psoriasis(−) group. The index date for the patients with psoriasis was the date between 2001 and 2006 on which they were first registered as having psoriasis. The index dates for the Psoriasis(−) group were matched based on the index dates of the Psoriasis(+) group. A visit to a physician approximately
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on the index date (±30 days) was required for each patient in the Psoriasis(−) group. Other comorbidities that may have been presented before the index date were defined as follows: DM (ICD-9 code 250.x), HTN (ICD-9 codes 401.x–405.x), CHD (ICD-9 codes 410.x–414.x, A270, and A279), hyperlipidemia (ICD-9 code 272.x), obesity (ICD-9 code 278.x), and COPD (ICD-9 code 496.0). The comorbidities were identified only through a corresponding diagnosis made during admission or by a physician at an outpatient clinic during each of three visits. Controls (Psoriasis(−) group) were matched using a propensity score by age, gender, and comorbid DM, HTN, CHD, hyperlipidemia, obesity, COPD, geographic distribution, and monthly income. Diagnoses of psoriasis and newly developed RVO (ICD-9 codes 362.35 and 362.36) were provided by referral teaching hospitals and tertiary referral medical centers. To investigate the association between the occurrence of RVO and the disease progress of psoriasis, only patients with newly diagnosed psoriasis between 2001 and 2006 were included. The claims data from 1996 to 2000 were used to confirm that none of the enrolled patients had ever been diagnosed with psoriasis or RVO before 2001. The dates of look back were January 1, 1996, to December 31, 2000, before the first index date of January 1, 2001. We assumed that a latent period was necessary for the chronic disease, that is, psoriasis in this case, to have an effect on the occurrence of RVO. Hence, patients were followed-up for a minimum of 6 years (2006–2011) to determine the incidence of RVO until the end of 2011 or until they were censored because of death. Each enrolled patient had to have been registered in this National Health Insurance system since 1996 without termination until the end of 2011, unless they were censored because of death. The identification numbers of all the patients in the National Health Insurance Research Database are encrypted to protect their privacy. The Institutional Review Board of Chi Mei Medical Center approved this study. Statistical Analyses Descriptive statistical analyses using Pearson’s x2 tests were done to compare the differences in sociodemographic characteristics and comorbidities between the Psoriasis(+) and Psoriasis(−) groups. The incidence rate was calculated as the number of RVO cases identified during follow-up divided by the total person-years for each group by gender, age, and comorbidities. The risk of developing RVO was compared by estimating the incidence ratio using a Poisson regression. The risk of developing RVO associated with the comorbidities of DM, HTN, CHD, hyperlipidemia, obesity, and
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COPD was estimated using a Cox proportional hazard models. A Cox proportional hazard regression analysis with propensity score matching was used to estimate the hazard ratio between the Psoriasis(+) and Psoriasis(−) groups. To compare the risk of RVO between two groups, we used propensity score (for diagnosed Psoriasis(+) as the treatment assignment) matching by a greedy algorithm to ensure better comparability among the two groups and minimize possible selection bias in choosing Psoriasis(+) or Psoriasis(−). Propensity score matching, which can bundle many confounding covariates that may be present in an observational study with this number of variables, was used to reduce any selection bias in our hypothesis.26 Score matching identified the predicted probability of obtaining one Psoriasis(+) patient versus one Psoriasis(−) patient from the logistic regression model according to the baseline covariates of age, gender, and the six comorbidities. Afterward, an SAS matching macro, “%OneToManyMTCH,” which was proposed by the Proceedings of the 29th SAS Users Group International,27 was used in this study. It allows propensity score matching from 1-to-1 to 1-to-N based on user specifications using the greedy-matching algorithm (without replacement). The macro makes “best” matches first and “next-best” matches next, in a hierarchical sequence, until no more matches can be made. Each control is selected once at most. The final matched-pair samples contain closely matched individual pairs and balanced Psoriasis(+) and Psoriasis(−) groups (Figure 1). A Cox proportional hazard regression analysis and a Kaplan–Meier survival analysis were used to calculate the cumulative incidence rates of RVO in the two cohorts, and the log-rank test was used to analyze the
Fig. 1. The distribution of propensity scores in patients with psoriasis (Psoriasis(+)) and without (Psoriasis(−)). The distribution of propensity scores in Psoriasis(+) and Psoriasis(−) groups revealed a C statistic value of 0.57 that indicated a big overlap between Psoriasis(+) and Psoriasis(−) groups in our study.
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differences between the survival curves. SAS 9.3 for Windows (SAS Institute, Cary, NC) was used for all statistical analyses. Significance was set at P , 0.05 (two tailed). Results The Incidence of Retinal Vein Occlusion Based on Patient Characteristics Based on the 2001 to 2006 claims data, before the propensity score matching, 30,227 patients (females: 15,395; males: 14,832) with new psoriasis were defined. After the propensity score matching, 30,198 patients (females: 15,373 [50.91%]; males: 14,825) with psoriasis met the eligibility criteria and an additional 30,198 participants without medical claims for psoriasis who were gender, age (±30 days), comorbidity, geographic distribution, monthly income, and index date matched with the patients in the Psoriasis(+) group were selected as controls. The distribution of propensity scores of the Psoriasis(+) and Psoriasis(−) groups were illustrated in Figure 1. The annual incidence of psoriasis in Taiwan averaged 0.13% between 2001 and 2006. There were no significant differences in sociodemographic characteristics (age, gender, monthly income, and geographic distribution) or comorbid medical disorders between the Psoriasis(+) and Psoriasis(−) groups (Table 1). The estimated risks of developing RVO based on gender, age, and the comorbid diseases in the two groups were compared. By the end of the follow-up period, the cumulative incidence rate of RVO was higher in the Psoriasis(+) group than in the Psoriasis(−) group (P = 0.03) (Figure 2). The incidence rates of RVO classified by gender, age, and comorbid diseases were also compared. Psoriasis(+) patients 65 years or older had a significantly (P , 0.01) higher risk and an incidence rate 1.97 times higher (95% confidence interval [CI] = 1.19–3.26) than did their Psoriasis(−) counterparts (Table 2). In both groups, patients 65 years or older had a higher incidence of RVO than did patients 0 to 49 years old (adjusted hazard ratio [AHR]: 11.90; 95% CI = 6.77–20.92) (Table 3). The incidence rate of RVO was significantly (P = 0.03) higher only for women in the Psoriasis(+) group (incidence rate ratio [IRR]: 1.82; P = 0.03) than in the Psoriasis(−) group (Table 2). Association Between Retinal Vein Occlusion and the Comorbidities In general, the risk of developing RVO was higher in the Psoriasis(+) group than in the Psoriasis(−) group
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Table 1. Demographic Characteristics and Comorbid Medical Disorders for Psoriasis(+) Patients and Psoriasis(−) Patients in Taiwan
Age (years) 0–49 50–64 $65 Gender Female Male Baseline comorbidity DM HTN CAD Hyperlipidemia COPD Obesity Geographic distribution North Central South East Monthly income NT$ , 15,840 NT$ 15,841–25,000 NT$ . 25,001
Psoriasis(+)
Controls (Psoriasis(−))
n = 30,198
n = 30,198
21,443 (71.01) 4,392 (14.54) 4,363 (14.45)
21,449 (71.03) 4,492 (14.88) 4,257 (14.10)
15,373 (50.91) 14,825 (49.09)
15,448 (51.16) 14,750 (48.84)
P 0.30
0.54
1,654 3,624 1,255 1,097 892 45
(5.48) (12.00) (4.16) (3.63) (2.95) (0.15)
1,667 3,713 1,238 1,061 857 37
(5.52) (12.30) (4.10) (3.51) (2.84) (0.12)
14,309 5,892 9,109 888
(47.38) (19.51) (30.16) (2.94)
14,273 5,862 9,199 864
(47.26) (19.41) (30.46) (2.86)
12,107 (40.09) 8,441 (27.95) 9,650 (31.96)
12,027 (39.83) 8,460 (28.02) 9,711 (32.16)
0.82 0.27 0.73 0.43 0.40 0.38 0.83
0.79
CAD, coronary artery disease; NT$, New Taiwan dollars (U.S. $1 = ca. NT$ 30).
(AHR: 1.50; 95% CI = 1.07–2.10). The comorbid diseases were matched between the two groups. A multivariate Cox proportional hazard regression analysis, which included gender, age, geographic distribution, monthly income, and comorbidities in the model, revealed no significant differences in the risk of developing RVO between patients with and those without the comorbidities of CHD, hyperlipidemia, obesity, and COPD (Table 3). However, there were significant
differences in the risk of developing RVO between patients with and without the comorbidities of DM (AHR = 1.75; 95% CI = 1.14–2.67) and HTN (AHR = 1.72; 95% CI = 1.17–2.53) (Table 3). Subgroup analysis by comorbid disease showed that the risk of developing RVO was significantly higher only in the subgroup with comorbid HTN (IRR: 2.07; P , 0.01). Methotrexate is used as an alternative or second-line therapy to treat severe psoriasis when first-line creams, ointments, tar products, and phototherapy have not worked or cannot be used. A multivariate Cox proportional hazard regression analysis with gender, age, geographic distribution, monthly income, and comorbidities as variables revealed a significantly higher risk of RVO in Psoriasis(+) patients (AHR = 3.78; 95% CI = 1.18–12.09) who needed methotrexate treatment compared with Psoriasis(+) patients not treated with methotrexate (AHR = 1.47; 95% CI = 1.05–2.06) (Table 4). Discussion Higher Risk of Developing Retinal Vein Occlusion in Patients With Psoriasis
Fig. 2. The cumulative incidence rate in Taiwan (2001–2011) of RVO in patients with psoriasis (Psoriasis(+)) and without (Psoriasis(−)). By the end of 2011, the cumulative incidence rate of RVO was higher in the Psoriasis(+) group than in the Psoriasis(−) group (P = 0.03).
The major finding in this study was that patients diagnosed with psoriasis between the years 2001 and 2006 had a substantially higher incidence of RVO than
0.43 ,0.01 0.67 0.38 0.59 — (0.66–2.67) (1.22–3.50)† (0.50–2.93) (0.20–1.86) (0.46–3.84) — 1.33 2.07 1.21 0.61 1.33
Cohort Psoriasis Yes No Age (years) 0–49 50–64 $65
10 29 45
48 36
18 41 11 5 8 0
21,443 4,392 4,363
14,825 15,373
1,654 3,624 1,255 1,097 892 45
*Rate: per 10,000 person-years. †P , 0.05. BRVO, branch RVO; CAD, coronary artery disease; CRVO, central RVO; PY, person-years.
14 21 9 8 6 0 1,667 3,713 1,238 1,061 857 37 1.60 1.63 1.26 0.64 1.37 — 11,228.74 25,229.21 8,714.15 7,858.30 5,831.56 317.42
84 21 (25.0%) 63 (75.0%) 30,198
All CRVO BRVO Age (years) 0–49 50–64 $65 Gender Male Female Comorbidity DM HTN CAD Hyperlipidemia COPD Obesity
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Table 3. Crude and AHRs of Cox Proportional Hazard Regressions and 95% CIs for the Development of RVO for the Study Cohorts
11,596.82 26,708.13 8,657.63 7,651.22 5,832.08 272.49
1.21 0.79 1.04 1.05 1.03 —
0.28 0.03 1.27 (0.83–1.94) 1.82 (1.05–3.14)† 14,750 15,448 4.25 3.00 112,926.99 119,861.14
38 20
113,554.75 120,885.52
3.35 1.65
0.42 0.21 ,0.01 0.72 (0.32–1.61) 1.43 (0.81–2.50) 1.97 (1.19–3.26)† 21,449 4,492 4,257 0.59 8.71 14.98 169,454.35 33,284.11 30,049.66
14 21 23
169,778.47 34,385.39 30,276.41
0.82 6.11 7.60
0.03 0.03 0.17 1.46 (1.04–2.04)† 2.35 (1.08–5.13)† 1.29 (0.89–1.88) 2.47 0.38 2.09 234,440.27 58 9 (15.5%) 49 (84.5%) 30,198 3.61 0.90 2.71 232,788.12
RVO RVO n Characteristics
n Rate* PY
Controls (Psoriasis(−)) Psoriasis(+) Patients
Table 2. Risk of RVO for Psoriasis(+) Patients and Psoriasis(−) Controls
IRR (95% CI) Rate* PY
P
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Sex Female Male DM Yes No HTN Yes No CAD Yes No Hyperlipidemia Yes No COPD Yes No Obesity Yes No
Crude Hazard Ratio (95% CI)
AHR (95% CI)
1.46 (1.04–2.04)* 1.00
1.50 (1.07–2.10)* 1.00
1.00 1.00 10.54 (6.47–17.14)* 8.96 (5.33–15.05)* 16.02 (10.06–25.52) 11.90 (6.77–20.92) * * 0.61 (0.44–0.86)* 1.00
0.87 (0.62–1.23) 1.00
5.72 (3.86–8.48)* 1.00
1.77 (1.15–2.71)* 1.00
6.25 (4.49–8.72)* 1.00
1.79 (1.21–2.65)* 1.00
4.27 (2.66–6.84)* 1.00
1.00 (0.60–1.65) 1.00
2.97 (1.68–5.26)* 1.00
0.87 (0.48–1.57) 1.00
4.27 (2.46–7.42)* 1.00
1.27 (0.72–2.26) 1.00
— 1.00
— 1.00
Adjusted for age, gender, DM, HTN, CAD, COPD, hyperlipidemia, monthly income, and geographical area of residence. *P , 0.05. CAD, coronary artery disease.
did patients from the general population without psoriasis. To the best of our knowledge, this is the first cohort study to examine the risk of RVO in patients with psoriasis. Hence, we cannot find corresponding literature with which to compare our findings. In the Psoriasis(−) control group, the incidence of RVO increased with the age of the patients: patients 65 years or older had the highest incidence of RVO (7.60 per 10,000 person-years). Our findings agree with other reports.2 Most (53.6%) of the patients in the Psoriasis(+) group who developed RVO were in the 65 years or older group. Compared with the Psoriasis(−) group, patients in the 65 years or older age group had a significantly higher incidence of RVO but patients in the other age groups did not. This discrepancy between different age groups may reflect agerelated differences in the clinical manifestations of psoriasis. This was compatible with our finding in
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Table 4. Crude and AHRs of Cox Proportional Hazard Regressions and 95% CIs for the Development of RVO for the Study Cohorts Variable
Cases
RVO
PY
Rate*
Crude HR (95% CI)
AHR (95% CI)
Psoriasis(−) Psoriasis(+) Psoriasis(+) with methotrexate
30,198 29,855 343
58 81 3
234,440.27 230,040.13 2,747.99
2.47 3.52 10.92
1.00 1.42 (1.02–1.99)† 4.36 (1.37–13.93)†
1.00 1.47 (1.05–2.06)† 3.78 (1.18–12.09)†
*Rate: per 10,000 person-years. †P , 0.05. HR, hazard ratio; PY, person-years.
patients with RVO comorbid with systemic lupus erythematosus, another common autoimmune disease.28 The risk of patients with psoriasis developing central RVO was significantly higher (IRR = 2.35; 95% CI = 1.08–5.13) than for Controls. Psoriasis(+) patients who needed methotrexate treatment had a significantly higher risk for RVO than did Psoriasis(+) patients who were not treated with methotrexate. These findings support our hypothesis that the risk of developing RVO increases with the severity of psoriasis. Hypertension is believed to be one of the major causes of central RVO.29 In addition, we found a synergistic effect for comorbid HTN in the Psoriasis(+) group. The risk of developing RVO was higher in the Psoriasis(+) subgroup with comorbid HTN (IRR = 2.07) than in the overall Psoriasis(+) group (IRR = 1.46) (Table 2). We found a significant difference (IRR = 1.82; 95% CI = 1.05–3.14) between women in the Psoriasis(+) and Psoriasis(−) groups for developing RVO. However, a multivariate Cox proportional hazard regression analysis showed no significant difference in the risk of developing RVO based on gender (AHR = 0.89; 95% CI = 0.63–1.25). Mechanisms Underlying the Higher Risk of Retinal Vein Occlusion in Patients With Psoriasis The underlying mechanism of developing RVO in patients with psoriasis remains unclear. There is growing evidence that patients with psoriasis have a higher prevalence of associated comorbid diseases, such as COPD, obesity, coronary artery disease, hyperlipidemia, DM, and HTN.30 Comorbidities of Chronic Obstructive Pulmonary Disease, Obesity, Coronary Artery Disease, and Hyperlipidemia Patients with psoriasis have a greater risk of developing COPD.31,32 Similarly, patients with branch RVO also showed a greater prevalence of COPD than
did the U.S. white control population.33 For example, psoriasis is characterized by increases in cytokines, such as tumor necrosis factor a, an inflammatory cytokine involved in the pathogenesis of both psoriasis and COPD.34,35 Obesity is considered a chronic low-grade inflammatory condition.36 Adipose tissue may secrete adipocytokines, such as tumor necrosis factor a, interleukin 6, and leptin, which may also be involved in the pathogenesis of psoriasis.37 Patients with psoriasis have higher levels of leptin, and psoriasis itself is an independent risk factor for hyperleptinemia,38 which is associated with increased intimal media thickness of the common carotid artery and with arterial thrombosis.39 Patients with a higher body mass index have a greater risk for RVO.40,41 RVO is also associated with increased intimal media thickness and arterial thrombosis.42,43 Therefore, it is possible for comorbid obesity to be a contributing factor for the increased risk of RVO in patients with psoriasis. Psoriasis is independently associated with cardiovascular disease, and both branch RVO and central RVO are associated with a higher risk of cardiovascular disease compared with the age-standardized risk in the British population.44 Patients with a history of cardiovascular disease have a greater risk of developing central RVO than do those without a history of cardiovascular disease.45,46 Inflammatory cells and pro-inflammatory cytokines are common contributing factors for the development of psoriatic lesions and the breakdown of atherosclerotic plaques.47 For example, tumor necrosis factor a is involved in the pathogenesis of both psoriasis and atherosclerosis.48 Hence, it is possible that a shared mechanism for both psoriasis and RVO in association with cardiovascular diseases accounts for the higher risk of RVO in patients with psoriasis. Psoriasis is associated with a higher risk of dyslipidemia.17 Possible underlying contributing factors include the cytokines interleukin 1, interleukin 6, and tumor necrosis factor a, which mediate psoriasis. Inflammation and a higher level of adhesion and of oxidants in endothelial cells in psoriasis imply early
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atherogenesis.49 These processes might also contribute to the development of RVO because one of the proposed risk factors of RVO is microvascular compromise in the retina.7,29 For these reasons, the comorbidities of COPD, obesity, coronary artery disease, and hyperlipidemia were matched between the Psoriasis(+) and Psoriasis(−) groups in the present study. A multivariate Cox proportional hazard regression analysis, however, showed no significant increase in the risk for RVO in Psoriasis(+) patients with those four comorbidities. Comorbidities of Diabetes Mellitus and HTN Several epidemiological studies11,12,50 have also argued that psoriasis is an independent risk factor for incident type 2 DM. Overproduction of Th1 cytokines in psoriasis is thought to be a possible mechanism underlying the increase of insulin resistance.10,11,51 Furthermore, DM is associated with a higher risk of RVO.3,29 Hence, microangiopathy may be one of the mechanisms shared between psoriasis and RVO in association with DM. Several studies9,52 have reported elevated angiotensin-converting enzyme activity and impairment of the vasodilation mechanism of the endothelium in patients with psoriasis.48 Hypertension is a strong risk factor for all forms of RVO. Endothelin-1, a potent vasoconstrictor, is also elevated in the serum and lesioned skin of Psoriasis(+) patients.53 Hypertension may increase arteriosclerosis, damage endothelial cells, and give rise to abnormalities of intercellular adhesion molecules (ICAM-1) with leukostasis predisposing the patient to RVO.54 Hence, comorbid HTN might be a reason for a higher risk of RVO in patients with psoriasis. In the present study, we found that the comorbidities of DM and HTN were significant for developing RVO in the overall groups. Further subgroup analyses with 6 comorbidities showed that the risk of developing RVO did not increase with comorbid DM but that it did with comorbid HTN (IRR: 2.07; P , 0.01). This implies that comorbid HTN contributes to developing RVO, and the association in the subgroup was more pronounced than it was in the overall group in the present study. Because the baseline comorbidity of HTN was not significantly different between the Psoriasis(+) and Psoriasis(−) groups, we may conclude that there was a synergistic effect between HTN and psoriasis for developing RVO. Strengths and Limitations This study, with its large sample size, indicates that patients with psoriasis have an elevated risk of
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developing RVO. This nationwide population-based dataset, which includes a large sample of psoriasis cases and longitudinal follow-ups, allows researchers to analyze the risk factors for developing RVO with a minimal selection bias. The large sample size also increases the statistical power and precision of risk appraisal. This study has some limitations. Several suspected risk factors for RVO were not available in the insurance database, such as current blood pressure and laboratory data of serum cholesterol and triglyceride levels. The insurance claims data did not include information on the severity of RVO, severity status of the comorbid chronic diseases, or other laboratory test results. The inability to assess these factors may have introduced some bias. Awareness of the elevated risk of developing RVO in patients with psoriasis might prompt the early detection and treatment of RVO. Medications that control autoimmune activity may benefit patients with psoriasis who are at risk for developing RVO. With appropriate and timely medical interventions, the prognosis of RVO in patients diagnosed with psoriasis is good. Additional investigations of the mechanism behind the association between psoriasis and RVO are recommended. Conclusion Psoriasis was associated with a significantly higher risk of developing RVO, especially in patients who were 65 years or older and females. Key words: retinal vein occlusion, psoriasis, autoimmune disease. Acknowledgments This study was based in part on data from the Taiwan National Health Insurance Research Database provided by the Taiwan Bureau of National Health Insurance. The interpretation and conclusions contained herein do not represent those of the Taiwan Bureau of National Health Insurance. References 1. Shahid H, Hossain P, Amoaku WM. The management of retinal vein occlusion: is interventional ophthalmology the way forward? Br J Ophthalmol 2006;90:627–639. 2. Hayreh SS, Zimmerman MB, Podhajsky P. Incidence of various types of retinal vein occlusion and their recurrence and demographic characteristics. Am J Ophthalmol 1994;117:429–441. 3. Shrestha RK, Shrestha JK, Koirala S, Shah DN. Association of systemic diseases with retinal vein occlusive disease. JNMA J Nepal Med Assoc 2006;45:244–248.
PSORIASIS AND RETINAL VEIN OCCLUSION YEN ET AL 4. Bertelsen M, Linneberg A, Rosenberg T, et al. Comorbidity in patients with branch retinal vein occlusion: case-control study. BMJ 2012;345:e7885. 5. Schmidt D. Comorbidities in combined retinal artery and vein occlusions. Eur J Med Res 2013;18:27. 6. Koizumi H, Ferrara DC, Brue C, Spaide RF. Central retinal vein occlusion case-control study. Am J Ophthalmol 2007;144: 858–863. 7. Marcucci R, Bertini L, Giusti B, et al. Thrombophilic risk factors in patients with central retinal vein occlusion. Thromb Haemost 2001;86:772–776. 8. Adamczuk YP, Iglesias Varela ML, Martinuzzo ME, et al. Central retinal vein occlusion and thrombophilia risk factors. Blood Coagul Fibrinolysis 2002;13:623–626. 9. Liu T, Han Y, Lu L. Angiotensin-converting enzyme gene polymorphisms and the risk of psoriasis: a meta-analysis. Clin Exp Dermatol 2013;38:352–358. 10. Qureshi AA, Choi HK, Setty AR, Curhan GC. Psoriasis and the risk of diabetes and hypertension: a prospective study of US female nurses. Arch Dermatol 2009;145:379–382. 11. Brauchli YB, Jick SS, Meier CR. Psoriasis and the risk of incident diabetes mellitus: a population-based study. Br J Dermatol 2008;159:1331–1337. 12. Azfar RS, Seminara NM, Shin DB, et al. Increased risk of diabetes mellitus and likelihood of receiving diabetes mellitus treatment in patients with psoriasis. Arch Dermatol 2012;148:995–1000. 13. Pietrzak A, Bartosinska J, Chodorowska G, et al. Cardiovascular aspects of psoriasis: an updated review. Int J Dermatol 2013;52:153–162. 14. Ahlehoff O, Gislason G, Hansen PR. Cardiovascular aspects of psoriasis: an updated review. Int J Dermatol 2014;53:e337. 15. Ni C, Chiu MW. Psoriasis and comorbidities: links and risks. Clin Cosmet Investig Dermatol 2014;7:119–132. 16. Rocha-Pereira P, Santos-Silva A, Rebelo I, et al. Dislipidemia and oxidative stress in mild and in severe psoriasis as a risk for cardiovascular disease. Clin Chim Acta 2001;303:33–39. 17. Ma C, Harskamp CT, Armstrong EJ, Armstrong AW. The association between psoriasis and dyslipidaemia: a systematic review. Br J Dermatol 2013;168:486–495. 18. Mirshahi A, Hoehn R, Lorenz K, et al. Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts. J Ophthalmic Vis Res 2012;7:39–44. 19. Vergou T, Moustou AE, Maniateas A, et al. Central retinal vein occlusion following infliximab treatment for plaque-type psoriasis. Int J Dermatol 2010;49:1215–1217. 20. Deobhakta A, Chang LK. Inflammation in retinal vein occlusion. Int J Inflam 2013;2013:438412. 21. Montehermoso A, Cervera R, Font J, et al. Association of antiphospholipid antibodies with retinal vascular disease in systemic lupus erythematosus. Semin Arthritis Rheum 1999; 28:326–332. 22. Raychaudhuri SK, Maverakis E, Raychaudhuri SP. Diagnosis and classification of psoriasis. Autoimmun Rev 2014;13: 490–495. 23. Prieto-Perez R, Cabaleiro T, Dauden E, et al. Genetics of psoriasis and pharmacogenetics of biological drugs. Autoimmune Dis 2013;2013:613086. 24. Han R, Rostami-Yazdi M, Gerdes S, Mrowietz U. Triptolide in the treatment of psoriasis and other immune-mediated inflammatory diseases. Br J Clin Pharmacol 2012;74:424–436. 25. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361:496–509. 26. Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127:757–763.
1793
27. LoriS Parsons. Performing a 1:N case-control Match on propensity score. In: Ovation Research Group, ed. Seattle, Washington: Proceedings of the 29th SAS Users Group International. Montreal, Canada; 2004. 28. Yen YC, Weng SF, Chen HA, Lin YS. Risk of retinal vein occlusion in patients with systemic lupus erythematosus: a population-based cohort study. Br J Ophthalmol 2013;97:1192–1196. 29. Stem MS, Talwar N, Comer GM, Stein JD. A longitudinal analysis of risk factors associated with central retinal vein occlusion. Ophthalmology 2013;120:362–370. 30. Onumah N, Kircik LH. Psoriasis and its comorbidities. J Drugs Dermatol 2012;11:s5–10. 31. Chiang YY, Lin HW. Association between psoriasis and chronic obstructive pulmonary disease: a population-based study in Taiwan. J Eur Acad Dermatol Venereol 2012;26:59–65. 32. Dreiher J, Weitzman D, Shapiro J, et al. Psoriasis and chronic obstructive pulmonary disease: a case-control study. Br J Dermatol 2008;159:956–960. 33. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol 2001;131:61–77. 34. Fabbri LM, Luppi F, Beghe B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204–212. 35. Schon MP, Boehncke WH. Psoriasis. N Engl J Med 2005;352: 1899–1912. 36. Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010;2010: 289645. doi:10.1155/2010/289645. 37. Hamminga EA, van der Lely AJ, Neumann HA, Thio HB. Chronic inflammation in psoriasis and obesity: implications for therapy. Med Hypotheses 2006;67:768–773. 38. Chen YJ, Wu CY, Shen JL, et al. Psoriasis independently associated with hyperleptinemia contributing to metabolic syndrome. Arch Dermatol 2008;144:1571–1575. 39. Ciccone M, Vettor R, Pannacciulli N, et al. Plasma leptin is independently associated with the intima-media thickness of the common carotid artery. Int J Obes Relat Metab Disord 2001;25:805–810. 40. Lam HD, Lahey JM, Kearney JJ, et al. Young patients with branch retinal vein occlusion: a review of 60 cases. Retina 2010;30:1520–1523. 41. Xu L, You QS, Liu W, Jonas JB. Smoking and retinal vein occlusions. The Beijing Eye study. Graefes Arch Clin Exp Ophthalmol 2010;248:1045–1046. 42. Carbone J, Sanchez-Ramon S, Cobo-Soriano R, et al. Antiphospholipid antibodies: a risk factor for occlusive retinal vascular disorders. Comparison with ocular inflammatory diseases. J Rheumatol 2001;28:2437–2441. 43. Levy J, Baumgarten A, Rosenthal G, et al. Consecutive central retinal artery and vein occlusions in primary antiphospholipid syndrome. Retina 2002;22:784–786. 44. Martin SC, Butcher A, Martin N, et al. Cardiovascular risk assessment in patients with retinal vein occlusion. Br J Ophthalmol 2002;86:774–776. 45. Risk factors for central retinal vein occlusion. The Eye disease case-control study group. Arch Ophthalmol 1996;114:545–554. 46. Kohner EM, Cappin JM. Do medical conditions have an influence on central retinal vein occlusions? Proc R Soc Med 1974; 67:1052–1054. 47. Balta I, Balta S, Demirkol S, et al. Aortic arterial stiffness is a moderate predictor of cardiovascular disease in patients with psoriasis vulgaris. Angiology 2014;65:74–78. 48. Costa L, Caso F, D’Elia L, et al. Psoriatic arthritis is associated with increased arterial stiffness in the absence of known
1794 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES cardiovascular risk factors: a case control study. Clin Rheumatol 2012;31:711–715. 49. Tekin NS, Tekin IO, Barut F, Sipahi EY. Accumulation of oxidized low-density lipoprotein in psoriatic skin and changes of plasma lipid levels in psoriatic patients. Mediators Inflamm 2007;2007:78454. 50. Al-Mutairi N, Al-Farag S, Al-Mutairi A, Al-Shiltawy M. Comorbidities associated with psoriasis: an experience from the Middle East. J Dermatol 2010;37:146–155. 51. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005;115:1111–1119.
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52. Ena P, Madeddu P, Glorioso N, et al. High prevalence of cardiovascular diseases and enhanced activity of the reninangiotensin system in psoriatic patients. Acta Cardiol 1985; 40:199–205. 53. Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and hypertension: a systematic review and meta-analysis of observational studies. J Hypertens 2013;31: 433–442; discussion 442–433. 54. Noma H, Funatsu H, Sakata K, et al. Macular microcirculation in hypertensive patients with and without branch retinal vein occlusion. Acta Ophthalmol 2009;87:638–642.
