Abstract
Purpose:
To determine the correlations among symptoms and signs of dry eye disease (DED) in the Dry Eye Assessment and Management (DREAM) Study.
Methods:
535 patients with moderate-to-severe DED were assessed for symptoms using the Ocular Surface Disease Index (OSDI) and four DED signs in both eyes (conjunctival lissamine green staining, corneal fluorescein staining, Schirmer testing and tear break-up time (TBUT)) following standardized protocols at baseline and follow-up visits (months 3, 6 and 12). Spearman correlation coefficients (rho) were calculated for correlations among symptoms and signs of DED at baseline, and for correlations among changes of symptoms and signs from baseline at 12 months. The confidence intervals and p-values for correlation coefficients were calculated using cluster bootstrapping to account for inter-eye correlation.
Results:
At baseline, OSDI total score was not correlated with signs, however OSDI subscale score of ocular symptoms was weakly correlated with corneal staining score (rho=0.14, p=0.002) and Schirmer test score (rho=0.11, p=0.01).
There were statistically significant correlations among the four signs (p<0.001), with absolute correlation coefficient 0.14 (conjunctival staining score vs. TBUT) to 0.33 (conjunctival staining score vs. cornea staining score). The correlations among changes of symptoms and signs were weaker, with the highest correlation between change of conjunctival staining and corneal staining (rho=0.21, p<0.001).
Conclusions:
Consistent with previous studies, among DREAM participants with moderate-to-severe DED at baseline, correlations of DED symptoms with signs were low, and correlations among four objective signs were low to moderate. The correlations among changes of symptoms and signs were even weaker.
Keywords: Dry Eye, Signs, Symptoms, Correlation
INTRODUCTION
Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film accompanied by ocular symptoms.1 Ocular symptoms of DED are non-specific including redness, burning, stinging, foreign body sensation, photophobia, and pruritus.2 Symptoms can lead to a reduction in patients’ quality of life such as driving, reading, and computer use along with decreased workplace productivity.3,4
Diagnosis of DED is dependent on reports of ocular symptoms and measurement of signs. The quantity and severity of ocular symptoms can be assessed through the use of the Ocular Surface Disease Index (OSDI; Allergan, Inc, Irvine, California).5 Assessment for DED signs often include lissamine green staining of the interpalpebral conjunctiva, corneal fluorescein staining, Schirmer’s test, and tear break-up time (TBUT).1 Several previous studies reported inconsistent correlations ranging from no correlations or low correlations between DED symptoms and signs,6-10 while weak to moderate correlations among the DED signs.6,8,10 While the discordance between dry eye signs and symptoms is not well understood, one theory attributes the discordance to psychosomatic comorbidities (anxiety, depression, stress) leading to hyperalgesia and increased perception of clinical pain.11,12 The variations in results for correlations between DED signs and symptoms in previous studies could be due to the differences in study populations, sample size, or the procedures for evaluating DED symptoms or signs.
None of previous studies evaluated how the change over time of DED symptoms is correlated with change of signs, and correlations among changes of signs. Such evaluations may help improve our diagnosis and clinical care of DED, monitor the progression of DED, and provide useful information to select outcome measures for future clinical studies of DED. The Dry Eye and Assessment and Management (DREAM) study provides a large, diverse sample of dry eye patients with moderate to severe dry eye who underwent standardized procedures for assessment of signs and symptoms, providing a unique opportunity to evaluate their correlations at baseline and the correlations among their changes at 12 months.
METHODS
The details of the design and main results of the DREAM study have been described in previous publications,13,14 and only the major features of DREAM relevant to this project are described below.
The DREAM study was designed to include a broad spectrum of symptomatic patients with moderate-to-severe DED. From October 2014 through July 2016, 535 eligible patients were enrolled from 27 clinical centers in the United States and randomized 2:1 to an active oral omega-3 fatty acid supplement group or a placebo group (refined olive oil). To be eligible, the participant had at least two of the following four signs in the same eye at both the screening visit and the baseline visit: (1) a conjunctival lissamine-green staining score of 1 or more; (2) corneal fluorescein staining score of 4 or more; (3) tear break-up time of 7 seconds or less, (4) a result on Schirmer’s test with anesthesia of 1 to 7 mm in 5 minutes. The trial protocol was approved by the institutional review board associated with each center, carried out under an Investigational New Drug application for the Food and Drug Administration, and registered on ClinicalTrials.gov (NCT02128763). The trial followed the tenets of the Declaration of Helsinki, and written informed consent was obtained from all patients.
Measures for Dry Eye Symptoms and Signs
At screening visit, baseline visit, and at months 3, 6 and 12, patients were first assessed for dry eye symptoms and then four signs in both eyes following the order of TBUT, corneal fluorescein staining, lissamine green staining, and Schirmer’s tear test as described below.
Ocular Surface Disease Index (OSDI) Questionnaire:
The patient self-administered the 12-item OSDI questionnaire to assess DED symptoms. The total OSDI score and scores for three subscales (ocular symptoms, vision-related function, and environmental triggers) were calculated from the responses to each question. Scores on the OSDI range from 0 to 100 with lower score indicating less severity of dry eye symptoms.5
Tear Break-Up Time (TBUT):
The TBUT measures time (in seconds) from a complete blink to the appearance of the first dry spot (gap) in the tear film, with shorter times indicating more severe dry eye sign. Using a stopwatch, the TBUT was measured three times during the first minute, beginning 30 seconds after fluorescein instillation. The average of 3 repeated TBUT measurements was used for analysis.
Corneal Fluorescein Staining:
Corneal staining was graded using the cobalt blue filter of the slit lamp approximately 2.5 minutes after fluorescein instillation. Using methods standardized by the National Eye Institute (NEI),15 five areas of the cornea were graded on a scale of 0 to 3 with a total possible score of 0 to 15 per eye. Higher score indicates greater severity.
Lissamine Green Staining of the Interpalpebral Conjunctiva:
1% lissamine green was examined using white light and instilled into the lower conjunctival sac. After 1-2 minutes, the nasal-bulbar and temporal-bulbar conjunctiva were graded for staining on a scale of 0 to 3 with a total possible score of 18, following a modified version of the NEI/industry-recommended guidelines.15 Higher score indicates greater severity.
Schirmer’s Test:
Using the Schirmer’s test 2 with anesthesia, the length of wetting of paper strips positioned vaulting the lateral third of the lower eyelid margin over a 5-minute period was measured in millimeters, with shorter lengths indicating greater severity of sign.
Evaluation of Depression
Baseline depression status was assessed using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) version 2.0.16-18 The score of Mental Component Summary (MCS) of SF-36 has been seen to be an effective screening tool for depression.17 In one study, the SF-36 MCS score ≤42 yielded sensitivity of 73.7% and specificity of 80.6% for identifying clinical depression.17
Statistical Analyses
Data from eligible eyes at baseline were used for evaluating correlations among dry eye symptoms and signs, and data for changes from baseline at 12 months were used for evaluating correlations among changes in sign and symptoms. Spearman correlation coefficients (rho) were calculated due to the non-normality of the signs. The 95% confidence intervals (95% CI) for Spearman correlation coefficients and associated p-values were calculated using cluster bootstrap to account for the inter-eye correlation.19,20 For the correlation analysis among changes of symptoms and signs at 12 months, randomized treatment group was adjusted by calculating the partial correlation coefficients and with sensitivity analysis for correlation analysis stratified by treatment group. As the correlations between DED symptoms and signs may vary with sex,21 depression status,22-24 and Sjögren syndrome (SS) status, the stratified correlation analyses were performed by sex, baseline depression status and baseline SS status, and their differences and 95% confidence interval (95% CI) in correlation coefficients were calculated using cluster bootstrap. All statistical analyses were performed in SAS version 9.4 (SAS Institute Inc., Cary, NC), and two-sided p<0.05 was considered statistically significant.
RESULTS
Among 535 DREAM participants who completed both screening and baseline visits, 488 (91%) completed 12 months follow-up visit respectively. Baseline characteristics of all patients are displayed in Table 1, and the scores of dry eye symptoms and signs at baseline and 12 months follow-up visit were in Supplementary Table 1.
Table 1:
Baseline characteristics of patients (n=535)
| Baseline Characteristics | |
|---|---|
| Age – years, mean (SD) | 58 (13.2) |
| Sex – no. (%) | |
| Female | 434 (81.1) |
| Male | 101 (18.9) |
| Race – no. (%) | |
| White | 398 (74.4) |
| Black | 64 (12.0) |
| Other | 73 (13.6) |
| Ethnic Group – no. (%) | |
| Hispanic or Latino | 68 (12.7) |
| Other | 467 (87.3) |
| OSDI Score, mean (SD) | |
| Total | 44.4 (14.2) |
| Vision-related function subscale | 37.8 (17.7) |
| Ocular symptoms subscale | 46.6 (17.1) |
| Environmental triggers subscale | 55.6 (24.5) |
| Signs of Dry Eye Disease, mean (SD) | |
| Conjunctival Staining Score | 3.0 (1.4) |
| Corneal Staining Score | 3.9 (2.7) |
| Tear break-up time – sec | 3.1 (1.5) |
| Result on Schirmer’s test – mm in 5 minutes | 9.6 (6.5) |
| Depression Status§ – no. (%) | |
| Depression | 84 (15.7) |
| Non-Depression | 451 (84.3) |
| Sjögren Syndrome Status* – no. (%) | |
| Sjögren Syndrome | 52 (9.7) |
| Non- Sjögren Syndrome | 442 (82.6) |
| Unknown** | 41 (7.7) |
Depression was defined as SF-36 mental component summary score ≤ 42 at baseline.
Sjögren syndrome was defined by the 2012 American College of Rheumatology classification criteria for Sjögren Syndrome based on serology and ocular surface staining.
Without serology for antibody test for Sjögren syndrome.
Correlation between Dry Eye Signs and Symptoms at Baseline
Table 2 shows the Spearman correlation coefficients between DED signs and symptoms at baseline, for each of the four signs with the total OSDI score and each subscale score. Their correlations were all minimal (absolute value of Spearman correlation coefficient rho<0.15). Total OSDI score and subscale scores of vision-related function and environmental triggers were not significantly correlated with each of four signs (p≥0.07). However, OSDI subscale score of ocular symptoms was significantly correlated with corneal staining score (rho=0.14, p=0.002) and Schirmer test score (rho=0.11, p=0.01).
Table 2:
Correlations between dry eye symptoms and signs at baseline
| Dry Eye Signs (n= n=1022 eyes) |
OSDI (Lower is better) | |||||||
|---|---|---|---|---|---|---|---|---|
| Total Score | Vision-Related Function |
Ocular symptoms | Environmental triggers |
|||||
| rho* (95% CI) |
p | rho* (95% CI) |
p | rho* (95% CI) |
p | rho* (95% CI) |
p | |
| Conjunctival staining score (lower is better) | −0.00 (−0.08, 0.08) |
0.99 | −0.01 (−0.09, 0.06) |
0.79 | 0.03 (−0.04, 0.11) |
0.41 | −0.01 (−0.09, 0.07) |
0.75 |
| Corneal staining score (lower is better) | 0.06 (−0.02, 0.14) |
0.11 | 0.03 (−0.05, 0.11) |
0.47 | 0.14 (0.06, 0.22) |
0.002 | −0.01 (−0.09, 0.07) |
0.70 |
| Schirmer test (mm) (higher is better) | −0.07 (−0.15, 0.01) |
0.07 | −0.04 (−0.12, 0.03) |
0.30 | −0.11 (−0.19, −0.03) |
0.01 | 0.00 (−0.08, 0.08) |
0.97 |
| Tear break-up time (seconds) (higher is better) | −0.06 (−0.14, 0.02) |
0.15 | −0.02 (−0.09, 0.06) |
0.68 | −0.07 (−0.15, 0.00) |
0.07 | −0.06 (−0.14, 0.02) |
0.17 |
Partial correlation coefficients (rho) are calculated adjusting for treatment group.
95% confidence intervals (95% CI) and p-values were calculated using cluster bootstrap to account for two eyes from the same patient.
Table 3 shows results from comparisons of baseline OSDI scores among 3 groups of participants defined by number of signs (e.g., 2, 3, 4) meeting the thresholds used for determining eligibility for each sign. There was no statistically significant difference in the total OSDI score across 3 groups (p=0.30). However, participants with more signs ful filling the criteria had significantly higher baseline OSDI subscale score of ocular symptoms (mean score of 42.5, 45.4, 48.2 respectively, p=0.03, Table 3).
Table 3:
Comparison of symptoms across three groups of patients defined by number of signs filling the criteria at baseline
| Mean (SD) | P-value** | |||
|---|---|---|---|---|
| Baseline OSDI score | 2 signs filling criteria* (n= 192 patients) |
3 signs filling criteria* (n= 203 patients) |
4 signs filling criteria* (n= 140 patients) |
|
| Total score | 40.7 (15.2) | 42.7 (15.8) | 43.0 (15.5) | 0.30 |
| Vision-Related Function | 33.9 (19.0) | 36.3 (19.6) | 35.6 (18.9) | 0.44 |
| Ocular symptoms | 42.5 (18.2) | 45.4 (19.7) | 48.2 (19.2) | 0.03 |
| Environmental triggers | 53.0 (27.0) | 52.7 (27.6) | 52.0 (25.6) | 0.95 |
The enrollment criteria required the presence of at least two of the following four signs in the same eye at both the screening visit and the baseline visit: (1) a conjunctival lissamine-green staining score of 1 or more; (2) corneal fluorescein staining score of 4 or more; (3) tear break-up time of 7 seconds or less, (4) a result on Schirmer’s test with anesthesia of 1 to 7 mm in 5 minutes. The grouping of patients is based on the eye with more signs filling the criteria for this person-level comparison of OSDI scores.
From analysis of variance.
Table 4 shows the Spearman correlation coefficients between the changes in the signs and the changes in the symptoms at 12 months. The correlations between their changes were all minimal (absolute value of rho≤0.16). Change in total OSDI score was significantly correlated with changes in conjunctival staining score (rho=0.10, p=0.03) and TBUT (rho=−0.16, p<0.001), but was not significantly correlated with change in corneal staining score (rho=0.05, p=0.22). The correlations in OSDI subscales with change of signs were generally similar to those with the total OSDI. The correlation analysis by treatment group provided similar correlation coefficients (Supplementary Table 2).
Table 4:
Correlations between changes in dry eye symptoms and signs at 12 months from baseline (n=935 eye visits)
| Δ Signs | Δ OSDI (decrease is better) | |||||||
|---|---|---|---|---|---|---|---|---|
| Δ Total Score | Δ Vision-Related Function |
Δ Ocular symptoms | Δ Environmental triggers |
|||||
| rho* (95% CI) |
p | rho* (95% CI) |
p | rho* (95% CI) |
p | rho* (95% CI) |
p | |
| Δ Conjunctival staining score (decrease is better) | 0.10 (0.01, 0.17) | 0.03 | 0.06 (−0.01, 0.14) | 0.12 | 0.09 (0.01, 0.17) | 0.03 | 0.12 (0.04, 0.20) | 0.006 |
| Δ Corneal staining score (decrease is better) | 0.05 (−0.03, 0.13) | 0.22 | 0.07 (−0.02, 0.15) | 0.11 | 0.06 (−0.02, 0.15) | 0.13 | −0.00 (−0.08, 0.08) | 0.96 |
| Δ Schirmer test (mm) (increase is better) | 0.03 (−0.05, 0.12) | 0.48 | 0.02 (−0.08, 0.10) | 0.72 | −0.00 (−0.09, 0.08) | 0.95 | 0.01 (−0.07, 0.10) | 0.87 |
| Δ Tear break-up time (seconds) (increase is better) | −0.16 (−0.24, −0.09) | <0.001 | −0.16 (−0.23, −0.08) | <0.001 | −0.09 (−0.17, −0.00) | 0.03 | −0.13 (−0.21, −0.04) | 0.008 |
Partial correlation coefficients (rho) are calculated adjusting for treatment group.
95% confidence intervals (95% CI) and p-values are calculated using cluster bootstrap to account for multiple visits per patient and two eyes from same patient.
Correlations among Dry Eye Signs
There were statistically significant correlations among 4 DED signs (all p<0.001, Table 5) with increasing severity of one sign correlated with increasing severity of another sign. The absolute Spearman correlation coefficient ranged from 0.14 (conjunctival staining score vs. TBUT) to 0.33 (conjunctival staining score vs. cornea staining score). Schirmer test score was significantly correlated with conjunctival staining score (rho=−0.24, p<0.001), corneal staining score (rho=−0.33, p<0.001) and TBUT (rho=0.19, p<0.001).
Table 5:
Correlations among four dry eye signs at baseline (n = 1022 eyes)
| Dry Eye Signs | ||||||
|---|---|---|---|---|---|---|
| Conjunctival staining score (lower is better) |
Corneal staining score (lower is better) |
Schirmer test (mm) (higher is better) |
||||
| rho* (95% CI) | p | rho* (95% CI) | p | rho* (95% CI) |
p | |
| Conjunctival staining score (lower is better) | 1.00 | |||||
| Corneal staining score (lower is better) | 0.33 (0.26, 0.40) |
<0.001 | 1.00 | |||
| Schirmer test (mm) (higher is better) | −0.24 (−0.32, −0.16) |
<0.001 | −0.33 (−0.40, −0.26) |
<0.001 | 1.00 | |
| Tear break-up time (seconds) (higher is better) | −0.14 (−0.21, −0.06) |
<0.001 | −0.28 (−0.35, −0.21) |
<0.001 | 0.19 (0.11, 0.26) |
<0.001 |
Partial Spearman correlation coefficients (rho) were calculated adjusting for treatment group.
95% confidence intervals (95% CI) and p-values were calculated using cluster bootstrap to account for multiple visits per patient and two eyes from the same patient.
Table 6 shows the correlations among change of 4 DED signs at 12 months. Only change of conjunctival staining score was significantly correlated with change of corneal staining score (rho=0.21, p<0.001) and change of TBUT (rho=−0.12, p=0.002). Change of Schirmer test score was not significantly correlated with change other signs (p≥0.22). Similar correlation coefficients were found from analysis stratified by treatment group (Supplementary Table 3).
Table 6:
Correlations among change of dry eye signs at 12 months from baseline (n= 935 eyes)
| Δ Dry Eye Signs | ||||||
|---|---|---|---|---|---|---|
| Δ Conjunctival staining score (lower is better) |
Δ Corneal staining score (lower is better) |
Δ Schirmer test (mm) (higher is better) |
||||
| rho* (95% CI) |
p | rho* (95% CI) |
p | rho* (95% CI) |
p | |
| Δ Conjunctival staining score (decrease is better) | 1.00 | |||||
| Δ Corneal staining score (decrease is better) | 0.21 (0.14, 0.27) |
<0.001 | 1.00 | |||
| Δ Schirmer test (mm) (increase is better) | −0.01 (−0.08, 0.07) |
0.88 | −0.04 (−0.12, 0.03) |
0.22 | 1.00 | |
| Δ Tear break-up time (seconds) (increase is better) | −0.12 (−0.19, −0.04) |
0.002 | −0.07 (−0.14, 0.00) |
0.054 | 0.01 (−0.07, 0.10) |
0.75 |
Partial Spearman correlation coefficients (rho) were calculated adjusting for treatment group.
95% confidence intervals (95% CI) and p-values were calculated using cluster bootstrap to account for multiple visits per patient and two eyes from the same patient.
Correlation between Dry Eye Signs and Symptoms and among Signs Stratified by Sex
As shown in Table 7, the correlations between the total OSDI score and DED signs were all minimal in both females (absolute value of rho ranged from 0.01 to 0.06) males (absolute value of rho ranged from 0.02 to 0.14), and none of their differences were statistically significant. The absolute value of correlation coefficients among DED signs ranged from 0.14 (TBUT vs. conjunctival staining score) to 0.33 (corneal staining score vs. conjunctival staining score) in females and ranged from 0.08 (TBUT vs. conjunctival staining score) to 0.40 (Schirmer test score vs. corneal staining score) in males. None of their differences were statistically significant.
Table 7:
The correlation between dry eye symptoms and signs, and among signs for male and female at baseline (n = 1022 eyes)
| rho* (95% Confidence Interval) | |||
|---|---|---|---|
| Female (n= 835 eyes) |
Male (n= 187 eyes) |
Difference (Female - Male) |
|
| Between OSDI and Four Dry Dye Signs | |||
| OSDI vs. Tear break-up time | −0.04 (−0.12, 0.04) | −0.14 (−0.31, 0.03) | 0.10 (−0.10, 0.28) |
| OSDI vs. Schirmer test | −0.06 (−0.15, 0.02) | −0.06 (−0.24, 0.13) | −0.00 (−0.21, 0.20) |
| OSDI vs. Corneal staining score | 0.06 (−0.02, 0.15) | 0.02 (−0.21, 0.22) | 0.04 (−0.17, 0.28) |
| OSDI vs. Conjunctival staining score | −0.01 (−0.10, 0.07) | 0.03 (−0.15, 0.19) | −0.04 (−0.23, 0.15) |
| Among Four Dry Eye Signs | |||
| Tear break-up time vs. Schirmer test | 0.17 (0.09, 0.25) | 0.27 (0.10, 0.43) | −0.09 (−0.28, 0.07) |
| Tear break-up time vs. Corneal staining score | −0.27 (−0.35, −0.20) | −0.26 (−0.42, −0.09) | −0.02 (−0.20, 0.17) |
| Tear break-up time vs. Conjunctival staining score | −0.14 (−0.22, −0.06) | −0.08 (−0.24, 0.10) | −0.06 (−0.26, 0.12) |
| Schirmer test vs. Corneal staining score | −0.30 (−0.38, −0.22) | −0.40 (−0.56, −0.22) | 0.10 (−0.09, 0.27) |
| Schirmer test vs. Conjunctival staining score | −0.25 (−0.33, −0.17) | −0.17 (−0.36, 0.03) | −0.08 (−0.29, 0.13) |
| Corneal staining score vs. Conjunctival staining score | 0.33 (0.25, 0.41) | 0.29 (0.11, 0.45) | 0.04 (−0.12, 0.22) |
Confidence intervals and p-values were calculated using cluster bootstrap to account for correlation from two eyes of the same patient.
Correlation between Dry Eye Signs and Symptoms and among Signs Stratified by Baseline Depression Status
As shown in Table 8, the correlations between the total OSDI score and the DED signs were all minimal in both participants with depression (absolute value of rho: 0.02 to 0.05) and in participants without depression (absolute value of rho ranged from 0.01 to 0.09), and their differences were not statistically significant.
Table 8:
The correlation between dry eye symptoms and signs, and among signs for participants with and without depression at baseline (n = 1022 eyes)
| rho* (95% Confidence Interval) | |||
|---|---|---|---|
| Depression (n= 162 eyes) |
Non-depression (n= 860 eyes) |
Difference (Depression – without depression) |
|
| Between OSDI and Four Dry Dye Signs | |||
| OSDI vs. Tear break-up time | 0.02 (−0.15, 0.22) | −0.07 (−0.16, 0.01) | 0.09 (−0.09, 0.31) |
| OSDI vs. Schirmer test | 0.05 (−0.18, 0.27) | −0.09 (−0.18, −0.01) | 0.14 (−0.10, 0.37) |
| OSDI vs. Corneal staining score | 0.03 (−0.20, 0.23) | 0.06 (−0.02, 0.15) | −0.04 (−0.28, 0.19) |
| OSDI vs. Conjunctival staining score | 0.03 (−0.17, 0.23) | −0.01 (−0.10, 0.08) | 0.04 (−0.18, 0.26) |
| Among Four Dry Eye Signs | |||
| Tear break-up time vs. Schirmer test | 0.12 (−0.06, 0.28) | 0.20 (0.12, 0.28) | −0.08 (−0.29, 0.11) |
| Tear break-up time vs. Corneal staining score | −0.12 (−0.30, 0.06) | −0.30 (−0.38, −0.22) | 0.18 (−0.01, 0.39) |
| Tear break-up time vs. Conjunctival staining score | −0.13 (−0.30, 0.04) | −0.13 (−0.22, −0.06) | −0.00 (−0.18, 0.18) |
| Schirmer test vs. Corneal staining score | −0.29 (−0.46, −0.10) | −0.33 (−0.41, −0.25) | 0.04 (−0.14, 0.25) |
| Schirmer test vs. Conjunctival staining score | −0.16 (−0.34, 0.05) | −0.26 (−0.34, −0.17) | 0.10 (−0.09, 0.33) |
| Corneal staining score vs. Conjunctival staining score | 0.23 (0.06, 0.42) | 0.34 (0.26, 0.41) | −0.11 (−0.31, 0.09) |
Depression was defined as SF-36 mental component summary score ≤ 42 at baseline.
95% confidence intervals (95% CI) were calculated using cluster bootstrap to account for correlation from two eyes of the same patient.
For the correlation among the DED signs, the highest correlation was between corneal staining score and conjunctival staining score in participants without depression (rho=0.34, [95% CI: 0.26, 0.41]). while the correlations among DED signs tended to be higher in participants without depression than in participants with depression, none of their differences were statistically significant.
Correlation between Dry Eye Signs and Symptoms and among Signs Stratified by Baseline SS Status
As shown in Table 9, the correlation between total OSDI score and TBUT was significantly higher in participants with SS (rho=0.30) than participants without SS (rho=−0.09). Similarly, the correlations between the total OSDI score and conjunctival staining score was significantly stronger in patients with SS (rho=−0.26) than patients without SS (rho=0.02).
Table 9:
The correlation between dry eye symptoms and signs, and among signs for participants with and without Sjögrens Syndrome at baseline (n = 1022 eyes)
| rho* (95% Confidence Interval) | |||
|---|---|---|---|
| With SS (n= 108 eyes) |
Without SS (n= 914 eyes) |
Difference (With SS – without SS) |
|
| Between OSDI and Four Dry Dye Signs | |||
| OSDI vs. Tear break-up time | 0.30 (0.08, 0.47) | −0.09 (−0.17, −0.01) | 0.39 (0.15, 0.59) |
| OSDI vs. Schirmer test | 0.12 (−0.14, 0.35) | −0.09 (−0.17, 0.01) | 0.20 (−0.06, 0.45) |
| OSDI vs. Corneal staining score | 0.01 (−0.26, 0.26) | 0.06 (−0.02, 0.15) | −0.06 (−0.33, 0.21) |
| OSDI vs. Conjunctival staining score | −0.26 (−0.49, −0.01) | 0.02 (−0.06, 0.11) | −0.28 (−0.51, −0.03) |
| Among Four Dry Eye Signs | |||
| Tear break-up time vs. Schirmer test | 0.37 (0.15, 0.56) | 0.15 (0.07, 0.23) | 0.21 (−0.01, 0.44) |
| Tear break-up time vs. Corneal staining score | −0.23 (−0.48, 0.05) | −0.27 (−0.35, −0.19) | 0.05 (−0.22, 0.33) |
| Tear break-up time vs. Conjunctival staining score | −0.44 (−0.63, −0.23) | −0.08 (−0.16, 0.00) | −0.36 (−0.56, −0.13) |
| Schirmer test vs. Corneal staining score | −0.24 (−0.46, 0.01) | −0.31 (−0.38, −0.23) | 0.07 (−0.17, 0.33) |
| Schirmer test vs. Conjunctival staining score | −0.43 (−0.60, −0.25) | −0.19 (−0.27, −0.12) | −0.24 (−0.42, −0.03) |
| Corneal staining score vs. Conjunctival staining score | 0.56 (0.39, 0.71) | 0.28 (0.20, 0.36) | 0.29 (0.10, 0.45) |
SS= Sjögren Syndrome
Sjögren Syndrome was defined by the 2012 American College of Rheumatology SS classification criteria based on serology and ocular surface staining.
95% confidence intervals (95% CI) were calculated using cluster bootstrap to account for correlation from two eyes of the same patient.
For the correlations among DED signs at baseline, participants with SS had significantly stronger correlation between TBUT and conjunctival staining score (rho difference=0.36, [95% CI: 0.13, 0.56]), between Schirmer test vs. conjunctival staining score (rho difference=0.24, [95% CI: 0.03, 0.42]), and between corneal staining score vs. conjunctival staining score (rho difference=0.29, [95% CI: 0.10, 0.45], Table 9).
DISSICUSION
DED is typically defined by symptoms, such as OSDI questionnaire, and signs, but in past DED studies signs and symptoms did not correlate or only weakly so.25-27 Definitive reasons for their weak correlation are unknown. It could be that comorbidities involving neuropathic pain, or other chronic pain conditions increase the perception of ocular symptoms in DED patients.25,27 Among DREAM participants with moderate-to-severe DED who were assessed using standardized procedures in a multi-center clinical trial, we found that symptoms, as measured by total OSDI, were not significantly correlated with DED signs at baseline. However, the OSDI subscale, ocular symptoms, had significant weak correlations with corneal staining score and Schirmer test score at baseline. Their correlations did not differ by sex or depression status, but tended to be stronger in patients with Sjögren syndrome. Understanding the lack of a correlation between signs and symptoms in DED is a continuing conundrum that has escaped clear mechanisms to date.
Evaluation of the correlation among the four standard dry eye signs showed low correlations with the highest being between corneal staining and conjunctival staining (rho=0.33) in all participants, and was higher in participants with SS (rho=0.56). These findings were consistent with the findings reported by Sullivan et al in a study of 263 DED patients, that found highest correlation between corneal staining and conjunctival staining (rho=0.36).10
Patients’ mental health disorders can contribute to levels of symptoms of DED that are inconsistent with severity of DED signs.11,12 Zhou et al. found that DREAM participants with depression reported more severe symptoms of DED than patients without depression.24 Labbe et al. found that depression was significantly more prevalent in patients with DED, and was significantly correlated to DED symptoms but not correlated with DED signs.23 However, in our analysis, we found that the correlations between DED signs and symptoms tended to be weaker in participants with depression than participants without depression. Mental health issues, such as depression, may explain some of the discordance between signs and symptoms, but not likely the major cause of these findings. This data does suggest that other factors beyond the DED eye signs are significant for depression.
Better objective minimally invasive metrics that capture biologic changes on the eye might lead to better assessment of severity of ocular surface changes in DED and perhaps better correlation with symptoms.28 However, other pain syndromes, such as headache and back pain, have also found it hard to find objective metrics that correlate symptoms with disease signs, pointing out the difficulties in measuring and comparing subjective symptoms of a subject over time and to compare results among subjects and response to treatment.
There may be many reasons that signs and symptoms in DED do not correlate, including that the "objective" signs we use may not be free of bias; for instance, the Schirmer’s test has consistently shown low reproducibility with large differences seen between subjects and significant variations on different days and in different environments.29,30 Symptoms may vary in severity/frequency with season or throughout the day.31,32 For some DED patients, neuropathic pain may be a key issue and unrelated to signs of ocular surface abnormalities25, 27 or maybe the signs we use do not adequately measure surface changes.
Overall, our study had much strength including a large sample size, multi-center study, and standardized procedures for evaluating DED symptoms and signs. We evaluated both their correlations at baseline and correlation among their changes at 12 months. The large sample size allows us to perform stratified correlation analysis by sex, by baseline depression status and SS status. Despite the various strengths of our study, our DREAM study included only patients with moderate-to-severe DED; future research might benefit by including mild DED patients and those without DED.
In conclusion, this analysis of DED signs and symptoms in DREAM participants suggested total OSDI did not show correlations with signs at baseline, though the subscale, ocular symptoms, showed weak correlations with signs, especially corneal staining. The correlations among the 4 signs typically measured suggest they are all measuring ocular surface disease, with the best correlation between corneal and conjunctival staining. The absent or weak correlations among DED symptoms and signs point to the need for further research especially to develop minimally invasive objective metrics to classify DED, determine severity and response to treatment. The results of this study highlight the clinical challenge of appropriately diagnosing DED, classifying DED severity, and monitoring its progression. Further studies are needed to gain a better understanding of the etiopathogenesis of DED and objective ways to measure signs and symptoms.
Supplementary Material
Financial Support:
National Eye Institute Grants U10EY022879, U10EY022881, R21EY031338, and R01EY026972. The funding organization had no role in the design or conduct of this research.
Footnotes
Conflict of Interest: All authors do not have any conflicting of interest.
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