Clinical Characteristics and Influencing Factors of Primary Sjögren's Disease with Dryness and Blood-Stasis Syndrome

LEI Chunxin¹, ZHANG Xiya¹, ZHANG Yan¹, CHEN Jiaqi¹, LIU Zihan¹, LUO Jing², TAO Qingwen²

¹Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
²Department of Traditional Chinese Medicine Rheumatology, China-Japan Friendship Hospital/Beijing Key Laboratory of Immune Inflammatory Diseases, Beijing 100029, China

Corresponding authors: LUO Jing, Associate Chief Physician; E-mail: luojinggg@sina.com
TAO Qingwen, Chief Physician/Doctoral Supervisor; E-mail: taoqg1@sina.com

Abstract

Background: Primary Sjögren's disease (pSjD) is a chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, presenting mainly with xerostomia and xerophthalmia, and potentially involving multiple systems. Epidemiological studies indicate a prevalence of approximately 0.06%-0.08%, with an increasing trend over time. In recent years, expert consensus in traditional Chinese medicine (TCM) has recognized the dryness and blood-stasis pattern as one of the common syndromes; however, its clinical characteristics, influencing factors, and prognosis have not been systematically investigated.

Objective: To explore the integrative clinical features, influencing factors, and prognostic outcomes of patients with pSjD of dryness and blood-stasis syndrome.

Methods: A total of 970 patients with pSjD treated at the China-Japan Friendship Hospital from 2017 to 2022 were enrolled, including 185 with pSjD of dryness and blood-stasis syndrome and 785 without pSjD of dryness and blood-stasis syndrome. General information, clinical symptoms, laboratory indicators, and disease activity scores (EULAR Sjögren's Syndrome Disease Activity Index, ESSDAI) were compared between groups. Multivariate logistic regression analysis was used to identify independent factors associated with pSjD of dryness and blood-stasis syndrome. Survival outcomes, including all-cause mortality, malignancy, and incident interstitial lung disease (ILD), were analyzed using Kaplan-Meier survival curves and compared by the Log-rank test.

Results: Compared with the non-DBSS group, patients with pSjD of dryness and blood-stasis syndrome were more frequently female, had longer disease duration, and were younger at disease onset and enrollment (P<0.05). The top five symptoms in the pSjD of dryness and blood-stasis syndrome group were xerostomia (75%), xerophthalmia (75%), arthralgia (55%), fatigue (43%), and rampant caries (34%). The proportions of xerostomia, arthralgia, Raynaud's phenomenon, lymphadenopathy, parotid gland enlargement, purpura-like rash, arthritis, and bleeding were significantly higher in the pSjD of dryness and blood-stasis syndrome group, whereas cough and dyspnea were less frequent (P<0.05). Multivariate analysis identified older age at enrollment (OR=0.979, 95%CI=0.965-0.993, P=0.004) and higher platelet counts (OR=0.997, 95%CI=0.994-0.999, P=0.007) as independent protective factors for pSjD of dryness and blood-stasis syndrome, while anti-RNP positivity (OR=2.352, 95%CI=1.305-4.238, P=0.004), anti-CENP-B positivity (OR=2.490, 95%CI=1.404-4.415, P=0.002), anti-β2GP1 positivity (OR=2.269, 95%CI=1.057-4.872, P=0.036), and higher ESSDAI scores (OR=1.037, 95%CI=1.011-1.064, P=0.006) were identified as independent risk factors. Kaplan-Meier survival analysis showed no significant differences between groups in all-cause mortality, malignancy, or incident ILD (P>0.05).

Conclusion: Nearly 20% of pSjD patients had dryness and blood-stasis syndrome, and these patients exhibited a more chronic disease course, higher ESSDAI scores, and more prominent hematological involvement, although with a lower proportion of ILD. Older age at enrollment and higher platelet counts may be independent protective factors for pSjD of dryness and blood-stasis syndrome, while anti-RNP positivity, anti-CENP-B positivity, anti-β2GP1 positivity, and higher ESSDAI scores may be identified as independent risk factors. No significant differences were observed in all-cause mortality, malignancy, or incident ILD between the two groups.

Keywords: Primary Sjögren's disease; Dryness and blood-stasis syndrome; Clinical characteristics; Haematological involvement; Root cause analysis; Prognosis

Introduction

Primary Sjögren's disease (pSjD) is a chronic inflammatory autoimmune disease characterized by lymphocytic infiltration of exocrine glands, with xerostomia and xerophthalmia as the main clinical manifestations, and potentially involving multiple organs and systems in severe cases. Epidemiological surveys indicate that the annual prevalence of pSjD is approximately 0.060%-0.077%, with a rising trend year by year. The pathogenesis remains incompletely understood, but is generally considered to be related to genetics, infection, and autoimmune abnormalities. Currently, there is a lack of targeted therapeutic measures; systemic involvement is often managed with reference to rheumatoid arthritis and systemic lupus erythematosus treatment protocols, while glandular involvement relies heavily on tear and saliva replacement therapy with limited efficacy.

In TCM, pSjD belongs to the category of "dryness bi-syndrome." Modern practitioners generally believe that this disease is characterized by "yin deficiency as the root and dryness-heat as the manifestation," and clinically, methods of supplementing qi and nourishing yin, moistening dryness and generating fluids are commonly adopted. However, dryness bi-syndrome is often protracted and difficult to cure, and treatment focusing solely on nourishing yin and moistening dryness sometimes yields minimal results, failing to fundamentally alleviate the condition. In 2023, the Rheumatology Branch of the China Association of Chinese Medicine led the development of the "Expert Consensus on TCM Syndrome Patterns of Sjögren's Syndrome," which greatly standardized the TCM pattern differentiation for pSjD and first proposed dryness and blood-stasis syndrome as a common pattern. However, systematic research on the clinical characteristics and related factors of patients with this syndrome is still lacking. Therefore, this study enrolled consecutive pSjD cases from the China-Japan Friendship Hospital over the past five years to summarize and analyze the clinical characteristics and related factors of pSjD patients with dryness and blood-stasis syndrome, with long-term follow-up to clarify the clinical manifestations and prognosis of these patients, providing a reference for clinical diagnosis and treatment.

Methods

Study Design and Participants

This study employed a cohort design combining retrospective baseline data collection with prospective follow-up. All consecutive pSjD cases treated at the China-Japan Friendship Hospital from January 2017 to December 2022 were enrolled. Baseline data were retrospectively collected from patients' first-visit clinical information. Patient enrollment time served as the starting point for follow-up observation. All patients were prospectively followed up every six months via telephone or outpatient visits until the occurrence of outcome events or the follow-up cutoff date (February 1, 2024). Outcome events were defined as all-cause death, malignancy, or incident interstitial lung disease (ILD) (newly diagnosed ILD during follow-up in patients without baseline ILD). This study was approved by the Ethics Committee of the China-Japan Friendship Hospital (No.2021-144-K102). Informed consent was waived as no personal privacy information was involved.

Inclusion criteria: (1) Meeting the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for pSjD; (2) Complete medical records documenting diagnosis and treatment information.

Exclusion criteria: (1) Comorbid other connective tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus; (2) Pregnant or lactating women, patients with mental illness; (3) Patients with severe cardiovascular or cerebrovascular disease, liver or kidney failure, or malignancy.

Diagnostic Criteria for Dryness and Blood-Stasis Syndrome

Based on the 2023 "Expert Consensus on TCM Syndrome Patterns of Sjögren's Syndrome" from the Rheumatology Branch of the China Association of Chinese Medicine, patients with dryness and blood-stasis syndrome met three diagnostic criteria: (1) Main symptoms: Dry mouth without desire to drink, dry eyes with little tearing, and rough skin with ecchymosis or petechiae; (2) Secondary symptoms: Nasal dryness, throat dryness, joint and muscle pain, acral skin turning white or purple, persistent swelling of the submandibular region or scrofula; (3) Tongue and pulse: Dark tongue or with ecchymosis/petechiae, or sublingual vessels that are tortuous and cyanotic, with little and dry coating, and a choppy or thin-choppy pulse.

Two experienced TCM rheumatology specialists independently performed pattern differentiation according to the "Expert Consensus on TCM Syndrome Patterns of Sjögren's Syndrome (2023)" and other standards. If the two physicians agreed, the pattern was directly determined; if there was disagreement, a third senior physician reviewed the case and convened an expert panel to discuss and reach a final consensus based on symptoms, signs, and previous medical records. Patients were thus divided into the pSjD-dryness and blood-stasis group and the pSjD-non-dryness and blood-stasis group.

Data Collection

Demographic and medical history data: Patient sex, age at enrollment, age at disease onset, and disease duration (defined as time from first dry symptom onset to current enrollment) were recorded.

Clinical manifestations: Baseline clinical features were recorded as binary variables, including xerostomia, xerophthalmia, fever, night sweats, fatigue, Raynaud's phenomenon, purpura-like rash, cough, dyspnea, lymphadenopathy, arthralgia, arthritis, morning stiffness, rampant caries, parotid gland enlargement, and bleeding.

ILD diagnosis: pSjD-related ILD was diagnosed by clinicians based on comprehensive assessment of clinical symptoms, signs, and high-resolution CT (HRCT) imaging reports.

Splenomegaly diagnosis: Splenomegaly was determined by clinicians based on imaging ultrasound findings showing splenic thickness >4 cm or maximum length >11 cm, with spleen palpable below the left costal margin, confirmed by professional imaging physicians.

Disease activity: Assessed using the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI). Disease activity was categorized into three levels: low activity (ESSDAI<5), moderate activity (5≤ESSDAI≤13), and high activity (ESSDAI>13).

Laboratory tests: Recorded as binary variables within normal ranges for white blood cell count (WBC), neutrophil count (NEUT), lymphocyte count (LYMPH), red blood cell count (RBC), hemoglobin (Hb), platelet count (PLT), alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), creatinine (Cr), albumin (ALB), serum potassium, sodium, and chloride.

Baseline autoantibody testing: Antinuclear antibodies (ANA) were detected by indirect immunofluorescence (IIF) (EUROIMMUN, batch FA1800-101033). Anti-Sm, anti-SSA, anti-Ro52, anti-SSB, anti-ribonucleoprotein (RNP), anti-topoisomerase I (Scl-70), anti-centromere protein B (CENP-B), anti-AMA-M2, anti-PM-Scl, anti-cardiolipin antibody (aCL), anti-beta-2-glycoprotein 1 antibody (β2GP1), and anti-double-stranded DNA (dsDNA) antibodies were detected by immunoblotting (EUROIMMUN, batch DL1590-6401-3G).

Immunological indicators: The following indicators were recorded as binary variables: elevated immunoglobulin G (IgG) (>16.2 g/L), elevated immunoglobulin A (IgA) (>3.78 g/L), elevated immunoglobulin M (IgM) (>2.63 g/L), decreased complement C3 (<0.7 g/L), decreased C4 (<0.16 g/L), elevated C-reactive protein (CRP) (>8 mg/L), and elevated erythrocyte sedimentation rate (ESR) (female >20 mm/1h, male >15 mm/1h).

Quality Control

This was a real-world consecutive case cohort study enrolling all pSjD patients treated at the China-Japan Friendship Hospital from January 2017 to December 2022. No prior sample size calculation was performed; instead, continuous enrollment ensured completeness and representativeness of cases. The year 2017 was selected as the study start date primarily because the hospital's electronic medical record system and follow-up database were unified and comprehensive from that year onward, ensuring complete case information and traceable follow-up data, thereby improving data reliability. All data were sourced from the hospital's electronic medical record system, with baseline case information extracted retrospectively from patients' first visits. All laboratory tests were completed in the hospital laboratory. To ensure data quality, a dual independent entry with third-party verification model was employed for database establishment.

Statistical Analysis

Data processing was performed using SPSS 26.0 software and R 4.2.3. Categorical data were expressed as n (%) and compared between groups using χ² test or Fisher's exact test. Normally distributed continuous data were expressed as mean±standard deviation and compared using independent two-sample t-test. Non-normally distributed continuous data were expressed as median (P25, P75) and compared using Mann-Whitney U test. Factors with P<0.1 in univariate analysis were included as independent variables in multivariate logistic regression analysis to explore independent influencing factors for dryness and blood-stasis syndrome in pSjD patients. Survival outcomes (including all-cause death, malignancy, and ILD) were analyzed using Kaplan-Meier survival curves, with between-group differences assessed using Log-rank test. P<0.05 was considered statistically significant.

Results

General Characteristics

This study enrolled 970 pSjD patients, including 185 in the pSjD-dryness and blood-stasis group and 785 in the pSjD-non-dryness and blood-stasis group. Comparison of general data between the two groups showed significant differences (P<0.05). Compared with the non-dryness and blood-stasis group, the dryness and blood-stasis group had a higher proportion of females, longer disease duration, and younger age at both enrollment and disease onset (P<0.05) [TABLE:1].

Clinical Symptoms

Patient-reported chief complaints included xerostomia, xerophthalmia, fever, night sweats, fatigue, Raynaud's phenomenon, purpura-like rash, cough, dyspnea, lymphadenopathy, arthralgia, arthritis, morning stiffness, rampant caries, parotid gland enlargement, and bleeding. When ranked by frequency, the top five symptoms in the pSjD-dryness and blood-stasis group were xerostomia (75%), xerophthalmia (75%), arthralgia (55%), fatigue (43%), and rampant caries (34%). In the pSjD-non-dryness and blood-stasis group, the top five symptoms were xerostomia (82.5%), xerophthalmia (76.2%), fatigue (49.1%), cough (36.2%), and arthralgia (32.9%).

There were no significant differences between groups in the proportions of xerophthalmia, fatigue, rampant caries, morning stiffness, fever, or night sweats (P>0.05). However, significant differences were observed in xerostomia, arthralgia, Raynaud's phenomenon, lymphadenopathy, cough, dyspnea, parotid gland enlargement, purpura-like rash, arthritis, and bleeding (P<0.05). Specifically, the dryness and blood-stasis group had higher proportions of xerostomia, arthralgia, Raynaud's phenomenon, lymphadenopathy, parotid gland enlargement, purpura-like rash, arthritis, and bleeding, but lower proportions of cough and dyspnea compared with the non-dryness and blood-stasis group (P<0.05) [TABLE:2].

Laboratory Indicators

Comparison of laboratory indicators showed no significant differences between groups in WBC, NEUT, ALT, AST, TBIL, ALB, serum potassium, sodium, chloride, elevated IgA, elevated IgM, decreased C3, decreased C4, elevated CRP, elevated ESR, ANA≥320, anti-Sm positivity, anti-SSB positivity, anti-Scl70 positivity, anti-AMA_M2 positivity, anti-PMScl positivity, anti-ACL positivity, or splenomegaly proportions (P>0.05). However, the dryness and blood-stasis group had lower levels of LYMPH, RBC, Hb, PLT, and Cr, lower ILD proportion, but higher rates of elevated IgG, ANA≥1:160, anti-SSA positivity, anti-Ro52 positivity, anti-RNP positivity, anti-CENP-B positivity, anti-β2GP1 positivity, anti-dsDNA positivity, and higher ESSDAI scores compared with the non-dryness and blood-stasis group (P<0.05) [TABLE:3].

Multivariate Logistic Regression Analysis

In multivariate logistic regression analysis, due to significant linear correlation among age at enrollment, age at disease onset, and disease duration (duration = age at enrollment - age at disease onset), including all three variables simultaneously could cause collinearity interference. To ensure model stability and interpretability, only "age at enrollment" with more clinical intuitive meaning was retained in the multivariate model, while "age at disease onset" was excluded. Additionally, since the diagnostic criteria for dryness and blood-stasis syndrome already encompassed clinical symptom characteristics, including chief complaints in the model could cause explanatory redundancy and logical confusion. Therefore, this study did not include symptom variables in multivariate analysis, but primarily selected objective quantitative indicators such as laboratory parameters and disease activity (ESSDAI score) as independent variables.

Using pSjD patients' diagnosis of dryness and blood-stasis syndrome as the dependent variable, multivariate logistic regression analysis was performed with factors showing P<0.1 in univariate analysis as independent variables (variable assignment table shown in [TABLE:4]). Results showed that older age at enrollment (OR=0.979, 95%CI=0.965-0.993, P=0.004) and higher PLT level (OR=0.997, 95%CI=0.994-0.999, P=0.007) were independent protective factors for dryness and blood-stasis syndrome in pSjD patients. Anti-RNP antibody positivity (OR=2.352, 95%CI=1.305-4.238, P=0.004), anti-CENP-B antibody positivity (OR=2.490, 95%CI=1.404-4.415, P=0.002), anti-β2GP1 antibody positivity (OR=2.269, 95%CI=1.057-4.872, P=0.036), and higher ESSDAI score (OR=1.037, 95%CI=1.011-1.064, P=0.006) were independent risk factors [TABLE:5].

Kaplan-Meier Survival Analysis

During prospective follow-up, some patients experienced outcome events or were lost to follow-up. Among pSjD patients included in survival analysis, 95 cases (10.5%) of death, 30 cases (3.4%) of new malignancy, and 21 cases (3.9%) of new ILD were observed. Kaplan-Meier survival curve analysis showed no significant differences between the dryness and blood-stasis group and non-dryness and blood-stasis group in overall mortality, malignancy incidence, or ILD incidence (P>0.05) [FIGURE:1].

Discussion

Current clinical research on pSjD has primarily focused on immunological and clinical classification, while systematic description and research on TCM patterns, particularly dryness and blood-stasis syndrome, remain almost blank. This study enrolled 970 pSjD patients to clarify the clinical features, laboratory indicators, and prognosis of pSjD-dryness and blood-stasis syndrome patients, aiming to provide evidence-based correlation between TCM patterns and modern medical indicators and enrich individualized management of pSjD patients.

Findings revealed: (1) Compared with the non-dryness and blood-stasis group, the dryness and blood-stasis group had younger age at enrollment and disease onset, longer disease duration, and higher female proportion; (2) Clinically, the top five chief complaints in pSjD-dryness and blood-stasis patients were xerostomia, xerophthalmia, arthralgia, fatigue, and rampant caries; (3) Laboratory tests showed that the dryness and blood-stasis group more frequently had decreased peripheral blood LYMPH, RBC, Hb, and PLT levels, elevated IgG, higher positive rates of ANA≥1:160, anti-SSA, anti-Ro52, anti-RNP, anti-CENP-B, anti-β2GP1, and anti-dsDNA antibodies, higher ESSDAI scores, while Cr elevation and new ILD were less common; (4) Multivariate logistic regression showed that older age at enrollment and higher PLT level were independent protective factors for dryness and blood-stasis syndrome in pSjD patients, while anti-RNP positivity, anti-CENP-B positivity, anti-β2GP1 positivity, and higher ESSDAI score were independent risk factors; (5) Survival analysis indicated no significant differences in overall mortality, malignancy, or new ILD incidence between the two groups.

From a pathogenesis perspective, this study further confirms that the formation of dryness and blood-stasis syndrome aligns not only with traditional TCM theories of "fluid generating blood," "blood transforming into fluid," and "chronic disease causing deficiency, deficiency causing stasis," but also receives objective manifestation in modern immunological test results such as blood cell reduction, elevated immunoglobulin levels, and increased disease activity. This preliminary reveals the connection between pSjD pattern differentiation and objective material basis. Sjögren's syndrome has "dryness" as its core pathogenesis, gradually forming "dryness and blood-stasis intermingling" during disease progression, emphasizing simultaneous deficiency of fluid and blood and interweaving of deficiency and stasis. This pathological characteristic of "dryness" as the root and "stasis" as the manifestation may explain the unique clinical presentation of pSjD patients with concurrent xerostomia/xerophthalmia and hematological abnormalities.

Notably, pSjD patients with dryness and blood-stasis syndrome had a lower proportion of ILD complications, with disease manifestations primarily showing hematological and immunological abnormalities. This suggests that in clinical practice, for such patients, hematological function should be prioritized for assessment and timely intervention to prevent progression based on pattern differentiation. According to TCM theory, the treatment strategy of nourishing yin and moistening dryness combined with activating blood and resolving stasis may become an important approach to improve immunological abnormalities and hematological damage in these patients, warranting further clinical validation. During prospective follow-up, no significant differences were observed between the dryness and blood-stasis group and non-dryness and blood-stasis group in overall mortality, new malignancy, or new ILD incidence. This result may be closely related to the dynamic evolution of patterns. The dryness and blood-stasis syndrome at enrollment may change over time, and therefore, the correlation between baseline pattern and outcomes may not fully reflect the true impact of pattern changes during follow-up on prognosis. This dynamic nature may weaken the statistical power of survival analysis and represents an important reason why this study's survival analysis failed to yield positive results. Future studies need to dynamically assess pattern changes during long-term follow-up and combine longitudinal data to further clarify their impact on prognosis.

In conclusion, pSjD patients with dryness and blood-stasis syndrome exhibit a protracted disease course, higher ESSDAI scores, more significant hematological involvement, but lower ILD proportion. Older age at enrollment and higher PLT level may be independent protective factors for dryness and blood-stasis syndrome in pSjD patients, while anti-RNP positivity, anti-CENP-B positivity, anti-β2GP1 positivity, and higher ESSDAI score may be independent risk factors. In clinical practice, identifying characteristics of dryness and blood-stasis syndrome enables early detection of high-risk patients, prompting careful evaluation of blood routine and immunological indicators and vigilance for hematological involvement, providing evidence-based guidance for individualized patient management. The treatment strategy of nourishing yin and moistening dryness combined with activating blood and resolving stasis holds promise for improving disease activity and hematological damage in these patients, pending further clinical validation. This study utilized single-center data, and future multi-center, large-sample validation combined with long-term follow-up is needed to explore the long-term prognostic characteristics and comorbidity spectrum of pSjD-dryness and blood-stasis syndrome patients, providing basis and guidance for integrated Chinese and Western medicine individualized treatment.

Author Contributions: LEI Chunxin and LUO Jing conceived and designed the study; ZHANG Xiya, CHEN Jiaqi, ZHANG Yan, and LIU Zihan collected and organized data; LEI Chunxin, ZHANG Xiya, and ZHANG Yan performed statistical analysis and prepared tables; LEI Chunxin drafted the manuscript; LUO Jing revised the manuscript; LUO JING and TAO Qingwen were responsible for quality control and review, and overall supervision of the article.

Conflict of Interest: The authors declare no conflict of interest.

ORCID IDs:
LEI Chunxin: https://orcid.org/0009-0006-8935-7453
LUO Jing: https://orcid.org/0000-0002-2454-2168
TAO Qingwen: https://orcid.org/0000-0002-9163-8426

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(Received: August 18, 2025; Revised: September 20, 2025)
(This article edited by: KANG Yanhui)