Do not mistake symptomatic improvement for disease modification: therapeutic endpoints in secondary lower-extremity...

Secondary lower-extremity lymphedema has long been regarded primarily as a disorder of impaired lymphatic fluid return. However, growing evidence indicates that its core pathology is a lymph stasis-driven immune-stromal remodeling process characterized by chronic inflammation, extracellular matrix remodeling, and progressive adipose deposition, which gradually reduces limb reversibility as the disease advances. Yet this mechanistic understanding remains disconnected from clinical therapeutic evaluation. Current endpoints still rely mainly on limb volume, circumference, and the degree of swelling reduction, which are insufficient to quantify fibrosis and adipose remodeling and cannot capture ongoing inflammatory and tissue progression when volume remains unchanged. This may create a misleading appearance of symptomatic improvement while the disease continues to progress toward a late fibroadipose stage, delaying timely referral for lymphaticovenular anastomosis (LVA) or vascularized lymph node transfer (VLNT) and increasing clinical risk. Therefore, we propose the introduction of Inflammation-Fibrosis-Anchored Endpoints (IFAE), which integrate four dimensions beyond volume-based assessment: immune-inflammatory activity, tissue remodeling, lymphatic function, and clinical events. Within this framework, traditional volume-based measures should be downgraded to surrogate indicators of the fluid dimension rather than treated as definitive markers of disease modification. Meanwhile, complete decongestive therapy (CDT) and adjunctive physical therapies should be repositioned as strategies for fluid-symptom management rather than disease-modifying interventions, to avoid equating symptomatic improvement with mechanistic disease control or cure.