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Correlation among ocular surface changes and systemic hematologic indexes and disease activity in primary Sjögren’s syndrome: a cross-sectional study

BMC Ophthalmology volume 25, Article number: 270 (2025) Cite this article

Abstract

Background

To explore the relationship among ocular surface changes, systemic hematologic indexes, and disease activity in primary Sjögren’s syndrome patients.

Methods

Thirty-three primary Sjögren’s syndrome patients and 36 healthy controls were recruited in this cross-sectional study. All participants underwent complete ocular surface testing, including dry eye symptoms and signs, tear multi-cytokine analysis, and conjunctival impression cytology (CIC). Multiple systemic hematologic indexes and disease activity were also evaluated, including autoantibodies, immune cells, the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), and the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).

Results

Primary Sjögren’s syndrome patients exhibited significant dry eye, severe conjunctivochalasis, decreased goblet cell density, and severe squamous epithelial on the ocular surface. Interferon-inducible T cell alpha chemoattractant (I-TAC), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1β, IL-5, IL-8, IL-10, IL-13, IL-21, C-C motif chemokine ligand (CCL)4, interferon-gamma (IFN-γ), CCL20, and tumor necrosis factor-gamma (TNF-α) in the tear fluid of pSS patients changed significantly. Correlation analysis showed that anti-SSA was relevant to ocular surface disease index (OSDI) score, tear break-up time (TBUT), and meibomian gland secretion (MGS). CD8+ T cell percentages were relevant to TBUT and corneal fluorescein staining score (CFS). IL-8, IL-13, CCL4, and TNF-α were correlated with RF-IgA. IL-1β, CCL4, and TNF-α were correlated with CD8+ T cell counts. IL-5 and CCL20 were correlated with the ratio of helper T cells and suppressor T cells. Tear I-TAC, IL-8, CCL20, and TNF-α were significantly correlated with the ESSDAI of different domains.

Conclusions

Our results revealed that the ocular surface changes in pSS patients were significantly correlated with systemic hematologic indexes and disease activity.

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Background

Sjögren’s syndrome (SS) is a progressive autoimmune disease, characterized by chronic inflammation infiltration of exocrine glands, mainly the lacrimal and salivary glands, leading to dry eye and dry mouth [1]. Other exocrine glands and multi-system damage in about one-third of patients with SS, which may be accompanied by systemic manifestations like fatigue, pain, low fever, and diseases such as arthritis, cutaneous vasculitis, peripheral neuropathy, and glomerulonephritis [2, 3]. SS can be classified as primary or secondary, and SS without other autoimmune rheumatic diseases is called primary Sjögren’s syndrome (pSS) [4].

Dry eye is the most prevalent ocular disease in patients with pSS, however other conditions that can occur include chronic conjunctivitis, keratolysis, non-healing corneal ulcers, uveitis, scleritis, retinal vasculitis, and optic neuritis [5, 6]. Numerous studies have demonstrated that lymphocyte accumulation in the lacrimal gland, the meibomian gland, cornea, and conjunctiva, is linked to both aqueous-deficient dry eye and evaporative dry eye in pSS patients [7, 8]. Inflammation is a major risk factor or outcome in the development and progression of pSS-related ocular surface damage. Elevated levels of pro-inflammatory cytokines in tear fluid and exacerbation of ocular surface disease have been described in patients with pSS [9,10,11,12]. However, few studies have focused on the relationship between cytokines in tears and systemic characteristics in patients with pSS [13,14,15].

Innate and adaptive immune are associated with systemic damage in pSS patients [16]. The immune profile of pSS patients is characterized by the activation of immune cells and the production of various autoantibodies [17]. A variety of autoantibodies can be present in the patient’s serum [18]. At the same time, there is considerable evidence that CD4+ T cells, CD8+ cells, NK cells, B cells, and Th cells-mediated immune response are closely related to ocular surface damage in pSS [19,20,21,22,23,24]. Moreover, some papers provide solid evidence of the role of the adaptive immune response and the adverse environmental conditions in driving ocular surface pathology in the setting of desiccation [25,26,27,28]. Therefore, we speculate that the systemic immune status of pSS patients may be related to the pathogenesis of ocular surface damage. The European League Against Rheumatism (EULAR) has developed the EULAR SS Patient Reported Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI) as reference standards for measuring patient symptoms and systemic activity, respectively [29, 30]. However, there is a lack of research on the relationship between ocular changes and systemic disease activity. Whether ocular changes occur in isolation or are associated with systemic disease requires further investigation.

Therefore, in this study, we collected ocular signs and symptoms of pSS patients and assessed their ocular surface inflammation and pathology by tear multi-cytokines assay and conjunctival impression cytology (CIC), then collected systemic hematologic markers and assessed disease activity, and finally performed correlation analyses to investigate the relationship between ocular surface alterations, systemic hematologic characteristics, and disease activity in patients with pSS. The features of systemic disease in different ocular surface states were further explored, to provide a basis for overall observation and treatment in the future.

Methods

Study patients

Thirty-three primary Sjögren’s syndrome patients and 36 age and sex-matched healthy volunteers were enrolled in this study. All patients were hospitalized in the rheumatology and immunology department of The Second Xiangya Hospital of Central South University from March 2021 to August 2023. Major eligibility criteria were age ranging between 18 and 80 years, reported no use of contact lenses or punctual plugs, and no use of eye drops other than preservative-free artificial tears in the 30 days preceding the screening visit.

Evaluating systemic signs and disease activity of Sjögren’s syndrome

All patients were diagnosed primarily based on the 2016 American College of Rheumatology/European Ligue Against Rheumatism (ACR–EULAR) criteria. Clinical and laboratory data were recorded at the time of the blood draw when admitted to the hospital. Two disease activity indexes are currently being used as outcome criteria to evaluate SS: (i) ESSPRI: a patient self-reported questionnaire to assess symptoms, ranging from 0 to 10 [29]; and (ii) ESSDAI: an activity index to assess systemic complications [30]. An experienced rheumatologist scored disease activity in twelve domains (constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, central nervous system, hematological, and biological domain) of organ-specific involvement. For each domain, the different clinical manifestations were ranked from 0 = “no activity” to 3 = “high activity”, and the total score range from 0 to 123 was calculated by multiplying the weight of the domain by the level of activity [30]. The disease activity levels were defined as low activity (ESSDAI < 5), moderate activity (5 ≤ ESSDAI ≤ 13), and high activity (ESSDAI ≥ 14) levels [31].

Laboratory-based indexes included autoantibodies (RF-IgA, RF-IgM, RF-IgG, anti-U1 small nuclear ribonucleoprotein (anti-U1-snRNP), anti-Smith (Sm) antibody, anti-Ro-52 antibody, anti-histone antibody (AHA), anti-nucleosome antibody (ANuA), anti-SSA antibody and anti-SSB antibody), and lymphocytes population (the ratio of helper T cells and suppressor T cells (Th/Ts), the percentage and absolute count of CD4+ T cells, CD8+ T cells, T helper 1 cells, B cells, and natural killer (NK) cells).

Ocular surface measures

All patients who were diagnosed with pSS were thoroughly assessed by clinical history collection, clinical examination, and slit lamp examination for ocular surface measures on the same day as the blood draw. The ocular surface measures included dry eye symptoms using the Ocular Surface Disease Index (OSDI) questionnaire, 5 dry eye signs (tear break-up time (TBUT), Schirmer test without anesthesia, corneal fluorescein staining (CFS), meibomian gland secretions assessment, and Lid parallel conjunctival folds (LIPCOF) assessment).

The OSDI score includes 12 items, covering 3 subscales (vision-related function, ocular symptoms, and environmental triggers), and ranges from 0 (no ocular symptoms) to 100 (greatest severity) [32]. To facilitate the evaluation, we divided the OSDI score into 2 grades as reported: mild-moderate (scores ≤ 33), and severe (scores ≥ 33) [33]. For assessment of tear film stability, TBUT was performed. The fluorescein strip (Jingming, Tianjin, China) soaked with 1–2 drops of normal saline was contacted with the inferior conjunctival sac, and the duration required for the first dark spot on the cornea under the cobalt blue light was recorded [34]. The binocular average value of three TBUT measurements was used for analysis. Schirmer I test was performed without anesthesia by placing standardized Schirmer strips (Jingming, Tianjin, China) in the lateral one-third of the lower eyelid for 5 min. The length of the wet portion was measured [34]. Corneal fluorescein staining scores were determined in the cobalt blue light by the SICCA registry ocular examination protocol [35] and ranged from 0 to 5 grades by the Oxford grading scheme [36].

Meibomian gland secretions assessment was graded 0–3 according to the criteria identified at the 2011 international workshop on meibomian gland dysfunction [37]. 0 is normal - clear fluid; 1 - cloudy fluid; 2 - granular and cloudy fluid; 3 - toothpaste-like inspissated fluid or harder. LIPCOF assessments were evaluated with a slit-lamp microscope in the area perpendicular to the nasal and temporal bulbar conjunctiva in the lower lid, and classified into 0–3 grades based on the number of parallel conjunctival folds [38].

Tear multi-cytokine analysis

To collect tear samples, 10 µL of 0.9% normal saline was instilled in the patients’ inferior fornix (without topical anesthetics) and instructed to blink 3 times.

Tear fluid and buffer were collected by a disposable micro-capillary fluid collector (Seinda, Guangdong, China). 2.2 µl tears sample was collected per tube, 3 times per eye at 10-minute intervals. The tear samples were stored at − 80℃ until further examination. Tear cytokines concentration was analyzed using a Milliplex Map Human High Sensitivity T Cell Panel-Immunology Multiplex Assay (Millipore, Billerica, MA, USA)following the manufacturer’s procedure, twenty-one cytokines including I-TAC, GM-CSF, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12(p70), IL-13, IL-17 A, IL-21, IL-23, CCL3, CCL4, CCL20, CX3CL1, TFN-α, IFN-γ were detected and analyzed using liquid-phase chip detector MAGPIX (Luminex, Austin, TX, USA) with xPONENT® software (Luminex, Austin, TX, USA).

Conjunctival impression cytology and goblet cells evaluation

Conjunctival impression cytology combined with Periodic acid-Schiff (PAS) staining and hematoxylin counterstaining enables simultaneous visualization of mucin distribution and nuclear localization, providing a comprehensive method for assessing both the morphology and density of goblet cells and conjunctival epithelial cells. At least 15 min after all ocular examinations and superficial anesthesia, CIC was performed from the supratemporal bulbar conjunctiva using a 10 mm diameter sterile semicircular cellulose acetate membrane (Advantec, Tokyo, Japan). The collection area is about 39.25 mm2. The samples of the superior-temporal conjunctive in the eyes were then fixed in 95% ethanol for PAS staining [39, 40]. PAS staining was carried out by glycogen staining kit (G1360, Solarbio, Beijing, China), and mucin of conjunctival goblet cell reacted with Schiff reagent and generated a purple-magenta color. The density of goblet cell and conjunctival squamous metaplasia grade according to Nelson’s grading system were evaluated by PAS staining results under Invitrogen™ EVOS™ M7000 fully automatic live-cell fluorescence microscopy imaging system (Thermo Fisher Scientific, Massachusetts, U.S.), and five non-overlapping images were captured and analyzed by ImageJ software (National Institutes of Health, Maryland, USA) [40].

Statistical analysis

Data were analyzed using SPSS 20.0 software (IBM, Armonk, NY, USA). Continuous variables were described as the mean ± standard deviation (SD) and were compared using the Mann-Whitney U test. Categorical variables were frequencies and percentages and compared using the chi-squared test. Pearson’s and Spearman’s correlations were used to evaluate the association between clinical signs, disease activities, SS severity, and ocular surface findings, including dry eye symptoms, signs, tear cytokine concentration, goblet cell density, and conjunctival squamous metaplasia grade respectively. Values of P less than 0.05 were considered significant.

Results

Ocular surface characteristics in pSS patients

A total of 33 primary Sjögren’s syndrome patients and 36 age and sex-matched healthy controls participated in the study. The majority (87.88%) of the pSS patients consisted of women (Table 1).

Table 1 Characteristics and ocular surface evaluation of the pSS patients and healthy controls
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All pSS patients and healthy controls completed the OSDI questionnaires, 21.21% of SS patients showed abnormal OSDI scores higher than 33, indicating that they suffered from severe dry eye symptoms. However, the differences between pSS and controls were not statistically significant (Table 1).

The ocular surface examinations revealed that the pSS patients had significant alterations in their conjunctival situations, tear film, and meibomian gland (Table 1). 24.24% of pSS patients had 2 or more meibomian gland secretion scores. 21.22% of pSS patients had more than one conjunctival fold. For dry eye signs, 33.33% of the eyes of pSS patients had positive corneal fluorescein staining, and 57.58% of eyes had tear deficiency, with a result of the Schirmer I test less than 5 mm/5 min. 96.97% of eyes showed a decrease in tear film stability with a TBUT < 10s. The differences in meibomian gland secretion score, LIPCOF score, cornea fluorescein staining, Schirmer I test, Schirmer I test level, TBUT and TBUT level between pSS and controls were statistical (P < 0.05, Table 1).

Conjunctival impression cytology and detection of tear cytokines in pSS patients

As shown in Table 1, conjunctival impression cytology was performed in all pSS patients and healthy controls.

The PAS-stained goblet cell density in pSS patients (78.95 ± 58.47 cells/mm2) was almost half of that in healthy volunteers (144.79 ± 75.60 cells/mm2) (P < 0.05). Meanwhile, the Nelson grading, which reflects goblet cell density, the nucleus-cytoplasmic (N: C) ratio, and the shape and cell size of non-secretory epithelial cells, reached severest grade 3 in 72.73% of pSS patients, indicating that surface squamous metaplasia occurred in most patients, and the severity was much higher than that in the control group (P < 0.05). Figure 1A and B showed representative images of PAS staining for conjunctival impression cytology in the pSS group and healthy control group. As shown in Table 2, compared to the control groups, I-TAC, IL-5, IL-8, IL-10, IL-13, IL-21 IL-1β, CCL4, IFN-γ, and TNF-α significantly increased in tear of pSS patients, while CCL20 and GM-CSF decreased (P < 0.05).

Fig. 1
figure 1

Conjunctival impression cytology specimens. (A) Representative specimen of pSS patients. Goblet cells were less numerous, epithelial cells were enlarged and showed an abnormal appearance of squamous metaplasia with small and pyknotic nuclei. (B) Representative specimen from healthy controls. Goblet cells were abundant, and epithelial cells were small, round, and evenly distributed. Arrowheads indicate goblet cells. (Scale bar = 50 μm)

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Table 2 Tear cytokines evaluation of the pSS patients and healthy controls
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Correlations of dry eye evaluation, hematologic indexes, and disease activity in pSS patients

The ESSDAI score was designed as a consensus clinical index to measure disease activity in patients with pSS. The total ESSDAI score and all 12 domain scores have assessed the correlation with dry eye items separately.

As shown in Table 3, the OSDI score showed a significant positive relation with ESSPRI (P < 0.001, R2 = 0.541), anti-U1-snRNP (P = 0.045, R2 = 0.396) and a negative relation with CD4+ T cell counts (P = 0.041, R2 = -0.430), CD8+ T cell counts (P = 0.031, R2 = -0.449), ESSDAI serological domain (P = 0.0006, R2 = -0.468). TBUT showed a positive relation with NK cells percentage (P = 0.036, R2 = 0.438), NK cell counts (P = 0.444, R2 = 0.034) and a negative relation with anti-SSA (P = 0.020, R2 = -0.463), CD8+ T cells percentage (P = 0.032, R2 = -0.448), and Th1 cells percentage (P = 0.031, R2 = -0.450). Corneal fluorescein staining score showed a positive relation with RF IgA (P = 0.023, R2 = 0.662), anti-SSA (P = 0.017, R2 = 0.473), ESSDAI hematological domain score (P = 0.040, R2 = 0.360), and negative relation with ESSDAI pulmonary domain score (P = 0.007, R2 = -0.464). Meibomian gland secretion score showed a positive relation with CD8+ T cells percentage (P = 0.028, R2 = 0.457), and a negative relation with white cell counts (P = 0.019, R2 = -0.486), Th/Ts (P = 0.019, R2 = -0.486). Cornea opacity (P < 0.001, R2 = 0.696). LIPCOF score showed a positive relation with B cell counts (P = 0.045, R2 = 0.423), NK cell counts (P = 0.041, R2 = 0.430), and a negative relation with ESSDAI cutaneous domain score (P = 0.030, R2 = -0.378), ESSPRI (P = 0.010, R2 = -0.445), and ESSDAI total score (P = 0.020, R2 = -0.402) showed a positive relation with AHA (P = 0.003, R2 = 0.577), and the ESSDAI muscular domain score.

Table 3 Correlations of ocular surface indexes with hematologic indexes, and disease activity of pSS
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Overall, autoantibodies anti-U1-snRNP, anti-SSA, RF IgA, and AHA as well as lymphocyte CD8+ T cells percentage, CD4+ T cell counts, Th1 cells percentage, the ratio of helper T cells and suppressor T cells, NK cells percentage, NK cell counts and B cell counts in pSS patients were related to various ocular surface indications. CD8+ T cells percentage and the ratio of helper T cells and suppressor T cells were related to the evaporative dry eye. OSDI score and LIPCOF score were closely related to ESSPRI. OSDI score, CFS, cornea opacity, and LIPCOF score were closely related to ESSDAI of different domains. The existence of conjunctivochalasis was closely related to the ESSDAI total score.

Correlations of CIC, tear cytokine concentrations with hematologic indexes, and disease activity of pSS

As shown in Table 4, goblet cell density showed a negative relation with TBUT (P = 0.009, R2 = -0.451), and anti-SSA (P = 0.044, R2 = -0.407). Nelson’s grading of the ocular surface showed a positive relation with TBUT (P = 0.028, R2 = 0.383). Tear cytokines were significantly correlated with ocular surface signs, hematologic characteristics, and disease activity. I-TAC showed a positive relation with the ESSDAI muscular domain score (P = 0.021, R2 = 0.400). GM-CSF showed a positive relation with CFS (P = 0.006, R2 = 0.471) and a negative relation with MGS (P = 0.014, R2 = -0.425), Schirmer I (P = 0.023, R2 = -0.396). IL-1β showed a positive relation with CFS (P = 0.002, R2 = 0.530) and a negative relation with MGS (P = 0.023, R2 = -0.396), CD8+ T cell counts (P = 0.034, R2 = -0.443). IL-5 showed a positive relation with CFS (P = 0.014, R2 = 0.425) and Th/Ts (P = 0.020, R2 = 0.481). IL-8 showed a positive relation with RF IgA (P = 0.037, R2 = 0.582), ESSDAI systemic domain score (P = 0.048, R2 = 0.346), and a negative relation with Schirmer I (P = 0.047, R2 = − 0.349). IL-10 showed a positive relation with CFS (P < 0.001, R2 = 0.586) and a negative relation with Schirmer I (P = 0.014, R2 = -0.423). IL-13 showed a positive relation with CFS (P = 0.007, R2 = 0.460), RF IgA (P = 0.032, R2 = 0.594), anti-SSA (P = 0.050, R2 = 0.396) and a negative relation with LIPCOF (P = 0.028, R2 = -0.383), Schirmer I (P = 0.014, R2 = -0.423). IL-21 showed a negative relation with anti-SSB (P = 0.021, R2 = -0.458). CCL4 showed a positive relation with CFS (P < 0.001, R2 = 0.621), RF IgA (P <0.001, R2 = 0.830), and a negative relation with CD8+ T cell counts (P = 0.018, R2 = -0.490). CCL20 showed a positive relation with CD4+ T cell counts (P = 0.020, R2 = 0.483), Th/Ts (P = 0.026, R2 = 0.497), and a negative relation with ESSDAI muscular domain score (P = 0.026, R2 = -0.387). IFN-γ showed a positive relation with AHA (P = 0.047, R2 = 0.402). TNF-α showed a positive relation with CFS (P = 0.001, R2 = 0.533), RF IgA (P = 0.016, R2 = 0.653) and a negative relation with CD8+ T cell counts (P = 0.049, R2 = -0.415), ESSDAI lymphatic domain score (P = 0.037, R2 = -0.365).

Table 4 Correlations of GCD, tear cytokine concentrations with hematologic indexes, and disease activity of pSS
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Overall, tear GM-CSF, IL-8, IL-10, and IL-13 were related to the aqueous-deficient dry eye. Tear GM-CSF and IL-1β were related to the evaporative dry eye. Anti-SSA and TBUT are significantly associated with goblet cell density and the existence of mucin-deficient dry eye. Tear GM-CSF, IL-1β, IL-5, IL-10, IL-13, CCL4, and TNF-α were related to corneal fluoresce staining score. Significant correlations were found between IL-1β, IL-5, IL-8, IL-13, IL-21, CCL4, CCL20, IFN-γ, TNF-α and several hematologic characteristics. Tear IL-8, IL-13, CCL4, and TNF-α were related to RF-IgA. Tear IL-1β, CCL4, and TNF-α were related to CD8+ T cell counts. Tear CCL4 and TNF-α were closely related to RF-IgA and CD8+ T cell counts. Tear IL-5 and CCL20 were related to the ratio of helper T cells and suppressor T cells. Similarly, correlations were also found between tear cytokines and disease activity. Tear I-TAC, IL-8, CCL20, and TNF-α were closely related to ESSDAI of different domains.

Discussion

Primary Sjögren’s syndrome is a chronic autoimmune disease affecting the exocrine glands mainly. In addition to dry mouth and dry eyes caused by decreased function of salivary glands and lacrimal glands, other exocrine glands and organs outside the glands are also involved, resulting in symptoms of multisystemic damage [6]. Pathogenesis involves an inflammatory process with a large infiltration of lymphocytes in the affected tissues or organs. pSS is an incurable disease that is often not diagnosed until irreversible organ damage has occurred [41]. The ocular and systemic complications of primary SS are correlated, with the majority of patients presenting earlier with ocular manifestations in comparison [42]. Therefore, it is important to understand the ocular characteristics and related pathophysiological mechanisms of pSS patients to improve their quality of life and prognosis of pSS patients.

Our comprehensive evaluation of ocular surface manifestations in primary Sjögren’s syndrome (pSS) patients demonstrated clinically significant deteriorations, manifested through both symptomatic burden and anatomical alterations. Specifically, these patients exhibited elevated OSDI score concurrent with measurable degradation of tear film stability, meibomian gland dysfunction, and conjunctival-corneal impairment. Especially in our study, conjunctivochalasis in the patients with pSS is more severe. pSS patients had a decrease in Schirmer I test and TBUT values compared to controls, and their tears were abnormal in quantity and quality. pSS patients had damaged corneal epithelium, significantly reduced conjunctival goblet cells, and severe squamous metaplasia. Similar results were found in previous studies, which may be related to the ocular inflammation caused by pSS [43,44,45,46]. Invasion of lymphocytes and secretion of inflammatory cytokines can cause dysfunction of the lacrimal and meibomian glands, resulting in dry eye and pathological damage to the cornea and conjunctiva, ocular discomfort, and visual impairment [47]. Increased inflammation is associated with loss of conjunctival epithelial adherence and collagenolytic activity, which may lead to conjunctivochalasis [48]. Further studies are needed on conjunctivochalasis in patients with pSS. However, the subjective symptoms of dry eye in pSS patients were not found to be significantly different from controls in our study, which may be related to inflammation damaging corneal nerves and reducing corneal sensitivity [49].

In correlation analyses, although the mechanism of the effect of hematologic parameters and disease activity on the pSS-associated dry eye is unclear, limited data shows a specific association between them. Bunya, V. Y. et al. [50] suggested that abnormal conjunctival staining and abnormal Schirmer I test of pSS patients were significantly related to antibodies (anti-SSA or anti-SSB antibodies or RF positivity and ANA titer 1:320). Kim, J. E. et al. [51] found that log-transformed ocular staining score (OSS) and Anti-SSB /La antibody, RF were positively correlated in pSS patients. Lim, S. A. et al. [14] proved that conjunctival staining score and total OSS were correlated with RF and ANA levels in pSS patients. Maślińska, M. et al. [52] found that the Schirmer I test and OSS are associated with RF in pSS. Bunya, V. Y. et al. [53] demonstrated that corneal staining and conjunctival staining scores in pSS patients were highest in those positive for traditional autoantibodies (anti-SSA and anti-SSB antibodies) alone or both traditional and novel autoantibodies (SP-1, parotid secretory protein, carbonic anhydrase 6). Similar to the above research results, our study found that corneal fluorescein staining scores in pSS patients correlated significantly with anti-SSA and RF. In particular, we found that TBUT was negatively correlated with anti-SSA, and although the existing literature has not directly explored the relationship between them, patients with pSS often have anti-SSA positive and dry eye symptoms at the same time [50, 53]. CD8+ T cells percentage and the ratio of helper T cells and suppressor T cells were related to the evaporative dry eye, and systemic blood markers associated with goblet cells or mucin-deficient dry eye are anti-SSA. As a result, patients with abnormalities in these systemic indicators are more likely to be diagnosed with dry eye in the future. Few studies have described the association between dry eye and pSS disease activity. Ozek, D. et al. [13] showed a significant correlation between lissamine green staining score, osmolality, Schirmer I test score, TBUT score, Dry Eye Work Shop (DEWS) score and ESSDAI in pSS patients. Our study found that the corneal fluorescein staining score was significantly correlated with the disease activity of the involved hematological and pulmonary systems. Cornea opacity was significantly correlated with the disease activity of the involved muscle. LIPCOF score was significantly correlated with disease activity of the involved cutaneous system, ESSPRI, and ESSDAI total score, indicating that the severity of systemic disease in pSS patients with severe conjunctivochalasis is lower. We speculate that the pathological mechanism of conjunctivochalasis in SS is related to other factors, such as chronic mechanical friction or age-related conjunctivochalasis, and is not directly driven by systemic autoimmune responses [54, 55]. More studies may be needed to explore the mechanism of this negative association or to consider other confounding factors. In addition, anti-U1-snRNP antibodies in pSS patients have also been shown to be associated with systemic disease activity [56]. In our results, the OSDI score was significantly associated with the anti-U1-snRNP antibody, ESSPRI, and ESSDAI serological domain. Therefore, the CFS, cornea opacity, and LIPCOF score may be used to assess the severity of systemic organ damage in patients with pSS. CD4+ T cells, T helper cells, CD8+ T cells, B cells, and NK cells play a central role in the development of pSS [57,58,59,60]. We found that these immune cells were closely related to the ocular clinical examination of pSS patients, which provided a basis for understanding the pathophysiology of ocular lesions in pSS patients. CD8+ T cells were negatively correlated with TBUT and positively correlated with MGD score. NK cell counts were positively correlated with the LIPCOF score. Generally, SS patients have lymphopenia due to T cells and NK cells migration and infiltration [61, 62]. However, some studies have found an increased level of circulating peripheral blood CD8+ T cells and NK cells in patients with SS [63, 64]. CD8+ T cells and NK cells play a key role in the pathogenesis of SS, and different subpopulations and ratios of CD8+ T cells and NK cells may have pathogenic or regulatory effects on the ocular surface [22,23,24, 65, 66]. The systemic and local distribution of lymphocytes in different stages of SS and the role of lymphocyte subsets on the ocular surface need to be further elucidated.

Multicytokine analysis of human body fluid has become one of the most effective methods for studying human disease immune mechanisms [67]. The tear is closely related to ocular surface conditions, and collecting tear samples through microcapillaries is the least invasive method, making it an excellent choice for studying ocular diseases. To further investigate the role of different cytokines in the development of SS, we collected tears from pSS patients and examined the levels of 21 cytokines. The results showed that I-TAC, CCL4, IL-1β, IL-5, IL-8, IL-10, IL-13, IFN-γ, and TNF-α significantly increased in the tear of pSS patients, while GM-CSF and CCL20 decreased. IL-8, I-TAC, CCL4, and CCL20 are chemokines whose main function is to promote inflammation and recruit immune system cells to the site of inflammation or infection. Among them, IL-8 is mainly chemotactic neutrophils, I-TAC is mainly chemotactic Th1 lymphocytes, CCL4 is mainly chemotactic natural killer cells and monocytes, and CCL20 is mainly chemotactic lymphocytes [68, 69]. At present, studies have shown that the chemokine IL-8 and CCL4 in the tear of SS patients is significantly increased, while the changes of I-TAC and CCL20 have not been found before [11]. IL-1β, IL-5, IL-10, IL-13, IL-21 belong to the interleukin family. IL-1β mainly plays a pro-inflammatory role. IL-5 mainly promotes the proliferation and differentiation of eosinophils and also induces the differentiation of B cells [70]. IL-10 and IL-13 are mainly secreted by Th2 cells to play an anti-inflammatory role [71, 72]. IL-21 stimulates B cells and CD8+ T cells to differentiate and produce more antibodies [73]. SS used to be considered a Th1-dominant disease. However, we found that cytokines involved in the immune response of Th2 cells were also increased [74]. At the same time, there was an increased anti-inflammatory response in pSS, as well as an increased pro-inflammatory response. Previous studies have shown that the balance of Th1/Th2 cytokines may be related to the progression of the disease [75,76,77]. Similar to our study, several studies have shown a significant increase in IL-1β, IL-5, IL-10, and IL-21 in the eye of pSS patients, while there are few studies on IL-13 [9, 12, 78, 79]. GM-CSF, IFN-γ, and TNF-α are pro-inflammatory cytokines involved in the triggering of inflammatory responses, and TNF-α is mainly secreted by Th1 cells [80]. There is increasing evidence that T helper 17 cell-derived GM-CSF contributes to the development of inflammation and dry eye [9, 81]. Some studies have shown that IL-17 levels were not significantly elevated in dry eye and ocular chronic graft versus host disease (cGVHD) [82, 83]. However, in our study, we found that tear GM-CSF levels were significantly decreased in pSS patients, which was consistent with the results that IL-17 was not significantly. increased [84, 85]. Our study found increased IFN-γ and other Th1 cytokines but no significant increase in IL-17 in the tears of SS patients. This may be due to IL-17 is not as relevant as IFN-γ-predominant immunity in dry eye [86]. The difference in IL-17 level may be related to the course of pSS disease, and Th17 is more active in early inflammation [76]. IFN-γ and TNF-α have been shown to have an impact on the development of lesions in patients with pSS, with significantly elevated levels of ocular IFN-γ and TNF-α [9, 11, 12, 78, 87]. These findings provide clues to the occurrence of local and systemic immune responses in pSS patients.

Abnormalities in these cytokines may be important effectors in the pathogenesis of pSS, with multiple cytokines acting synergistically to cause pathological damage to the ocular surface and systemic organs in pSS patients. We found that GM-CSF was positively correlated with CFS and negatively correlated with Schirmer I. This may be due to the proinflammatory properties of GM-CSF aggravating ocular surface damage and the development of dry eye [84]. Many studies have shown that IL-1β directly or indirectly affects meibomian gland secretion by regulating inflammatory pathways and cell functions [88, 89]. Our study showed that IL-1β was negatively correlated with MGS, which may be related to the balance of other anti-inflammatory cytokines. Lee, S. Y. et al. [10] suggested IL-17 in the tear was significantly correlated with TBUT and Schirmer I test scores in the pSS group. Hernández-Molina, G. et al. [11] found that CXCL10 and CCL2 in the tear were associated with ocular symptoms, tear meniscus height, and ocular staining score. Chen, Xiangjun. et al. [12] demonstrated higher levels of IL-1ra, IL-2, IL-4, IL-8, IL-12p70, IL-17 A, IFN-γ, MIP-1β, and Rantes in the tear of pSS patients were significantly associated with Schirmer I test, TBUT and corneal fluoresce staining score. Willems, Bernd. et al. [32] demonstrated that Schirmer I test values of pSS patients were negatively correlated with IL-2, IL-4, IL-10, and IL-12p70, and IL-10 was significantly positively correlated with all standard patient evaluation of eye dryness questionnaire scores and significantly negatively correlated with TBUT. Similar to the above research, our study showed that altered tear cytokine levels were significantly associated with reduced tear production, tear film instability, and greater damage to the ocular surface.

On the other hand, our results demonstrated that cytokines in the tear of pSS patients are correlated with systemic hematologic indicators and disease activity, and these cytokines may play an important role in understanding systemic inflammation in pSS. Some studies have proved the influence of serum cytokines on serological indicators and disease activity. Ripsman, D. A. et al. [90] suggested a correlation between serum IL-14α levels and SS-related autoantibody anti-SSA /Ro and anti-SSB/La levels in pSS patients. Chen, C.et al. [91] showed that serological levels of TNF-α, IL-6, and YKL-40 in pSS patients correlated with ESSDAI, ESR, CRP, and IgG. Few studies have verified the relationship between ocular surface inflammation and systemic indicators. In our study, we found that cytokines in pSS tear were closely related to RF-IgA, CD8+ T cell counts, and the ratio of helper T cells and suppressor T cells suggesting that patients with elevated levels of these systemic indicators were more likely to have an inflammatory state of the ocular surface. I-TAC, IL-8, CCL20, and TNF-α showed a significant correlation with ESSDAI, especially in the muscular domain. These cytokines in the tear of pSS patients may be important tools for determining the activity and pathophysiological mechanisms of other organs outside the eye.

However, this study has several limitations. First, the relatively small sample size and restricted geographic recruitment may limit the generalizability of the findings to broader populations. Second, the cross-sectional nature of the study precludes the establishment of temporal relationships or causal inferences between observed variables. Additionally, the study is that no data were collected on the neurosensory aspects of dry eye. It is increasingly accepted that neurosensory abnormalities are a core feature of dry eye, which needs to be further explored in the future [92,93,94].

Conclusions

In summary, the coexistence of proinflammatory and anti-inflammatory responses on the ocular surface in patients with pSS, and these local immune states are closely related to systemic characteristics, especially RF-IgA, CD8+ T cell counts, and the ratio of helper T cells and suppressor T cells. In addition, Tear I-TAC, IL-8, CCL20, TNF-α, and conjunctivochalasis were significantly correlated with the ESSDAI, suggesting that these indicators help to understand the clinical severity of SS patients. These results provide new insights into the relationship between ocular surface and systemic status in patients with pSS.

Data availability

Data is provided within the supplementary information files.

Abbreviations

SS:

Sjögren’s syndrome

pSS:

Primary Sjögren’s syndrome

CIC:

Conjunctival impression cytology

ESSPRI:

EULAR Sjögren’s Syndrome Patient Reported Index

ESSDAI:

EULAR Sjögren’s Syndrome Disease Activity Index

I-TAC:

Interferon-inducible T cell alpha chemoattractant

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

CX3CL1:

C-X3-C motif chemokine 1

IL:

Interleukin

CCL:

C-C motif chemokine ligand

IFN-γ:

Interferon-gamma

TNF-α:

Tumor necrosis factor-gamma

anti-SSA:

Anti-Sjogren’s syndrome A antibody

anti-SSB:

Anti-Sjogren’s syndrome B antibody

anti-U1-snRNP:

Anti-U1 small nuclear ribonucleoprotein

AHA:

Anti-histone antibody

ANuA:

Anti-nucleosome antibody

anti-Ro-52:

Anti-Ro-52 antibody

anti-Sm:

Anti-Smith antibody

RF:

Rheumatoid factor

OSDI:

Ocular surface disease index

LIPCOF:

Lid-parallel conjunctival folds

CFS:

Corneal fluorescein staining

TBUT:

Tear film break-up time

MGS:

Meibomian gland secretion

GCD:

Goblet cell density

Th1:

T helper 1 cells

Th/Ts:

The ratio of helper T cells and suppressor T cells

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Acknowledgements

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Funding

This work is supported by the National Natural Science Foundation of China grants (82371034, 82171028), the Natural Science Foundation of Hunan Province grants (2022JJ30065), and the Beijing Physician Scientist Training Project (BJPSTP-2024-06).

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  1. Yan He and Jianing Feng contributed equally to this work.

Authors and Affiliations

  1. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmic and Visual Science Key Laboratory, Beijing, China

    Yan He, Yingyi Liu & Ying Jie

  2. Xi’an People’s Hospital (Xi’an Fourth Hospital), Shaanxi Eye Hospital, Northwest University Affiliated People’s Hospital, Xi’an, Shaanxi, China

    Jianing Feng

  3. Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Wen Shi & Yuerong Ren

  4. Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan, China

    Wen Shi & Yuerong Ren

  5. Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Huanmin Kang

  6. Department of Rheumatism and Immunology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Jing Tian

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Contributions

YH, JT, and YJ contributed to the study design. YYL, JNF, YRR, WS, and HMK performed the data collection. JNF and YH performed the data analysis and wrote the draft. JT and YJ conducted a critical review of the manuscript.

Corresponding authors

Correspondence to Jing Tian or Ying Jie.

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All subjects participated in the program voluntarily and signed informed consent forms. The study obtained written informed consent from all enrolled patients, approved by the Ethics Committee of The Second Xiangya Hospital of Central South University (Ethics code, LYF2021028). This study strictly followed the Helsinki declaration, which was implemented to in ensuring the rights and safety of the subjects.

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He, Y., Feng, J., Shi, W. et al. Correlation among ocular surface changes and systemic hematologic indexes and disease activity in primary Sjögren’s syndrome: a cross-sectional study. BMC Ophthalmol 25, 270 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12886-025-04050-7

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BMC Ophthalmology

ISSN: 1471-2415

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