Sjögren’s Disease Management: A Decade in Review

Sjögren’s disease (SjD) is one of the most prevalent autoimmune rheumatic diseases, yet it lacks a single approved systemic therapy—current management is predominantly symptomatic, with minimal impact on disease progression or mortality. Despite longstanding use of immunomodulators like hydroxychloroquine and rituximab, randomized controlled trials have not consistently demonstrated clinically meaningful improvements in disease activity or patient-reported outcomes.

Taking a closer look at the SjD therapeutic landscape over the past decade, a systematic review published in July 2025 in Best Practice & Research Clinical Rheumatology aims to address this unmet need by synthesizing trial results, assesses risk of bias, and highlights emerging strategies across immunologic and symptomatic domains.

Here’s a summary of what it found.

Systematic Scope and Methodology
To build this analysis, the authors conducted a systematic review covering ten years of research (2015 to 2025), identifying 112 studies relevant to therapeutic development in SjD. This included 20 randomized controlled trials evaluating 19 distinct agents, 20 observational studies, 34 preclinical or early-phase investigations, and 21 active registered randomized controlled trials. Therapeutic agents were categorized by molecular targets, such as B-cell depletion, cytokine blockade, kinase inhibition, and immune modulation.

The Efficacy Landscape: Mixed Results from Targeted Agents
Taking a look at the findings, across B-cell targeting trials, rituximab failed to achieve primary endpoints in fatigue and oral dryness (for example, TRACTISS and TEARS), although it improved glandular ultrasound parameters in some secondary analyses. Combined regimens like belimumab plus rituximab demonstrated safety but lacked statistical power for efficacy.

Dazodalibep, a CD40 ligand inhibitor, emerged as the most promising agent. In a large phase 2 trial, it significantly reduced both systemic disease activity (ESSDAI) and symptom burden (ESSPRI) in two stratified patient populations. Smaller studies of iscalimab, a CD40 inhibitor, and RSLV-132, which targets type I interferon signaling via RNA degradation, also demonstrated partial benefits, though results for other targets such as PI3Kδ, BAFF-R, and IL-6R inhibition were generally neutral.

Topical and Symptomatic Interventions
For ocular and oral manifestations, topical agents offered tangible improvements. Fluorometholone and tacrolimus eyedrops showed statistical improvements in corneal staining, tear production, and ocular discomfort, with modest differences compared to cyclosporine. Malic acid lozenges outperformed citric acid mouthwash in xerostomia-related indices.

Structural Limitations in Clinical Trials
Despite increasing therapeutic activity in Sjögren’s disease research, the design and execution of clinical trials continue to face structural limitations. Nearly half of the randomized controlled trials reviewed were rated as having “some concerns” for risk of bias, primarily due to high attrition, inadequate blinding, or inconsistent endpoint specification. Demographic representation was narrow: 94 percent of trial participants were female and 83 percent identified as White/Caucasian. Only half of trials reported ethnicity at all.

Endpoints varied widely, with 25 different primary measures used across 20 randomized controlled trials. This heterogeneity, combined with the absence of validated surrogate biomarkers and the insensitivity of existing indices like ESSDAI/ESSPRI, complicates comparative effectiveness assessment and likely contributes to repeated trial failures.

Future Directions and Investigational Activity
Looking ahead, 18 ongoing randomized controlled trials targeting pathways such as BAFF/APRIL, FcRn, and CD40 are underway, with expected completions extending to 2030. Newer constructs like CAR-T cells targeting B-lineage cells and bispecific T cell engagers are also under evaluation, echoing successes in refractory lupus and dermatomyositis.

Trial design shifts are also emerging. Composite outcome tools such as STAR and CRESS are being validated to better capture treatment response, especially for fatigue and dryness—priorities identified by patients but poorly reflected in legacy measures.

Implications for Research and Care
This review underscores the critical need to expand therapeutic development in SjD beyond B-cell depletion and to tailor trial design around heterogeneous disease phenotypes. Improved outcome measures, longer trial durations, and greater demographic inclusivity will be essential for translating mechanistic insights into approved therapies. Pending agents represent meaningful advances in concept and clinical design, but broader structural changes are required to realize their potential in practice.

Reference:
Cristina Pelkas et al., Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2025.102084