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Age Associations with Dry Eye Clinical Signs and Symptoms in the Dry Eye Assessment and Management (DREAM) Study

  • Megan Zhao
    Affiliations
    Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

    Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis Tennessee
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  • Yinxi Yu
    Affiliations
    Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

    Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis Tennessee
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  • Gui-shuang Ying
    Affiliations
    Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

    Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis Tennessee
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  • Penny A. Asbell
    Affiliations
    Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

    Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis Tennessee
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  • Vatinee Y. Bunya
    Correspondence
    Corresponding Author: Vatinee Y. Bunya, MD MSCE, Scheie Eye Institute, 51 N. 39th Street, Philadelphia, PA 19104, Phone: 215-662-9791,
    Affiliations
    Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

    Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis Tennessee
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  • and theDry Eye Assessment and Management Study Research Group
Open AccessPublished:January 11, 2023DOI:https://doi.org/10.1016/j.xops.2023.100270

      Abstract

      Purpose

      To evaluate how increasing age is associated with dry eye disease (DED) signs and symptoms in the Dry Eye Assessment and Management (DREAM) study. This study was undertaken to better understand how DED signs and symptoms differ across decades of life with goals to help assess detection and treatment of DED.

      Design

      Secondary analysis of the DREAM study

      Subjects

      120, 140, 185, 90 participants aged <50, 50-59, 60-69, ≥70 years, respectively.

      Methods

      We performed a secondary analysis of data from the DREAM study, a multi-center randomized clinical trial, to evaluate the effect of omega-3 fatty acid supplementation for the treatment of DED. At baseline, 6- and 12-months follow-up, participants underwent assessment of DED symptoms and signs using Ocular Surface Disease Index (OSDI), Brief Pain Inventory (BODI), Tear Break-Up Time (TBUT)(sec), Schirmer’s test with anesthesia (mm/5 min), conjunctival staining, corneal staining, meibomian gland dysfunction evaluation, and tear osmolarity (mOsm/L). Multivariable generalized linear regression models were used to compare DED symptoms and signs across four age groups (<50, 50-59, 60-69, ≥70 years) among all participants and by gender.

      Main Outcome Measures

      Scores of DED symptoms, individual signs, and composite scores of DED signs.

      Results

      Among 535 DED patients, increasing age was significantly associated with worse TBUT (p=0.01), corneal staining (p<0.001), a composite severity score of DED signs (p=0.007), and tear osmolarity (p=0.001). Similar significant differences were found across 4 age groups of 334 women in TBUT, corneal staining score, composite severity score of DED signs, tear osmolarity (all p<0.05), but not in men.

      Conclusion

      We found that corneal staining, TBUT, tear osmolarity, and a composite severity score of DED signs were significantly more severe with increasing age, in women but not men; worsening symptoms did not increase with increasing age.

      Introduction:

      Dry eye disease (DED) has a severe impact on patients’ quality of life
      • Schiffman R.M.
      • et al.
      Utility assessment among patients with dry eye disease.
      ,
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      Dry Eye Disease: Impact on Quality of Life and Vision.
      and has a prevalence that increases with age in both sexes
      • Schaumberg D.A.
      • et al.
      Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies.
      ,
      • Schaumberg D.A.
      • et al.
      Prevalence of dry eye syndrome among US women.
      ,
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      . Prevalence differences across age groups present a distinct disparity: only 8.4% of individuals younger than 60 reporting a diagnosis of DED compared to 15% in individuals from 70-79 years of age and 20% in individuals older than 809, 10. With an increasingly aging population across the world, DED will continue to grow as a public health issue.
      However, there is uncertainty regarding whether aging is a DED causal factor or if DED is simply an age-related disease. The effects of aging on DED appear to be multifaceted. For example, aging appears to cause various changes on the ocular surface. Aging has been found to be a risk factor for increased goblet cell loss 11,12,13,14,15,16 as well as for profound lacrimal gland and ocular surface alterations
      • Rocha E.M.
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      The aging lacrimal gland: changes in structure and function.
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      . From a structural standpoint, aging may also cause other anatomic changes, such an anterior shift of Marx’s line
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      Marx line: fluorescein staining line on the inner lid as indicator of meibomian gland function.
      . Theorized mechanisms that contribute to the increased prevalence of DED in older age include immunosenescence, or aging of the immune system, causing effects such as a decrease in naïve T cells and increased state of chronic inflammation
      • Boren E.
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      .
      In addition, aging may affect various ocular surface signs in different ways. For example, in a study of 140 volunteers (70 males and 70 females) with no ocular symptoms or ocular surface disorders, Ozdemir and colleagues found a significant decrease in tear break-up time (TBUT) with increasing age across the seven decades spanning 11-86 years of age, with an especially highly significant difference between the younger and older decades
      • Ozdemir M.
      • Temizdemir H.
      Age- and gender-related tear function changes in normal population.
      . However, the same group found that while Schirmer test results decreased with increasing age, these changes were not significant
      • Ozdemir M.
      • Temizdemir H.
      Age- and gender-related tear function changes in normal population.
      . In another study, Maissa et al reported that in individuals without DED, tear film stability was impacted by age with a significantly shorter TBUT in older individuals
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      Tear film dynamics and lipid layer characteristics--effect of age and gender.
      . Additionally, the lipid layer was significantly thinner for patients older than 45. In particular, older women had significantly thinner lipid layers in comparison to younger women and older men
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      Tear film dynamics and lipid layer characteristics--effect of age and gender.
      . Obata et al also reported that signs of lacrimal gland deterioration, as indicated by diffuse fibrosis and atrophy in orbital lobes, increases with age and may be more frequent in women than men
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      • et al.
      Histopathologic study of human lacrimal gland. Statistical analysis with special reference to aging.
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      • Obata H.
      Anatomy and histopathology of the human lacrimal gland.
      . We previously reported on sex-related differences in DED in the Dry Eye Assessment and Management (DREAM) study, noting that women demonstrate more severe signs in comparison to men and that post-menopausal women have more severe signs in comparison to pre-menopausal women

      Megan Zhao, Y.Y., Neeta S. Roy, Gui-shuang Ying, Penny A. Asbell, Vatinee Y. Bunya, DREAM Study Research Group, Sex-Related Differences and Hormonal Effects in the Dry Eye Assessment and Management (DREAM) Study. Pending Review, 2022.

      .
      Overall, a more comprehensive overview that includes a wide range of DED signs and symptoms regarding age-related differences is needed to improve our understanding of associations of DED and age differences. This study aims to provide a detailed analysis of age-related effects on DED symptoms and signs by conducting a secondary analysis of rich data from the DREAM study. The DREAM study, a multi-center randomized clinical trial assessing the efficacy and safety of oral omega-3 supplementation for treatment of DED, provides standard comprehensive assessment of DED symptoms and signs in a large and well-defined cohort
      • Dry Eye A.
      • et al.
      n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease.
      . As a result, an in-depth analysis of this well-established cohort may provide insight into clinically relevant differences in the dry eye symptoms and signs across various age groups among patients with DED.

      Methods:

      This is a secondary analysis of data from the DREAM Study (ClinicalTrials.gov identifier, NCT02128763). The results of the DREAM study were previously published and showed that the active treatment group that received omega-3 supplementation did not show a significant difference in DED signs and symptoms compared to the placebo group that received olive oil pills
      • Dry Eye A.
      • et al.
      n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease.
      . Briefly, 535 patients with moderate to severe DED and ≥18 years of age were enrolled in the study. All enrolled patients had moderate to severe DED symptoms for at least 6 months prior to the screening visit, use or desired use of artificial tears twice daily in the 2 weeks prior to the screening visit, and an Ocular Surface Disease Index (OSDI) score of 25-80 at the screening visit and 21-80 at the baseline visit. Full details on the inclusion and exclusion criteria as well as outcome measures can be found in the previously published primary results paper of the DREAM Study
      • Dry Eye A.
      • et al.
      n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease.
      . The study was approved by the institutional review board/ethics committee at each center (centers listed in Credit Roster for the DREAM Study, available at www.aaojournal.org), followed the tenets of the Declaration of Helsinki, and written informed consent was obtained from all patients.
      Dry eye symptom outcome measures taken at baseline, 6- and 12-months follow-up included the OSDI score (scale of 0-100) and the Brief Pain Inventory (BODI) score
      • Pistilli M.
      • et al.
      Evaluation of a Modification of the Brief Pain Inventory (BODI) as a Measure of Severity of Dry Eye Disease.
      , with higher scores indicative of more severe symptoms. The measures for dry eye signs (measured per eye) included conjunctival staining scores (ranging from 0 to 6) and corneal staining scores (0 to 15), tear break-up time (TBUT), and Schirmer test with anesthesia. More severe signs were indicated by lower TBUT, lower Schirmer test, higher conjunctival staining score, higher corneal staining score, and higher tear osmolarity.
      Tear film osmolarity was measured from both eyes at baseline, 6 months, and 12 months at the 19 of the 27 clinical centers that had the TearLab Osmolarity System (OcuSense Inc., San Diego, CA).
      Each patient was also administered the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) version 2.0 at baseline, 6- and 12-months follow-up. Two summary scores were generated from SF-36: the physical component summary (PCS) and mental component summary (MCS). The MCS is scored between 0 and 100, with higher scores indicating greater psychological wellbeing. The recommended cutoff of 42 in MSC score has sensitivity of 73.7% and specificity of 80.6% for identifying clinical depression
      • Jenkinson C.
      The SF-36 physical and mental health summary measures: an example of how to interpret scores.
      .

      Statistical Analysis

      To evaluate how the age is associated with DED symptoms and signs which can be nonlinear, we categorized age into four age groups including <50, 50-59, 60-69, and ≥70 years. We compared the demographics, comorbidities, scores for dry eye symptoms and signs across these four age groups using generalized linear regression models for continuous measurements and the chi-square test or Fisher’s exact test for categorical measurements. For the comparison of dry eye symptoms and signs, the generalized linear regression models were performed with and without an adjustment for sex, race, smoking status and several comorbidities that were previously found to be associated with the severity of dry eye symptoms and signs in the DREAM study including facial rosacea, rheumatoid arthritis, peripheral artery disease, Sjögren’s syndrome
      • Yu K.
      • et al.
      Systemic Conditions Associated with Severity of Dry Eye Signs and Symptoms in the Dry Eye Assessment and Management Study.
      and depression defined as mental component summary score ≤4238. We performed these analyses using the combined data of baseline, 6 months and 12 months with time modelled as categorical variable to improve statistical power. The correlations from repeated measures across visits and between eyes within the same participant (for comparison of eye-specific dry eye signs) were accounted for by using generalized estimating equations. Similar analyses were performed for each time point separately to check the consistency of results across time. Because omega-3 supplementation did not show a significant effect on DED signs and symptoms compared to placebo
      • Dry Eye A.
      • et al.
      n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease.
      , all these evaluations were based on the data from the two treatment groups combined.
      For the comparison of each DED sign across age groups, individual signs from both eyes of all time points were used. In addition, we adapted a method from previous studies
      • Yu K.
      • et al.
      Systemic Conditions Associated with Severity of Dry Eye Signs and Symptoms in the Dry Eye Assessment and Management Study.
      ,
      • Zhou Y.
      • et al.
      Association Between Depression and Severity of Dry Eye Symptoms, Signs, and Inflammatory Markers in the DREAM Study.
      to calculate a composite dry eye severity score of signs by transforming the individual score of each of the five dry eye signs (TBUT, Schirmer testing, corneal staining, conjunctival staining, and meibomian gland dysfunction) to a common unit severity score between 0 (no DED signs) and 1 (most severe signs). A composite signs severity score for each eye was then calculated by averaging severity scores of the six individual DED signs. The composite sign severity score ranges from 0 to 1, with 1 indicating the most severe dry eye signs. This composite score allows for one continuous metric of assessing objective DED sign severity based on five separate dry eye sign measures
      • Sullivan B.D.
      • et al.
      An objective approach to dry eye disease severity.
      ,
      • Ong E.S.
      • et al.
      Epidemiology of discordance between symptoms and signs of dry eye.
      .
      All statistical analyses were performed using SAS v9.4 (SAS Institute Inc, Cary, NC), and two-sided P<0.05 was considered statistically significant.

      Results:

      Table 1 shows the comparison of baseline characteristics among four age groups of DREAM participants. Across four age groups (<50, 50-59, 60-69, ≥70 years), older age groups had a higher percent of white race (67.5% vs. 69.3% vs. 78.9% vs. 82.2%, p<0.001), and a higher percent of non-Hispanic or Latino ethnicity (77.5% vs. 82.1% vs. 91.9% vs. 94.4%, p<0.001). Older age groups had a lower percent of never smokers (80.8% vs. 69.3% vs. 66.5% vs. 55.6%, p<0.001), a higher percent of self-reported ongoing peripheral artery disease (7.5% vs. 3.6% vs. 10.8% vs. 14.4%, p=0.002), and a higher percent of hypertension (12.5% vs. 16.4% vs. 20.0% vs. 21.1%, p<0.001). Older age groups also had a higher percent with osteoarthritis (5.8% vs. 15.0% vs. 33.5% vs. 48.9%, p<0.001), hypercholesteremia (8.3% vs. 29.3% vs. 43.2% vs. 44.4%, p<0.001), taking statin medications (6.7% vs. 17.9% vs. 31.9% vs. 41.1%, p<0.001), and a higher mean summary component measure of mental health (49.6 vs. 50.8 vs. 54.5 vs. 54.1, p<0.001). Regarding treatment for dry eye, older age groups had a higher percent of using tears or gel (71.7% vs. 73.6% vs. 83.2% vs. 90.0%, p=0.002), using more cyclosporine drops (10.0% vs. 20.7% vs. 23.2% vs. 23.3%, p=0.02) and warm liquid soaks (14.2% vs. 16.4% vs. 27.6% vs. 25.6%, p=0.01). They also used more other dry eye treatments beyond artificial tears or gel, cyclosporine drops, warm lid soaks, lid scrubs, or baby shampoo (21.7% vs. 30.7% vs. 38.9% vs. 38.9%, p=0.009).
      Table 1Comparison of baseline characteristics among different age groups
      Age (years)P-value
      <50 (N=120)[50, 59] (N=140)[60, 69] (N=185)≥70 (N=90)
      Sex, n (%)0.231
      Female95 (79.2%)113 (80.7%)158 (85.4%)68 (75.6%)
      Male25 (20.8%)27 (19.3%)27 (14.6%)22 (24.4%)
      Ethnicity, n (%)<.001
      • Uchino M.
      • Schaumberg D.A.
      Dry Eye Disease: Impact on Quality of Life and Vision.
      Hispanic or Latino26 (21.7%)24 (17.1%)15 (8.1%)3 (3.3%)
      Not Hispanic or Latino93 (77.5%)115 (82.1%)170 (91.9%)85 (94.4%)
      Unable to answer1 (0.8%)1 (0.7%)0 (0.0%)2 (2.2%)
      Race, n (%)<.001
      • Uchino M.
      • Schaumberg D.A.
      Dry Eye Disease: Impact on Quality of Life and Vision.
      White81 (67.5%)97 (69.3%)146 (78.9%)74 (82.2%)
      Black or African American11 (9.2%)21 (15.0%)23 (12.4%)9 (10.0%)
      Asian9 (7.5%)3 (2.1%)5 (2.7%)2 (2.2%)
      American Indian or Alaskan Native0 (0.0%)0 (0.0%)1 (0.5%)2 (2.2%)
      More than one race4 (3.3%)1 (0.7%)3 (1.6%)1 (1.1%)
      Unable to answer15 (12.5%)18 (12.9%)7 (3.8%)2 (2.2%)
      Cigarette smoking, n (%)<.001
      • Schiffman R.M.
      • et al.
      Utility assessment among patients with dry eye disease.
      Never97 (80.8%)97 (69.3%)123 (66.5%)50 (55.6%)
      Former15 (12.5%)33 (23.6%)58 (31.4%)36 (40.0%)
      Current8 (6.7%)10 (7.1%)4 (2.2%)4 (4.4%)
      Taking statin, n (%)0.009
      • Schiffman R.M.
      • et al.
      Utility assessment among patients with dry eye disease.
      No112 (93.3%)115 (82.1%)126 (68.1%)53 (58.9%)
      Yes8 (6.7%)25 (17.9%)59 (31.9%)37 (41.1%)<.001
      • Schiffman R.M.
      • et al.
      Utility assessment among patients with dry eye disease.
      Rosacea (facial), Yes (%)19 (15.8%)22 (15.7%)44 (23.8%)24 (26.7%)0.071
      Sjögren’s syndrome met 2012 ACR criteria, Yes (%)11 (9.2%)16 (11.4%)16 (8.6%)9 (10.0%)0.901
      Self-reported Peripheral artery disease, ongoing (%)9 (7.5%)5 (3.6%)20 (10.8%)13 (14.4%)0.002
      • Uchino M.
      • Schaumberg D.A.
      Dry Eye Disease: Impact on Quality of Life and Vision.
      Self-reported Thyroid dysfunction, ongoing (%)15 (12.5%)23 (16.4%)37 (20.0%)19 (21.1%)0.072
      Self-reported Hypertension, ongoing (%)11 (9.2%)34 (24.3%)67 (36.2%)37 (41.1%)<.001
      • Uchino M.
      • Schaumberg D.A.
      Dry Eye Disease: Impact on Quality of Life and Vision.
      Self-reported Diabetes, ongoing (%)7 (5.8%)13 (9.3%)24 (13.0%)13 (14.4%)0.252
      Self-reported Rheumatoid arthritis, ongoing (%)8 (6.7%)16 (11.4%)14 (7.6%)9 (10.0%)0.532
      Self-reported Irritable Bowel, ongoing (%)13 (10.8%)12 (8.6%)11 (5.9%)8 (8.9%)0.642
      Self-reported Osteoarthritis, ongoing (%)7 (5.8%)21 (15.0%)62 (33.5%)44 (48.9%)<.001
      • Uchino M.
      • Schaumberg D.A.
      Dry Eye Disease: Impact on Quality of Life and Vision.
      Self-reported Hypercholesterolemia, ongoing (%)10 (8.3%)41 (29.3%)80 (43.2%)40 (44.4%)<.001
      • Uchino M.
      • Schaumberg D.A.
      Dry Eye Disease: Impact on Quality of Life and Vision.
      Self-reported Depression, ongoing (%)19 (15.8%)26 (18.6%)27 (14.6%)15 (16.7%)0.981
      Taking anti-depressants, yes (%)26 (21.7%)35 (25.0%)37 (20.0%)20 (22.2%)0.761
      Summary Component Measures of Physical Health, mean (SD)48.8 (9.85)47.9 (10.29)46.7 (9.56)46.7 (8.47)0.233
      Summary Component Measures of Mental Health, mean (SD)49.6 (9.50)50.8 (10.03)54.5 (8.31)54.1 (8.98)<.001
      • Schaumberg D.A.
      • et al.
      Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies.
      MCS <=42, yes (%)21 (17.5%)30 (21.4%)22 (11.9%)11 (12.2%)0.091
      Treatments used for dry eye disease*, n (%)
      Artificial tears or gel86 (71.7%)103 (73.6%)154 (83.2%)81 (90.0%)0.002
      • Schiffman R.M.
      • et al.
      Utility assessment among patients with dry eye disease.
      Cyclosporine drops12 (10.0%)29 (20.7%)43 (23.2%)21 (23.3%)0.02
      • Schiffman R.M.
      • et al.
      Utility assessment among patients with dry eye disease.
      Warm lid soaks17 (14.2%)23 (16.4%)51 (27.6%)23 (25.6%)0.01
      • Schiffman R.M.
      • et al.
      Utility assessment among patients with dry eye disease.
      Lid scrubs or baby shampoo16 (13.3%)19 (13.6%)31 (16.8%)17 (18.9%)0.611
      Other26 (21.7%)43 (30.7%)72 (38.9%)35 (38.9%)0.009
      • Schiffman R.M.
      • et al.
      Utility assessment among patients with dry eye disease.
      1Chi-Square p-value; 2Fisher Exact p-value; 3ANOVA F-test p-value;
      *Participants can take more than 1 treatment for DED at the same time
      Table 2 compares DED symptoms and signs across the four age groups using the combined data from baseline, 6-month visit, and the 12-month visit. In both the unadjusted and adjusted analysis, there were no significant differences across age groups in dry eye symptom scores as measured by the OSDI and BODI. In analyses adjusted by sex and race, the older age group had more severe signs including lower mean TBUT (4.06 vs. 3.59 vs. 3.26 vs. 3.36 sec; p=0.001), lower Schirmer test score (11.22 vs. 9.85 vs. 9.08 vs. 9.46; p=0.007), higher mean score in corneal staining (2.47 vs. 3.37 vs. 3.60 vs. 4.31; p<0.001), more meibomian gland abnormality (2.69 vs. 2.85 vs. 3.10 vs. 3.05; p=0.03). Composite dry eye severity scores based on signs (0.42 vs. 0.52 vs. 0.53 vs. 0.53; p<0.001) were higher in older age groups. Tear osmolarity (300.2 vs. 303.6 vs. 303.0 vs. 305.8; p=0.006) was also significantly greater in older groups. Even after adjusting for sex, race, smoking status, Sjogren’s syndrome, facial rosacea, rheumatoid arthritis, peripheral artery disease, depression, these significant differences across four age groups still remained significant for TBUT (p=0.01), corneal staining (p<0.001), composite dry eye severity score based on signs (p=0.007), and tear osmolarity (p=0.001), while the differences in Schirmer test (p=0.07) and meibomian gland abnormality (p=0.13) were no longer significant.
      Table 2Association of DED symptoms and signs and age among DREAM participants (combining baseline, 6M and 12M). Table 2A: Association of DED symptoms and signs and age among DREAM participants at baseline. Table 2B: Association of DED symptoms and signs and age among DREAM participants at 6M. Table 2C: Association of DED symptoms and signs and age among DREAM participants at 12M
      <50[50, 59][60, 69]≥70
      Dry eye symptoms and signsNMean (SD)NMean (SD)NMean (SD)NMean (SD)P-valueAdjusted P-value*Adjusted P-value**
      OSDI total score32435.73 (18.71)39236.19 (19.70)52534.92 (17.75)26333.26 (17.61)0.240.180.16
      BODI score32426.06 (17.51)39227.65 (19.10)52524.47 (17.46)26325.74 (17.86)0.440.670.92
      BODI #3 pain score32436.36 (21.20)39138.13 (21.57)52536.50 (20.92)26338.06 (22.01)0.660.630.56
      Tear Break-up Time (sec)6484.06 (3.27)7843.59 (2.22)10503.26 (2.02)5263.36 (2.01)0.0010.0050.01
      Schirmer test (mm in 5 minutes)64611.22 (7.82)7769.85 (7.50)10469.08 (6.42)5249.46 (5.59)0.0070.030.07
      Corneal staining score6482.47 (2.33)7843.37 (3.12)10503.60 (2.87)5264.31 (3.01)<0.001<0.001<0.001
      Conjunctival staining score6482.47 (1.54)7842.94 (1.68)10502.56 (1.59)5262.79 (1.53)0.400.270.29
      Meibomian gland abnormality6482.69 (1.91)7842.85 (1.82)10483.10 (1.98)5263.05 (1.84)0.030.010.13
      Composite dry eye severity score based on Signs6480.42 (0.27)7840.52 (0.30)10500.53 (0.29)5260.53 (0.28)<0.0010.0010.007
      Tear osmolarity (mOsms/L)490300.19 (14.99)539303.62 (18.33)772302.99 (16.73)364305.76 (18.72)0.0060.0040.001
      Dry eye symptoms and signs<50[50, 59][60, 69]>=70
      NMean (SD)NMean (SD)NMean (SD)NMean (SD)P-valueAdjusted P-value*Adjusted P-value**
      OSDI total score12043.13 (15.54)14043.10 (16.34)18541.67 (15.23)9039.83 (14.71)0.100.120.13
      BODI score12032.13 (17.51)14032.66 (17.53)18529.34 (16.47)9029.49 (16.30)0.090.150.32
      BODI #3 pain score12042.08 (18.83)13944.17 (19.33)18542.43 (19.05)9042.56 (19.58)0.940.910.86
      Tear Break-up Time (sec)2403.51 (2.01)2803.12 (1.56)3702.88 (1.48)1803.19 (2.07)0.0530.100.21
      Schirmer test (mm in 5 minutes)24011.28 (8.30)2809.50 (7.70)3708.79 (6.17)1808.97 (5.38)0.0040.030.047
      Corneal staining score2402.83 (2.39)2803.92 (3.22)3703.97 (2.81)1804.56 (3.21)<0.001<0.001<0.001
      Conjunctival staining score2402.73 (1.44)2803.21 (1.58)3702.89 (1.57)1802.94 (1.46)0.620.340.37
      Meibomian gland abnormality2402.94 (1.90)2803.05 (1.72)3703.21 (1.93)1803.10 (1.79)0.280.140.48
      Composite dry eye severity score based on Signs2400.42 (0.27)2800.53 (0.30)3700.53 (0.28)1800.51 (0.30)0.010.010.04
      Tear osmolarity (mOsms/L)186300.66 (16.22)197302.41 (16.50)283302.83 (15.57)128305.55 (16.91)0.0450.060.04
      <50[50, 59][60, 69]>=70
      Dry eye symptoms and signsNMean (SD)NMean (SD)NMean (SD)NMean (SD)P-valueAdjusted P-value*Adjusted P-value**
      OSDI total score10132.13 (19.45)12733.61 (19.87)16832.08 (18.48)8530.26 (18.94)0.430.300.33
      BODI score10122.30 (14.99)12726.31 (19.42)16823.44 (17.65)8524.84 (18.78)0.660.410.17
      BODI #3 pain score10133.17 (21.30)12736.46 (21.21)16835.06 (20.82)8536.82 (22.48)0.370.280.23
      Tear Break-up Time (sec)2024.37 (4.09)2543.82 (2.69)3363.44 (2.12)1703.41 (1.97)0.0070.010.02
      Schirmer test (mm in 5 minutes)20211.61 (7.72)2509.81 (7.19)3349.23 (6.77)1689.63 (5.78)0.020.0530.10
      Corneal staining score2022.29 (2.16)2543.24 (3.08)3363.49 (2.89)1704.02 (2.85)<0.001<0.001<0.001
      Conjunctival staining score2022.36 (1.63)2542.96 (1.67)3362.38 (1.57)1702.73 (1.60)0.750.600.51
      Meibomian gland abnormality2022.63 (1.91)2542.77 (1.85)3343.02 (2.00)1702.94 (1.89)0.120.080.46
      Composite dry eye severity score based on Signs2020.42 (0.27)2540.52 (0.30)3360.52 (0.29)1700.54 (0.28)0.0030.0060.03
      Tear osmolarity (mOsms/L)149299.48 (13.49)173305.33 (21.21)242303.61 (16.37)112304.19 (18.16)0.090.030.01
      <50[50, 59][60, 69]>=70
      Dry eye symptoms and signsNMean (SD)NMean (SD)NMean (SD)NMean (SD)P-valueAdjusted P-value*Adjusted P-value**
      OSDI total score10330.65 (18.77)12531.06 (20.86)17230.42 (17.47)8829.45 (17.27)0.630.450.32
      BODI score10322.69 (17.99)12523.38 (19.34)17220.24 (17.14)8822.78 (17.99)0.550.700.57
      BODI #3 pain score10332.82 (22.42)12533.12 (22.84)17231.51 (21.49)8834.66 (23.34)0.820.820.99
      Tear Break-up Time (sec)2064.41 (3.46)2503.89 (2.25)3443.50 (2.35)1763.47 (1.99)0.0030.010.02
      Schirmer test (mm in 5 minutes)20410.75 (7.34)24610.28 (7.59)3429.25 (6.34)1769.80 (5.63)0.110.240.42
      Corneal staining score2062.24 (2.38)2502.90 (2.96)3443.30 (2.87)1764.34 (2.95)<0.001<0.001<0.001
      Conjunctival staining score2062.27 (1.51)2502.60 (1.75)3442.39 (1.58)1762.70 (1.54)0.160.140.23
      Meibomian gland abnormality2062.46 (1.90)2502.71 (1.87)3443.06 (2.00)1763.10 (1.85)0.0030.0030.02
      Composite dry eye severity score based on Signs2060.42 (0.28)2500.50 (0.30)3440.53 (0.29)1760.55 (0.26)<0.001<0.0010.006
      Tear osmolarity (mOsms/L)155300.30 (14.88)169303.28 (17.11)247302.58 (18.33)124307.40 (20.88)0.020.030.006
      *Adjusted by sex and race.
      **Adjusted by sex, race, smoking status, Sjögren syndrome, facial rosacea, rheumatoid arthritis,peripheral artery disease and depression defined by MCS <=42.
      All the p-values are from the linear trend test
      *Adjusted by sex and race
      **Adjusted by sex, race, smoking status, Sjögren syndrome, facial rosacea, rheumatoid arthritis, peripheral artery disease and depression defined by MCS <=42
      All the p-values are from the linear trend test.
      *Adjusted by gender and race
      **Adjusted by gender, race, smoking status, Sjögren syndrome, facial rosacea, rheumatoid arthritis, peripheral artery disease and depression defined by MCS <=42
      All the p-values are from the linear trend test
      *Adjusted by gender and race
      **Adjusted by gender, race, smoking status, Sjögren syndrome, facial rosacea, rheumatoid arthritis, peripheral artery disease and depression defined by MCS <=42.
      All the p-values are from the linear trend test
      When analyzing combined data from baseline, 6-month, and 12-month visits for female patients with an adjustment for demographic and comorbidities (Table 3), older age groups had a lower mean TBUT (4.08 vs. 3.48 vs. 3.18 vs. 3.18 sec; p=0.002), higher mean corneal staining score (2.37 vs. 3.72 vs. 3.77 vs. 4.55; p<0.001), a higher composite dry eye severity score based on signs (0.42 vs 0.55 vs. 0.55 vs 0.55; p=0.003) and higher tear osmolarity (299.7 vs. 303.7 vs. 303.3 vs. 307.8; p<0.001). However, in male participants, there were no significant differences in any DED symptoms nor signs nor symptoms across the four age groups (Table 4). Further, there was no significant interaction of each covariate with age for each outcome of signs and symptoms.
      Table 3Association of DED symptoms and signs and age among DREAM Female participants (combining baseline, 6M and 12M)
      <50[50, 59][60, 69]>=70
      Dry eye symptoms and signsNMean (SD)NMean (SD)NMean (SD)NMean (SD)P-valueAdjusted P-value*Adjusted P-value**
      OSDI total score25936.81 (19.26)31736.44 (19.41)45135.73 (17.60)19832.95 (17.74)0.170.110.14
      BODI score25927.36 (18.04)31727.22 (18.90)45124.27 (17.61)19825.41 (18.31)0.170.280.57
      BODI #3 pain score25937.99 (21.27)31638.26 (21.02)45136.45 (20.86)19838.23 (22.54)0.810.790.99
      Tear Break-up Time (sec)5184.08 (3.12)6343.48 (2.06)9023.18 (1.98)3963.18 (1.87)<0.0010.0010.002
      Schirmer test (mm in 5 minutes)51610.76 (7.63)6268.99 (6.66)8988.64 (6.22)3949.19 (5.33)0.030.110.18
      Corneal staining score5182.37 (2.30)6343.72 (3.22)9023.77 (2.91)3964.55 (3.11)<0.001<0.001<0.001
      Conjunctival staining score5182.42 (1.54)6343.01 (1.67)9022.65 (1.63)3962.85 (1.54)0.200.130.13
      Meibomian gland abnormality5182.71 (1.89)6342.93 (1.85)9003.16 (1.96)3963.09 (1.79)0.040.020.10
      Composite dry eye severity score based on Signs5180.42 (0.28)6340.55 (0.29)9020.55 (0.28)3960.55 (0.27)<0.0010.0010.003
      Tear osmolarity (mOsms/L)384299.72 (14.35)416303.71 (16.77)680303.34 (16.90)283307.76 (19.47)<0.001<0.001<0.001
      *Adjusted by race
      **Adjusted by race, smoking status, Sjögren syndrome, facial rosacea, rheumatoid arthritis,peripheral artery disease and depression defined by MCS <=42
      All the p-values are from the linear trend test
      Table 4Association of DED symptoms and signs and age among DREAM Male participants (combining baseline, 6M and 12M)
      <50[50, 59][60, 69]>=70
      Dry eye symptoms and signsNMean (SD)NMean (SD)NMean (SD)NMean (SD)P-valueAdjusted P-value*Adjusted P-value**
      OSDI total score6531.46 (15.74)7535.10 (20.96)7429.96 (18.01)6534.23 (17.31)0.720.730.95
      BODI score6520.88 (14.16)7529.47 (19.94)7425.70 (16.58)6526.76 (16.48)0.230.190.30
      BODI #3 pain score6529.85 (19.72)7537.60 (23.93)7436.76 (21.46)6537.54 (20.47)0.160.130.18
      Tear Break-up Time (sec)1304.01 (3.80)1504.08 (2.75)1483.76 (2.18)1303.89 (2.32)0.680.810.85
      Schirmer test (mm in 5 minutes)13013.04 (8.30)15013.43 (9.50)14811.77 (6.93)13010.28 (6.28)0.080.110.09
      Corneal staining score1302.88 (2.42)1501.92 (2.16)1482.53 (2.29)1303.58 (2.58)0.140.210.50
      Conjunctival staining score1302.68 (1.52)1502.62 (1.69)1482.06 (1.21)1302.62 (1.49)0.500.560.63
      Meibomian gland abnormality1302.62 (2.01)1502.52 (1.63)1482.74 (2.02)1302.92 (1.99)0.420.370.87
      Composite dry eye severity score based on Signs1300.41 (0.24)1500.37 (0.29)1480.37 (0.26)1300.47 (0.30)0.460.510.97
      Tear osmolarity (mOsms/L)106301.89 (17.06)123303.31 (22.91)92300.42 (15.26)81298.77 (13.79)0.300.380.90
      *Adjusted by race
      **Adjusted by race, smoking status, Sjögren syndrome, facial rosacea, rheumatoid arthritis, peripheral artery disease and depression defined by MCS <=42
      All the p-values are from the linear trend test
      When we compared the four age groups for changes in symptoms and signs from baseline at 6-month and 12-month visits, there were no significant differences across age groups (Table 5). When analyzing for females and males separately, only change from baseline in TBUT was significantly different in females with older age group had less change (0.85 vs. 0.66 vs. 0.61 vs. 0.12, p=0.04, Supplemental Table 3). However, the TBUT change from baseline in males was not significant (p=0.91, Supplemental Table 4).
      Table 5Association of change in DED symptoms and signs from baseline and age among DREAM participants (combining 6M and 12M)
      <50[50, 59][60, 69]>=70
      Dry eye symptoms and signsNMean (SD)NMean (SD)NMean (SD)NMean (SD)P-valueAdjusted P-value*Adjusted P-value**
      OSDI total score204-12.19 (20.11)252-10.62 (20.13)340-10.84 (16.33)173-9.72 (15.56)0.360.540.65
      BODI score204-10.31 (18.55)252-7.03 (17.32)340-7.41 (16.81)173-5.28 (16.29)0.0520.040.07
      BODI #3 pain score204-10.54 (22.53)250-8.60 (22.41)340-8.85 (21.01)173-6.30 (21.22)0.180.140.24
      Tear Break-up Time (sec)4080.94 (3.59)5040.72 (2.33)6800.64 (1.99)3460.31 (2.21)0.0530.070.09
      Schirmer test (mm in 5 minutes)4060.09 (7.33)4960.53 (6.55)6760.57 (6.53)3440.72 (5.39)0.410.510.53
      Corneal staining score408-0.68 (2.05)504-0.73 (2.29)680-0.64 (2.34)346-0.42 (2.65)0.340.420.37
      Conjunctival staining score408-0.47 (1.33)504-0.42 (1.46)680-0.47 (1.31)346-0.23 (1.38)0.220.360.64
      Meibomian gland abnormality408-0.42 (1.83)504-0.26 (1.95)678-0.21 (2.01)346-0.08 (1.77)0.080.160.21
      Composite dry eye severity score based on Signs408-0.02 (0.24)504-0.01 (0.24)680-0.01 (0.26)3460.03 (0.25)0.110.220.31
      Tear osmolarity (mOsms/L)2930.90 (16.71)3282.37 (21.00)4770.27 (19.57)2290.00 (21.42)0.470.590.81
      *Adjusted by gender and race
      **Adjusted by gender, race, smoking status, Sjögren syndrome, facial rosacea, rheumatoid arthritis, peripheral artery disease and depression defined by MCS <=42
      All the p-values are from the linear trend test

      Discussion:

      In this secondary analysis of data from the DREAM study of subjects with moderate to severe DED, we found that there were significant differences across the four age groups (<50, 50-59, 60-69, ≥70 years) for TBUT, meibomian gland abnormalities, corneal staining, tear osmolarity, and for a composite severity score of DED signs, with older age groups having more severe dry eye signs. These differences across the age groups held true for the cohort of women, but not in men in the DREAM study. We did not find any significant difference in dry eye symptoms across age groups in either men or women.
      Our finding that dry eye signs worsen with increasing age is mostly consistent with previous studies. For example, Lemp et al
      • Lemp M.A.
      • et al.
      Tear osmolarity in the diagnosis and management of dry eye disease.
      studied 314 subjects between 18 and 82 years of age and found that the relative level of severity and rate of people with DED increased with increasing age. Similarly, in a large Iranian study that included patients 40-64 years of age, Hashemi and colleagues found that the prevalence of abnormal TBUT, corneal staining, and Schirmer test increased significantly with age
      • Hashemi H.
      • et al.
      Prevalence of dry eye syndrome in an adult population.
      . However, Hashemi et al looked at a smaller age range, and therefore our study may be more informative by examining DED signs and symptoms across broader age groups
      • Hashemi H.
      • et al.
      Prevalence of dry eye syndrome in an adult population.
      . Further, in contrast to Hashemi et al that evaluated the prevalence of abnormal values across clinical DED signs and symptoms – our study allowed us to examine significant differences in mean values, not whether or not they fall within a certain range
      • Hashemi H.
      • et al.
      Prevalence of dry eye syndrome in an adult population.
      . Thus, our study provides more detailed data of significant differences involving TBUT decreasing with age, corneal staining increasing with age, and Schirmer testing decreasing with age.
      The evaluation of meibum gland dysfunction (MGD) with increasing age is of particular interest in relation to DED. For example, Noland and colleagues compared tear osmolarity, TBUT, ocular surface staining, corneal staining, Schirmer test, and meibum expressibility and quality across 1823 DED Norwegian patients across 20-39 years, 40-59 years, and ≥60 years
      • Tellefsen Noland S.
      • et al.
      Sex and age differences in symptoms and signs of dry eye disease in a Norwegian cohort of patients.
      . This study found that increasing age was significantly associated with lower TBUT, lower Schirmer test score, and worse meibum expressibility. The findings of this study are similar to our findings of significant associations of increasing age with lower TBUT, lower Schirmer scores, and greater meibomian abnormalities. However, in contrast to Noland et al, we also found significantly higher corneal staining and higher composite dry eye severity scores.
      In another recent study, Badian et al analyzed 900 subjects who presented for DED evaluation and found that MGD was highly prevalent in over 93% of patients, but that the prevalence was not associated with age or sex
      • Badian R.A.
      • et al.
      Meibomian gland dysfunction is highly prevalent among first-time visitors at a Norwegian dry eye specialist clinic.
      . However, there was an association between MGD and symptoms. Finally, a large Spanish study of 1000 participants found that the prevalence of asymptomatic MGD increased with age and was higher in men than women. The authors noted that the subjects with asymptomatic MGD also had higher abnormal TBUT and fluorescein staining compared to symptomatic MGD patients
      • Viso E.
      • et al.
      Prevalence of asymptomatic and symptomatic meibomian gland dysfunction in the general population of Spain.
      . A lack of signs, thus, does not necessarily indicate the degree of ocular damage. Further investigation to help elucidate these mechanisms are needed.
      There are several possible explanations as to why dry eye signs worsen with increasing age. One possibility explaining this trend involves the role of oxidative stress
      • Dogru M.
      • et al.
      Potential Role of Oxidative Stress in Ocular Surface Inflammation and Dry Eye Disease.
      , which develops with aging
      • Junqueira V.B.
      • et al.
      Aging and oxidative stress.
      . For example, Augustin et al
      • Augustin A.J.
      • et al.
      Oxidative reactions in the tear fluid of patients suffering from dry eyes.
      reported that oxidative reactions increased inflammatory markers in patients with more severe DED. They also found that the oxidative damage to the ocular surface was significantly correlated with increased lipid peroxidase in tear films. This study provides the basis for several theories of why DED severity may increase with age. There are also several other hypotheses as to why DED severity may increase with age. For example, it is possible that changes in epithelial damage and DNA alterations are exacerbated by inflammatory processes in the conjunctival epithelium, corneal epithelium, and accessory lacrimal glands
      • Grossweiner L.I.
      Photochemistry of proteins: a review.
      , which are more likely to occur with the progression of time in one’s lifetime. Further, it is possible that the healing process from oxidative damage is either partially or completely hindered by oxidative strain, leading to increased damage from these reactions
      • Tseng S.C.
      Staging of conjunctival squamous metaplasia by impression cytology.
      ,
      • Lemp M.A.
      Recent developments in dry eye management.
      ,
      • Lemp M.A.
      • et al.
      An in vivo study of corneal surface morphologic features in patients with keratoconjunctivitis sicca.
      . Lifetime exposure to factors such as pollutants, ultraviolet (UV) radiation, ozone, and eyedrops are noted to increase oxidative stress and inflame the ocular surface which may contribute to DED progression
      • Seen S.
      • Tong L.
      Dry eye disease and oxidative stress.
      . More importantly, these processes may contribute to the destruction of lacrimal glands as shown in mouse models
      • Uchino Y.
      • et al.
      A new mouse model of dry eye disease: oxidative stress affects functional decline in the lacrimal gland.
      ,
      • Uchino Y.
      • et al.
      Oxidative stress induced inflammation initiates functional decline of tear production.
      .
      While oxidative stress, inflammation, and environmental factors may be key components as to why there is increasing severity of DED with age, it is also notable that in our study, we found that DED signs worsened with increasing age in women but not men. There are limited reports in the literature that could partially explain this finding. One previous small study that evaluated the correlation between estrogen receptor-positive basal cells of the meibomian glands and age found that there was an increasing proportion of cells expressing estrogen receptors with increasing age, independent of gender. However, this study did not find any differences between men and women in correlation of estrogen receptor positivity with dry eye symptoms, TBUT, or Schirmer I and II results
      • Auw-Haedrich C.
      • Feltgen N.
      Estrogen receptor expression in meibomian glands and its correlation with age and dry-eye parameters.
      . Thus, there are likely factors other than estrogen receptor expressivity involved with the relationship of DED signs in relation to both sex and increasing age.
      In contrast to the notable associations between dry eye signs and age, our finding of a lack of association between DED symptoms and age is consistent with some reports in the literature, while it differs from others. Similar to our study, Lekhanont et al found in their study of 550 Thai subjects that dry eye symptoms were not significantly associated with age
      • Lekhanont K.
      • et al.
      Prevalence of dry eye in Bangkok, Thailand.
      . Additionally, Bourcier et al found that age was not correlated with dry eye symptoms of itching, burning, or stinging across age groups of <40, 40-55, and >50 years
      • Bourcier T.
      • et al.
      Decreased corneal sensitivity in patients with dry eye.
      . However, in contrast to our study, a recent Norwegian study found that increasing age was significantly associated with higher OSDI scores
      • Tellefsen Noland S.
      • et al.
      Sex and age differences in symptoms and signs of dry eye disease in a Norwegian cohort of patients.
      . As Bourcier et al showed in their study, the thresholds for mechanical, chemical, and thermal stimulation increases with age
      • Bourcier T.
      • et al.
      Decreased corneal sensitivity in patients with dry eye.
      . Given these findings, decreased corneal sensitivity could be contributing to the lack of association between DED symptoms and age
      • Bourcier T.
      • et al.
      Decreased corneal sensitivity in patients with dry eye.
      .
      While this secondary analysis of the DREAM study data has provided greater insight regarding DED associations with age, there are limitations in this study. First, this study included only participants with moderate to severe DED, which excludes comparison of signs and symptoms of patients with less severe DED. Moreover, since patients already have DED, we are unable to compare their DED signs and symptoms prior to their development of their disease.
      Overall, we found that older age is associated with more severe dry eye signs, but not associated with dry eye symptoms. However, there are still many unanswered questions regarding the complex pathophysiology underlying these findings. Future studies that study the role of oxidative stress with increasing age and other potential factors affecting DED as patients get older would be helpful.

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      • et al.
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      Supplementary data

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