Clinical bottom line
Refractory dry eye disease (DED) in Sjögren’s syndrome (SS) remains a challenging clinical problem despite conventional therapies. Emerging topical treatments, including cyclosporine A formulations and novel biologics such as mesenchymal stem cell-derived exosomes, show promise in improving ocular surface inflammation and symptoms. However, current evidence is limited by small sample sizes and short follow-up durations. Clinicians should consider these novel agents as adjuncts in patients with persistent symptoms after standard care, while awaiting more robust data to guide long-term management.
What the evidence shows
Sjögren’s syndrome-related dry eye disease is characterized by autoimmune epithelitis and chronic inflammation of lacrimal glands and ocular surface tissues, leading to tear film instability and epithelial damage (Ogawa et al., 2021). Conventional management includes artificial tears and anti-inflammatory agents, but many patients experience refractory symptoms.
Topical 0.05% cyclosporine A has demonstrated efficacy in reducing ocular surface inflammation and improving tear production in SS-related DED. Devecı et al. (2014) reported significant symptomatic and objective improvements in patients treated with cyclosporine A compared to baseline, supporting its role as a standard immunomodulatory therapy.
More recently, novel biologic approaches have been explored. Habibi et al. (2025) conducted a randomized clinical trial evaluating topical mesenchymal stem cell-derived exosomes in SS-related DED, finding improvements in clinical signs and patient-reported symptoms compared to placebo. This suggests a potential regenerative and anti-inflammatory mechanism distinct from conventional immunosuppressants.
Additional strategies focus on comprehensive chronic care models integrating patient education, environmental modifications, and multimodal therapy. Liu et al. (2026) demonstrated that a chronic care model improved dry eye symptoms and quality of life in primary SS patients, highlighting the importance of holistic management.
Mechanistically, novel medications targeting inflammatory pathways and tear film homeostasis are under investigation. Wong et al. (2024) reviewed emerging agents including lifitegrast and novel formulations of cyclosporine, emphasizing their mechanisms, safety profiles, and preliminary efficacy data in DED, though specific SS populations require further study.
Diagnostic advances also aid in identifying refractory cases. Del Rosario Sánchez Valerio et al. (2023) summarized current diagnostic tests for SS-related DED, underscoring the need for objective measures such as tear osmolarity and meibography to tailor therapy.
Caveats and uncertainty
The evidence base for novel therapies in SS-related refractory dry eye is limited by small, often single-center studies with short follow-up periods. For example, the mesenchymal stem cell exosome trial by Habibi et al. (2025) was promising but requires replication and longer-term safety data.
Heterogeneity in disease severity, diagnostic criteria, and outcome measures complicates comparison across studies. Many trials include mixed DED populations, limiting generalizability to SS-specific patients.
Potential risks such as increased infection susceptibility in SS patients with compromised ocular surface barriers warrant caution (Maslinska et al., 2016). Long-term immunomodulation may exacerbate this risk, necessitating vigilant monitoring.
Furthermore, the cost and accessibility of novel biologics and advanced therapies may limit widespread adoption pending health economic evaluations.
How this may change practice
Clinicians managing refractory SS-related dry eye should consider incorporating topical cyclosporine A as a foundational immunomodulatory agent when conventional lubricants fail. Emerging biologics like mesenchymal stem cell-derived exosomes represent a promising adjunct, especially for patients with persistent inflammation despite standard care.
Adopting a chronic care model that integrates patient education, environmental and lifestyle modifications, and multimodal therapy may enhance outcomes and patient satisfaction.
Objective diagnostic tools such as meibography and tear osmolarity testing can help identify refractory cases and monitor response to novel therapies.
Ongoing vigilance for infection risk and adverse effects is essential, particularly with newer immunomodulatory agents.
Further high-quality randomized controlled trials are needed to establish long-term efficacy, safety, and cost-effectiveness of these novel therapies in SS-related dry eye disease.