Immunologic Characteristics and Predictive Risk Factors of Primary Sjögren’s Syndrome Complicated with Malignant Lymphoma: A Multicenter Case-Control Study
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease characterized by the progressive destruction of exocrine glands, primarily the salivary and lacrimal glands, leading to symptoms such as dry mouth (xerostomia) and dry eyes (xerophthalmia). Although the disease progression is generally slow, pSS patients are at an increased risk of developing various cancers, including malignant lymphoma (ML). Malignant lymphoma, particularly non-Hodgkin lymphoma (NHL), is a significant cause of excess mortality in pSS patients. This study aimed to investigate the immunologic characteristics and predictive risk factors associated with pSS complicated by ML, providing insights into early diagnosis and intervention strategies.
Study Design and Methodology
This multicenter case-control study was conducted across three hospitals in China: Peking University People’s Hospital, Linfen Third People’s Hospital, and the Affiliated Hospital of North Sichuan Medical College. A total of 120 pSS patients were enrolled between January 2010 and June 2022. Among these, 40 patients with pSS and lymphoma were included in the study group, while 80 pSS patients without lymphoma served as controls. All patients met the 2002 revised American-European Consensus Group (AECG) classification criteria for pSS. Lymphoma diagnosis was confirmed through pathology biopsy or positron emission tomography-computed tomography (PET-CT).
The study was approved by the ethical committee of Peking University People’s Hospital. As a retrospective study using anonymized patient data, written consent was waived. Statistical analyses were performed using IBM SPSS version 20.0. Continuous variables were compared using Student’s t-test or Mann-Whitney U test, while categorical data were analyzed using chi-squared or Fisher’s exact tests. Kaplan-Meier curves were used to assess overall survival, and binary logistic regression was employed to explore associations between pSS and lymphoma, estimating odds ratios (ORs) and 95% confidence intervals (CIs). A p-value below 0.05 was considered statistically significant.
Clinical and Immunologic Characteristics of pSS-ML Patients
The study group consisted of 40 pSS patients with lymphoma, of which 90% were women (n=36). The mean age was 55.6 ± 13.6 years, and the median disease duration of pSS was 9 years (range: 1–30 years). Among these patients, 9 developed lymphoma before pSS diagnosis, 18 developed lymphoma after pSS diagnosis, and 13 were diagnosed with both conditions simultaneously.
Pathological data were available for 28 lymphoma patients, all of whom had NHL. The majority (25/28) had B-cell lymphoma, while 3 had T-cell lymphoma. The most common B-cell lymphoma subtype was marginal zone lymphoma (MZL), accounting for 57% of cases. This included malignant mucosa-associated lymphoid tissue (MALT) lymphoma (46%), nodal marginal zone lymphoma (NMZL) (7%), and splenic marginal zone lymphoma (SMZL) (4%). Diffuse large B-cell lymphoma (DLBCL) was the second most common subtype, representing 32% of cases. Lymphomas were primarily located in extranodal tissues (45%) and lymph nodes (38%).
Comparison of Clinical and Laboratory Data
Clinical characteristics and laboratory data were compared between the pSS-ML group and the control group. No significant differences were observed in common pSS symptoms such as dry mouth, dry eyes, and rampant caries. However, the pSS-ML group had a higher incidence of lymphocytopenia (p=0.001) and anemia (p=0.010). Additionally, interstitial lung disease and renal tubular acidosis were more prevalent in the pSS-ML group (p=0.036 and p=0.027, respectively).
The pSS-ML group also exhibited higher EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) scores compared to the control group (26.85 ± 7.87 vs. 11.58 ± 5.86, p<0.001). Immunological parameters revealed elevated IgA levels and monoclonal (M) protein in the pSS-ML group (p<0.001 for both). Conversely, anti-SSB antibodies were more common in the control group (p=0.006). Furthermore, the pSS-ML group had lower percentages of regulatory T (Treg) cells (6.38 ± 2.15% vs. 8.19 ± 1.87%, p=0.016) but higher percentages of peripheral T follicular helper (pTfh) cells (3.24 ± 1.52% vs. 2.27 ± 0.92%, p=0.032), tumor necrosis factor-alpha-producing T helper 1 cells (Th1-TNF-α) (49.20 ± 13.93% vs. 36.60 ± 12.37%, p=0.006), and T helper 17 (Th17) cells (1.85 ± 0.62% vs. 1.37 ± 0.50%, p=0.021).
Treatment and Prognosis
Among the 40 pSS-ML patients, 6 underwent surgery, 17 received chemotherapy, 15 were treated with pSS maintenance therapy, 7 received rituximab, 1 underwent surgery combined with rituximab, and 1 received hormone therapy. Two patients developed thrombocytopenia following rituximab treatment, which was managed with cyclosporin. Two untreated patients died at a mean age of 64 years. Among the 38 treated patients, 31 (82%) remained stable, 5 (13%) experienced relapse, and 2 (5%) died. The causes of death were viral encephalitis and recurrence after chemotherapy, both of which were related to the primary disease.
In the control group, 3 patients died at a mean age of 71 years due to infection (n=2) and pulmonary arterial hypertension (n=1), which were unrelated to pSS. The mean survival time for pSS patients with lymphoma was significantly shorter than that of the control group (24.2 ± 2.6 years vs. 34.5 ± 0.9 years, p=0.006).
Predictive Risk Factors for Malignant Lymphoma
Multivariate logistic regression analysis adjusted for pSS duration was performed to identify risk factors for ML in pSS patients. Higher ESSDAI scores (OR=1.475, 95% CI=1.260–1.727), anemia (OR=2.768, 95% CI=1.241–6.173), lymphocytopenia (OR=4.467, 95% CI=1.958–10.192), elevated IgA levels (OR=5.168, 95% CI=2.087–12.796), and increased Th1-TNF-α percentages (OR=1.066, 95% CI=1.009–1.127) were significantly associated with an increased risk of ML.
Discussion
This study highlights the immunologic characteristics and predictive risk factors associated with pSS complicated by ML. NHL, particularly MZL and DLBCL, was the most common lymphoma subtype in pSS patients. MALT lymphoma, often located in extranodal tissues such as the parotid glands, was the predominant subtype, underscoring the importance of pathological examination in early lesion detection.
Higher ESSDAI scores, anemia, lymphocytopenia, elevated IgA levels, and increased Th1-TNF-α percentages were identified as significant risk factors for ML in pSS patients. These findings suggest that pSS patients with these characteristics should be closely monitored for the development of lymphoma. Additionally, the imbalance in T-cell subsets, particularly the lower Treg cell percentages in pSS-ML patients, may contribute to the pathogenesis of secondary lymphomas.
Therapeutic approaches for pSS-ML patients were tailored based on immunopathological and histological classifications, as well as disease staging. Rituximab, a CD20 monoclonal antibody, showed promising results in MALT lymphoma patients, leading to remission and improved clinical outcomes. However, the efficacy of rituximab in pSS-ML patients remains unclear, warranting further investigation.
Limitations
This study has several limitations. As a case-control study, it is susceptible to selection bias. Additionally, the analysis of death rates and causes of death was limited. Larger prospective cohort studies or controlled trials are needed to confirm these findings and further elucidate the characteristics and risk factors of pSS-ML patients.
Conclusion
In conclusion, NHL, particularly MALT lymphoma, is the most common pathologic type in pSS patients complicated by ML. Higher ESSDAI scores, anemia, lymphocytopenia, elevated IgA levels, and increased Th1-TNF-α percentages are significant risk factors for ML in pSS patients. The development of lymphoma negatively impacts survival time and disease prognosis in pSS patients. Early diagnosis and intervention, guided by these risk factors, may improve outcomes for pSS-ML patients.
doi.org/10.1097/CM9.0000000000002912
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