Reframing Sjögren’s Syndrome: Insights from a Comprehensive Review

Sjögren’s Syndrome (SS) presents significant diagnostic and therapeutic challenges due to its heterogeneous manifestations, variable disease course, and limited treatment efficacy across patient subgroups. Aiming to improve understanding of these factors, a 2025 review published in MedComm presents an integrated summary of current research on SS, compiling data from global cohort studies, molecular analyses, and clinical trials to describe the clinical variability and immunologic complexity of the disease.

Here’s a summary of the review’s key points.

Epidemiology
SS exhibits global prevalence estimates ranging from 0.01 percent to 0.05 percent, with considerable variation due to differences in diagnostic methodology and population selection.

A defining epidemiologic feature is the strong female predominance, with a gender ratio of approximately 14:1. Data from the Big Data Sjögren Project and other cohort studies confirm this sex bias and report higher disease activity scores and systemic complications—including pulmonary and neurologic involvement—in male patients.

Regional disparities also persist, particularly in underrepresented areas such as Africa and parts of the Americas, where epidemiologic data remain limited or absent.

Classification Criteria
The diagnostic framework for SS has evolved through consensus-based iterations. The most widely adopted system is the 2016 ACR/EULAR classification criteria, which assign weighted scores based on the presence of anti-SSA/Ro antibodies, histopathologic evidence of focal lymphocytic sialadenitis, objective ocular signs, and reduced salivary flow. These criteria achieve 96 percent sensitivity and 95 percent specificity, making them effective for research purposes and increasingly referenced in clinical practice.

And they are not diagnostic in isolation. When combined with imaging modalities such as salivary gland ultrasonography (SGUS), particularly using OMERACT criteria, diagnostic accuracy improves further, with area under the curve values approaching 0.974 and sensitivity exceeding 96 percent.

Molecular Pathogenesis
SS pathogenesis is driven by immune-epithelial interactions. Salivary gland epithelial cells (SGECs) are active participants in the disease process, responding to environmental or viral stimuli via toll-like receptors (TLRs) and producing cytokines such as IL-6, BAFF, and type I interferons. These mediators promote lymphocyte recruitment and sustain chronic inflammation.

Plasmacytoid dendritic cells (pDCs) contribute through IFN-I production, while B cells undergo hyperactivation and autoantibody generation, and T cells—especially Th1, Th17, and CD8+ subsets—participate in glandular damage.

Genetic risk factors, including polymorphisms in IRF5, STAT4, and IL12A, reinforce this immune axis by upregulating interferon-stimulated gene expression and promoting sustained autoimmunity.

Diagnosis
When it comes to SS diagnosis, a combination of clinical, serologic, histologic, and imaging findings helps shape it. Labial salivary gland biopsy remains the gold standard for confirming focal lymphocytic sialadenitis, particularly in patients with ambiguous serologic results. Anti-SSA/Ro and anti-SSB/La antibodies, ANA, and rheumatoid factor (RF) are commonly used serological markers, though their presence alone is insufficient for diagnosis.

Two standardized assessment tools developed by EULAR—the ESSPRI for symptoms and the ESSDAI for systemic activity—are used to monitor disease burden and guide treatment decisions. SGUS has emerged as a non-invasive alternative for glandular assessment, and when integrated into the classification workflow, it improves specificity and reduces biopsy reliance.

Research continues into biomarkers such as BAFF receptor expression and interferon gene signatures to support earlier and more accurate stratification.

Treatment
Finally, SS treatment remains symptom-focused for most patients, with systemic therapy reserved for those with active extraglandular involvement. Glucocorticoids, antimalarials, immunosuppressants, and intravenous immunoglobulin are used selectively, depending on organ involvement and disease severity. More than a dozen agents are in clinical trials, including interferon pathway inhibitors (for example, anifrolumab and filgotinib), JAK inhibitors (such as tofacitinib and upadacitinib), and B-cell-targeting therapies (like belimumab, telitacicept, and iscalimab).

BTK inhibitors, FcRn blockers like nipocalimab and chimeric antigen receptor (CAR) T-cell therapy are being tested in advanced-stage trials, reflecting a move toward intracellular and receptor-mediated interventions.

Nonpharmacologic therapies such as structured resistance training have also shown benefit in reducing fatigue, which remains refractory to medical treatment in many patients.

Looking Ahead in SS Care
Sjögren’s Syndrome represents a clinically and biologically heterogeneous autoimmune disorder marked by systemic immune activation and glandular dysfunction. While classification criteria and diagnostic tools have advanced significantly, challenges persist in translating molecular insights into effective treatments.

Clinical trial outcomes suggest that response heterogeneity may stem more from inadequate patient stratification than from therapeutic failure. As a result, stratification by interferon signature, disease activity indices, and imaging findings may guide future trial design and therapeutic use.

As the disease paradigm shifts from symptom suppression to immunologic targeting, integrated diagnostic frameworks and personalized treatment algorithms are likely to define the next phase of SS management.

Reference:
Hu Y, Wen B, Zhang Y, et al. Sjögren’s syndrome: epidemiology, classification criteria, molecular pathogenesis, diagnosis, and treatment. MedComm. 2025;6:e70297. doi:10.1002/mco2.70297