The Proportion of Ocular Involvement and Characteristics of Dry Eye Parameters in Primary Sjögren Syndrome Referred from the Rheumatology Department
Article information
Abstract
Purpose
To report the proportion of ocular involvement in primary Sjögren syndrome (pSS) and to analyze various dry eye indexes and serum titers of markers depending on whether ocular involvement has occurred or not.
Methods
This retrospective study considered 214 patients referred from the rheumatology department for pSS workup. Symptom questionnaires, ocular surface stain score (OSS), Schirmer test, tear breakup time (TBUT), meibomian gland dropout, meibum quality, meibum expressibility, lid margin abnormalities, and lipid layer thickness were evaluated. Anti-Ro, anti-La, and antinuclear antibodies, rheumatoid factor, erythrocyte sedation rate, and C-reactive protein were included as systemic serum titers of markers. Patients with (group 1) and without (group 2) ocular involvement were compared. We conducted a further subgroup analysis of group 1 by dividing it into two groups based on whether or not the cases met all the ocular criteria for pSS diagnosis.
Results
Among the 214 referred patients, 118 were diagnosed as pSS: 87 out of 118 (73.7%) in group 1 and 31 (26.3%) in group 2. Group 1 showed higher meibum quality scores (p = 0.016), meibum expressibility (p = 0.010), and lid margin abnormalities on the lower lid (p = 0.029) and lower TBUT (p = 0.016) than group 2. OSS, TBUT, and the Schirmer test statistically differed (p < 0.001, p = 0.041, and p = 0043, respectively) between the patients who satisfied both ocular criteria (n = 46) and those who satisfied only one criterion (n = 41). There were no statistical differences in serum titers of markers between the two groups.
Conclusions
About half of patients referred from the rheumatology department for diagnosis of pSS were diagnosed with pSS. The proportion of ocular involvement in the pSS patients was 73.7%, and half of these patients met both ocular criteria. Only anti-Ro antibodies negatively correlated with TBUT. Also, OSS, TBUT, and Schirmer test were statistically different between the two subgroups.
Sjögren syndrome (SS) is a systemic autoimmune disease and manifests as chronic inflammation mainly affecting exocrine glands such as the lacrimal and salivary glands, resulting in sicca symptoms to the eye (keratoconjunctivitis sicca) and mouth (xerostomia) [1]. Primary SS (pSS) can be differentiated from secondary SS, which includes systemic rheumatic disorders such as rheumatoid arthritis or systemic lupus erythematosus. Based on previous research, the prevalence of pSS is estimated as 0.06% worldwide [2] and 2.34 per 100,000 in South Korea [3]. One study emphasized the underdiagnosis of pSS from dry eye disease: approximately 1 in 10 patients with clinically significant dry eye has underlying SS [4]. Not only is it important to differentiate pSS from dry eye to enable systemic SS care and treatment, but careful ophthalmologic evaluation in pSS is crucial considering that dry eye symptom is known to be very common, ranging from 33.3% to 99.1% in pSS [1,5,6]. The only study conducted in Korea to date reported that ocular signs were found in 104 out of 113 pSS patients (92%) according to the 2012 American College of Rheumatology (ACR) classification criteria [5], and no studies have evaluated the proportion of ocular involvement in pSS according to the 2016 ACR/European League Against Rheumatism (EULAR) diagnostic classification criteria.
There have been continuous efforts to develop a simplified, quantitative dry eye grading scheme. The 2016 ACR/EULAR refined ocular criterion is ocular surface stain score (OSS) ≥5 according to Whitcher protocol or van Bijsterveld score (VBS) ≥4 with at least one eye scoring 1, whereas the criterion of keratoconjunctivitis sicca defined by the 2012 ACR guidelines is OSS ≥3 according to Whitcher protocol, scoring equal to serologic assay results. Differently assigned OSS standard score from 3 to 5 are based on the derived conversion algorithm between the OSS and the VBS, leading this threshold more specific for diagnostic purposes [7]. Moreover, in serology, the 2016 ACR/EULAR no longer considers the positivity of anti-La antibodies to be a criterion, and additional modifications include the removal of the high-titer antinuclear antibodies (ANA) and positive rheumatoid factor (RF) as items due to the nonspecificity of those items.
In this study, we aim to determine the proportion of ocular involvement in patients referred to ophthalmology from the rheumatology department for SS evaluation according to the most recently updated 2016 ACR/EULAR classification criteria. Furthermore, we seek to investigate whether there are differences in dry eye indicators or serum titers of markers between those who meet both ocular diagnostic criteria and those who meet only one.
Materials and Methods
Ethics statement
This study was approved by the Institutional Review Board of Ewha Womans University Mokdong Hospital (No. 2024-08-026). The requirement for informed consent was waived due to the retrospective nature of the study. The study followed the principles of the Declaration of Helsinki.
Subjects and study design
We reviewed the medical charts of 214 patients who visited the ophthalmology department of Ewha Womans University Mokdong Hospital (Seoul, Korea) between December 2016 and February 2024. A total of 214 patients were first visited to rheumatology department due to several reasons, and they were suspected for pSS by rheumatologists and referred to ophthalmologists. The pSS diagnoses were made after the ophthalmology referral. At the time of the visit, serum titer marker results of anti-Ro antibodies or the results of minor salivary gland biopsies had not been reported for most patients. All the patients referred to were asked to be evaluated whether they met the diagnostic criteria for ocular involvement based on the 2016 ACR/EULAR (OSS ≥5 or Schirmer test <5 mm in at least one eye) for the first time.
Subjects were excluded if they do not have at least one symptom of ocular or oral dryness according to 2016 ACR/EULAR inclusion criteria and if they do not meet either following criteria: (1) labial salivary gland with focal lymphocytic sialadenitis and focus score ≥1; or (2) positive titer of anti-Ro antibodies [7]. Also, subjects who were diagnosed with secondary SS, had a history of ocular surgery, including corneal surgery and retinal surgery or ocular trauma, or were using contact lenses, glaucoma eyedrops, or other topical eye drops such as autologous serums were excluded. After exclusion, final total of 118 patients with pSS diagnoses were included in this study population. Of these 118 patients, patients with (group 1) and without (group 2) ocular involvement were compared using various parameters.
If both eyes were involved, the more severe eye was selected. Both Schirmer test and OSS were considered to determine the more severe eye. If one criterion had same scores on both eyes, the other criterion’s scores were compared, and the eye with higher score was selected. If both Schirmer test and OSS had same scores in both eyes, we selected right eye.
Clinical assessment of dry eye parameters and serum markers
Subjective symptoms were collected using the Ocular Surface Disease Index (OSDI) and the Standardized Patient Evaluation of Eye Dryness (SPEED). OSDI is a 12-item self-administered questionnaire that consists of ocular symptoms (three items), vision-related function (six items), and environmental triggers (three items). Each OSDI item is scored on a Likert-type scale ranging from 0 (none) to 4 points (all the time). The OSDI score sums all 12 items and is multiplied by 100 and then divided by 4 multiplied number of answered items [8]. The composite score of the SPEED questionnaire is derived by summing the scores from the frequency and severity sections of the questionnaire. The summary scores of the frequency and severity questions in the SPEED were derived by summing the 0 to 4 responses of frequency and the 0 to 3 responses of severity [9].
OSS was recorded using Sjögren’s International Collaborative Clinical Alliance (SICCA) OSS grading. Corneal and conjunctival epithelial staining was evaluated after fluorescein staining under cobalt blue light with a yellow filter. If there were no punctate epithelial erosions (PEEs), the score was 0. If one to five PEEs were seen, the corneal score was 1; 6 to 30 PEEs were scored as 2; and more than 30 PEEs were scored as 3. An additional point was added if as follows: (1) PEE occurred in the central 4-mm diameter portion of the cornea; (2) one or more filaments were seen anywhere on the cornea; or (3) one or more patches of confluent staining, including linear stains, were found anywhere on the cornea [10]. Tear secretion was evaluated using the Schirmer test without anesthesia, and tear breakup time (TBUT) was measured as the time between the last eye blink and the time of tear breakup upon fluorescein instillation. Lipid layer thickness and meibomian gland (MG) images of the upper and lower eyelid for MG dropout evaluation were acquired by the LipiView II system (Tear Science Inc). MG dropout was evaluated using the meiboscore assessing the morphologic change with a score from 0 to 3 points (0, no reduction; 1, <25% reduction; 2, 25%–75% reduction; 3, >75% reduction) [11]. The lid margin abnormalities were scored as 0 (absent) or 1 (present); vascular engorgement, plugged MG orifices, anterior displacement of the mucocutaneous junction, and irregularity of the lid margin and sum of each score (range, 0–4) were recorded. A higher score indicated more severe lid margin abnormality [11]. Meibum expressibility was scored by applying MG forceps (Charmant) on five glands of the central third of the lower or upper lid, with a score range from 0 to 3 (0, all five glands expressible; 1, three to four glands expressible; 2, one to two glands expressible; 3, no glands expressible) [12,13]. Eight lower eyelid MGs were assessed using a scale of 0 to 3 for meibum quality (grade 0, clear; grade 1, cloudy; grade 2, cloudy with granular debris; grade 3, thick like toothpaste; grade 4, no meibum) [12,13]. Anti-Ro and anti-La antibodies, ANA, RF, erythrocyte sedation rate (ESR), and C-reactive protein (CRP) were collected as systemic serum titers of markers.
Subgroup analysis
Based on the 2016 ACR/EULAR classification criteria, subgroup analysis was performed for those satisfying both diagnostic criteria for ocular involvement and those satisfying only one of the diagnosis criteria. Whether difference in proportion of ocular involvement occurs according to the number of satisfied ocular diagnostic criteria was evaluated. Furthermore, dry eye indicators and serum titers of markers were compared between these two groups.
Statistical analysis
We performed all statistical analyses with IBM SPSS ver. 26.0 (IBM Corp). The difference between those with and without ocular involvement was analyzed using the parametric Student t-test or the nonparametric Mann-Whitney U-test according to the normal distribution of the data. To compare categorical variables between groups, the chi-square test or Fisher exact test was used. Pearson correlation analysis was carried out to investigate the association between the dry eye parameters and systemic serum titers of markers. Statistical significance was defined as a p-value of <0.05.
Results
Among the 214 patients referred from the rheumatology department, 118 were diagnosed with pSS. Among the 118 pSS patients, 108 (91.5%) were female. The mean age of the 118 pSS patients was 55.01 ± 15.27 years (range, 17–95 years). As regards systemic diseases, diabetes mellitus was found in 7 patients, hypertension in 26 patients, and hypothyroidism in 13 patients. Group 1 consisted of 87 patients (83 female patients) and group 2 consisted of 31 patients (25 female patients). The mean age of group 1 was 55.67 ± 15.41 years, and that of group 2 was 53.12 ± 12.71 years.
The proportion of ocular involvement in pSS patients was 73.7% (87 of 118 patients). Group 1 showed higher meibum quality (p = 0.016), meibum expressibility (p = 0.010), and lid margin abnormalities on the lower lid (p = 0.029). Group 1 also showed shorter TBUT than group 2 (p = 0.016) (Table 1). In the analysis of systemic serum titers of markers, anti-Ro antibodies had a negative correlation with TBUT (r = −0.190, p = 0.048) in all patients. In group 1, anti-Ro antibodies had a positive correlation with OSS (r = 0.230, p = 0.034) and a negative correlation with TBUT (r = −0.284, p = 0.011). In group 2, anti-La antibodies showed a negative correlation with the Schirmer test (r = −0.421, p = 0.021) (Table 2).
Comparison of clinical and serologic features between patients with (group 1) and without (group 2) ocular involvement
Correlation between dry eye parameters and autoantibodies in patients with (group 1) and without (group 2) ocular involvement
Among group 1 patients, 41 of 87 patients (47.1%) met the criteria of both OSS and the Schirmer test. OSS was statistically higher in patients who satisfied both ocular criteria than in patients who satisfied only one criterion (p < 0.001). The Schirmer test and TBUT were lower in patients who met all the ocular criteria (p = 0.043 and p = 0.041, respectively) (Table 3).
Comparison of clinical and serologic features between patients who met both ocular criteria and patients who met only one criterion
Discussion
In this study, about half of the patients referred from the rheumatology department were diagnosed with pSS, and the proportion of ocular involvement in pSS was 73.7%. In group 1, where ocular involvement had occurred, meibum quality, meibum expressibility, and lower lid margin abnormalities were higher, and TBUT was lower than in group 2, where ocular involvement had not occurred. In a correlation analysis, anti-Ro antibodies was negatively correlated with TBUT. In patients who satisfied both the OSS and Schirmer test criteria, TBUT and the Schirmer test were significantly lower and OSS was higher than in those satisfying only one criterion. To our knowledge, this is the first study to discover the proportion of ocular involvement in pSS referred from a rheumatology department based on the revised 2016 ACR/EULAR classification criteria.
Dry eye symptom is known to be the most common symptom of SS, ranging from 33.3% to 99.1% of patients with SS [1,5,6]. Saldanha et al. [14] reported that among 2,961 SS patients, 96% experienced dry eye monthly/almost monthly or more frequently, 85% experienced significant dry eye daily or almost daily, and 53% experienced severe dry eye daily or almost daily with a severe impact on daily life. However, there has been a lack of reporting on the exact rate of ocular involvement according to recent criteria rather than the subjective dry eye symptom itself. To develop better classification criteria with higher sensitivity and specificity, the 2012 ACR guidelines suggested SICCA grading OSS. Moreover, the 2016 ACR/EULAR refined ocular criteria as OSS ≥5 according to Whitcher protocol or VBS ≥4 in at least one eye scoring 1. The differently assigned scores in OSS from 3 (2012 ACR) to 5 (2016 ACR/EULAR) are based on the derived conversion algorithm between the OSS and the VBS; leading a new threshold more specific for diagnostic purposes [7]. In this study, most patients experienced dry eye discomfort as an OSDI mean of 24.45 ± 20.50 and a SPEED mean of 7.51 ± 5.62. Only 10 patients answered 0 in OSDI; patients satisfying ocular criteria either OSS or Schirmer test were 78% in pSS.
Although the pathogenesis of dry eye in SS is not completely understood, dry eye in SS is commonly classified as the aqueous-deficient type, which is the result of reduced secretion of the aqueous component in tears [15]. However, several recent studies focusing on evaporative dry eye in SS have suggested that MG dysfunction (MGD) may also be part of the mechanism of dry eye in SS. According to Hikichi et al. [16], lymphocyte infiltration at the tarsal conjunctival epithelium of patients with SS was greater than that found in patients without SS. Shimazaki et al. [17] reported that the destruction of MGs and an increase in tear evaporation are related to ocular surface changes in SS patients. Kang et al. [18] reported that dry eye patients in SS had more severe MGD with poorer mean meiboscore and MG expressibility than non-SS dry eye patients. The present study also showed the possibility of MGD involvement, at least in part, in ocular surface changes in pSS, reporting that meibum quality, meibum expressibility, and lid margin abnormalities on the lower lid were higher in group 1 than in group 2. The meiboscore showed a trend of higher scores in group 1 than group 2, but it was not statistically significant. Our study result may be due to a somewhat common discrepancy between functional and morphological changes of MGs in reality, which is theoretically known to be well correlated [19]. Moreover, further research to determine the relationship between the focus score of salivary gland biopsy and the severity of MGD in pSS would be helpful considering that previous research using the focus score showed that the lymphocyte infiltration of the salivary gland was correlated with a higher meiboscore and lower lipid layer thickness [20]. Tear film instability, represented as TBUT, was reported to be related significantly to pSS patients with ocular involvement in previous studies. Zhao and Le [21] suggested that shorter TBUT had a close relationship with the presence of corneal fluorescein staining in SS. In our study, TBUT was shorter in group 1 than group 2 as well as in patients who met both ocular criteria rather than patients who met only one criterion.
On the other hand, subjective symptom indicators like OSDI and SPEED did not show any significant differences between the two groups. This discrepancy may be due to inconsistency of corneal sensitivity in pSS [22]. It is known that tear hyperosmolarity in dry eye induces cascades of inflammatory events that result in damage to the nerve endings. Also, Xu et al. [23] showed that corneal sensitivity is decreased in SS-related dry eye. However, Tuisku et al. [24] reported decreased corneal detection thresholds in pSS implicating corneal mechanical hypersensitivity.
Considering that SS is a systemic autoimmune disorder, much research on serologic findings has been carried out to determine general systemic involvement or relations in SS patients [20,25]. The EULAR Sjögren’s Syndrome Disease Activity Index is widely used to check disease activity systemically [14]. Of various serologic factors, such as anti-Ro and anti-La antibodies, ANA, and RF, the 2016 ACR/EULAR classification criteria only take anti-Ro antibodies as a diagnostic criterion, but not the others, such as anti-La antibodies, due to its nonspecificity. Negrini et al. [25] mentioned that ANA is present in the sera of up to 85% in SS, and RF is commonly positive in SS. Baer et al. [26] reported that anti-Ro antibodies was positive in 50% to 70% of pSS cases and anti-La antibodies was positive in 45% to 60% of pSS cases simultaneously with anti-Ro antibodies. Lee et al. [20] reported that examining anti-La and anti-Ro antibodies would help predict clinical severities of SS.
In the present study, we aimed to determine whether serologic titers of antibodies might have a meaningful correlation with ocular involvement in pSS. Only the RF titer showed a higher trend in the ocular involvement group, although it did not reach statistical significance. The titer of anti-Ro and anti-La antibodies, ESR, and CRP did not differ between groups with and without ocular involvement. We carried out a further statistical analysis excluding the patients who had a history of usage of hydroxychloroquine (HCQ) before the first ophthalmic and serologic examination (data not shown). Seven patients had already started HCQ under the rheumatologic department before visiting the ophthalmology department, and 12 patients claimed that they had used HCQ under the care of another clinic but had no specific medical records attached. However, there was no statistically significant difference according to the current HCQ administration either. Past research has reported that HCQ treatment may improve ESR, CRP, and immunoglobulins [27]. Several studies have reported a nonrelevant relation between pSS disease activity and serologic findings, such as ESR and CRP [28,29]. A few have suggested that extraglandular ocular findings or other extraglandular systemic manifestations are relevant with higher systemic inflammatory markers [30].
Furthermore, anti-Ro antibodies was negatively correlated with TBUT in the study population, and anti-Ro antibodies had a positive correlation with OSS and a negative correlation with TBUT in group 1. This shows a link between the presence of particular autoantibodies and clinical ocular surface characteristics, in alignment with previous studies [31,32]. On the other hand, anti-Lo antibodies and other serum markers were not in a statistically meaningful relationship. Lee et al. [20] reported that there were no significant differences in the dry eye parameters regardless of the presence of anti-La antibodies although higher titer anti-La antibodies with anti-Ro antibodies together would imply a higher severity of the disease. Thus, it would be helpful for ophthalmologists to take into consideration these serologic findings in pSS.
On the other hand, this study showed no significant correlations with the anti-Ro titer and Schirmer test but only with OSS and TBUT. Previous studies revealed that clinical relevance of serum anti-Ro antibodies with ocular parameters, but the results were lack of consistency. Several studies reported the negative correlation of anti-Ro antibodies with tear production [20,32]. However, according to Lim et al. [33], significantly higher conjunctival staining scores were observed in the serum of patients with positive high titer of anti-Ro antibodies in pSS, but Schirmer test results were not in correlation. Chung et al. [31] demonstrated that severe SS group with higher corneal staining grades using Oxford grading scheme showed higher anti-Ro and anti-La antibodies titers than those with mild SS, but Schirmer test results did not show such correlation. Also, Versura et al. [34] mentioned inaccuracy of Schirmer test in relation of anti-Ro antibodies in pSS explaining on the basis of the fact that Schirmer test has low repeatability and it may be influenced by the stage of the disease and by the therapy. Further studies with disease severity regarding serum markers and ocular indexes would be helpful to understand the disease more.
There are several limitations in the present study. Firstly, the study design was retrospective, and it was carried out in only one tertiary care university hospital. Furthermore, the subjects were all referred from our rheumatology department, and among them were 12 patients whose medical records were slightly vague about the first diagnosis. Secondly, topical agents including artificial tears or other medications could significantly affect the results of the dry eye parameters. In this study, only two patients reported their usage of artificial tear to us. One was in group 1 and the other in group 2. Additionally, extraglandular ocular involvement research in terms of evaluating disease activity along with EULAR Sjögren’s Syndrome Disease Activity Index or EULAR Sjögren’s Syndrome Patient Reported Index was not considered, and doing so would be helpful to understand the disease fully and deeply. However, these limitations do not compromise the significance of this study’s results, which is the first to provide information on the proportion of ocular involvement in pSS based on recent diagnosis criteria and to compare various dry eye parameters and serum titer of markers between ocular involvement group and noninvolvement group.
Acknowledgements
None.
Notes
Part of this study was presented online at the 131st meeting of the Korean Ophthalmological Society in Jeju, Korea, in April 2024. This study was also presented at the 42nd Congress of the European Society of Cataract and Refractive Surgeons in Barcelona, Spain, in September 2024.
Conflicts of Interest:
None.
Funding:
None.