Anti-SSA/SSB antibody double-negative Sjögren's disease patients: a comprehensive clinical study and immune profile.

Introduction/objectives: Anti-Sjögren's syndrome A (SSA/Ro60) and anti-Sjögren's syndrome B (SSB/La) antibodies are not present in up to 25% of patients with primary Sjögren's disease (SjD). Our observational study aims to provide a clinical perspective on the presentation, extra-glandular manifestations, as well as the immune profile of anti-SSA/SSB antibody double-negative SjD patients.

Method: A total of 615 SjD patients of age 53.21 (± 0.59) were enrolled without acute infection or ongoing treatment that could affect the immune system. Of our participants, 254 (41.3%) were seronegative for both SSA (Ro60) and SSB (La) autoantibodies (SSA/SSB double-negative). A 1:1 propensity score matching was performed to balance age at diagnosis, disease duration, and gender for extra-glandular involvement analyses and immune profiling. Peripheral blood mononuclear cells (PBMCs) were derived from all patients. Flow cytometry was performed to further define the immune cell subsets.

Results: Our study revealed that anti-SSA/SSB seronegative patients had a delayed onset by an average of 7.43 years and exhibited a lower prevalence of parotid gland enlargement compared to the seropositive group (50.8% vs. 59%, p < 0.05). In terms of extra-glandular involvement, seronegative patients exhibited a lower prevalence of white blood cell (WBC), hemoglobin (HGB), and platelet (PLT) reduction (OR 0.406, 95% CI 0.314-0.523; OR 0.751, 95% CI 0.587-0.959; OR 0.56, 95% CI 0.383-0.818, respectively) compared to anti-SSA/SSB antibody-positive group. Additionally, the double-negative group tended to hold higher CD4 + T helper cells and lower CD8 + T cell proportions compared with the anti-SSA/SSB-positive group (40.52% vs. 37.38%, p < 0.001; 28.25% vs. 32.55%, p < 0.001 respectively). Higher proportions of NK cells (13.05% vs. 10.32%, p < 0.001) and CD161 + Treg cells (13.69% vs. 12.03%, p < 0.001) were found in the double-negative group.

Conclusion: The observed higher frequency of CD161 + Tregs and NK cells, as well as the lower frequency of CD8 + T cells and B cells, in anti-SSA/SSB antibody double-negative patients suggests a potential role of innate immunity in this subgroup of Sjögren's syndrome. Our findings hint at the importance of serological and immune profiles in tailoring personalized management strategies for these patients. Key Points • Our analyses suggested a potential role of innate immunity in anti-SSA/SSB antibody double-negative SjD patients in comparison to seropositive counterparts. • Higher frequencies of CD4 + T cells, CD161 + Tregs, and NK cells were observed in the peripheral blood of double-negative patients, alongside lower proportions of CD8 + T cells and B cell subsets. • Double-negative patients exhibited a lower prevalence of reductions in white blood cell counts, hemoglobin level, and platelet level.