From Molecular Pathophysiology to Clinical Trial Design in Sjögren's Disease: A Three-Axis Framework.

Sjögren's disease (SjD) remains one of the few major systemic autoimmune diseases without an approved disease-modifying therapy, despite decades of pathogenic insight and several randomised trials. We contend that these repeated failures reflect not intrinsic therapeutic refractoriness, but trial designs insufficiently aligned with the underlying biological heterogeneity of SjD. We propose a tripartite framework in which SjD is organised around three dominant biological axes: an interferon-driven systemic axis, a B-cell/lymphoproliferative axis, and a symptom/fibro-structural axis. Each axis carries its own characteristic biomarkers, histopathology, prognostic features, candidate endpoints, and therapeutic targets, and each implies a distinct trial enrolment strategy. Recent positive trials-phase III for ianalumab in NEPTUNUS-1/2, phase 2b for iscalimab in TWINSS, phase 2 for nipocalimab in DAHLIAS, and phase 2 for dazodalibep in a phenotype-defined symptom-dominant cohort-illustrate that meaningful clinical benefit becomes detectable once stratification is aligned to biology. By integrating molecular endotypes, validated biomarkers, composite endpoints, and phenotype-matched therapies onto a single explicit architecture, SjD shifts from a recurring example of translational failure to a model for precision medicine in heterogeneous autoimmune disease. The central message is that SjD may be less intrinsically treatment-resistant than it has historically been treatment-mistargeted.