Sjögren’s disease (SjD) is a systemic autoimmune disorder characterized by glandular dysfunction and diverse extraglandular manifestations. Despite a strong immunological rationale, many immunomodulatory trials have failed to show consistent efficacy, largely due to clinical heterogeneity and limitations of conventional outcome measures. Growing evidence indicates a dissociation between systemic inflammatory activity and patient-reported symptom burden, leading to recent trials stratifying patients into systemic activitydominant and symptom-dominant phenotypes and aligning primary endpoints accordingly. The European Alliance of Associations for Rheumatology (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) remains a key endpoint for systemic disease activity; however, it is affected by intrinsic variability and regression to the mean, contributing to high placebo responses. The EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) captures core symptoms but demonstrates limited sensitivity to change and weak correlations with objective glandular function. To address these limitations, composite response measures, such as Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS) and Sjögren's Tool for Assessing Response (STAR), have been developed to integrate systemic activity, symptoms, glandular function, and serologic markers. Recent phase 2 randomized controlled trials have demonstrated this paradigm shift. Inhibition of the CD40-CD40L pathway with dazodalibep and iscalimab showed efficacy when phenotype-appropriate endpoints were applied. B-celldirected therapies, including B-cell activating factor (BAFF) receptor blockade with ianalumab and BAFF/A Proliferation Inducing Ligand dual inhibition with telitacicept, have demonstrated improvements in systemic activity with supportive biomarker changes. Remibrutinib, an oral Bruton's tyrosine kinase (BTK) inhibitor, improves systemic disease activity; however, symptom-based endpoints remain a challenge. Neonatal Fc receptor (FcRn) blockade with nipocalimab reduced clinical disease activity in seropositive high-activity subgroups without consistent symptom improvement. Overall, effective therapeutic development for SjD requires mechanism-informed patient stratification and endpoint strategies that link biological activity to clinically meaningful outcomes.
Kyung‐Ann Lee (Mon,) studied this question.