Therapeutic selective leukotriene b4 antagonism for human lymphedema

Abstract

Despite a high prevalence and extensive morbidity, there are no approved pharmacological interventions for lymphedema. Selective inhibition of leukotriene B 4 has been identified as a potential therapeutic target to address the morbidity and symptomatology associated with lymphedema. We aim to evaluate the impact of a novel, selective, orally administered leukotriene B 4 antagonist on objective and subjective measures of lymphedema severity. This is an open-label, prospective cohort study conducted in a single-site tertiary care medical institution on patients with chronic Stage II lymphedema of the lower extremity. Twelve months of daily oral acebilustat (100 mg), superimposed upon continued maintenance lymphedema self-management. Lymphedematous limb volume, skin thickness, tissue architecture, detectable extracellular fluid excess, and quality-of-life were measured throughout treatment, at 3-month intevals. Limb volume was calculated using a standard conical formula conversion of circumferential tape measurements. Skin thickness was evaluated by skinfold caliper, and skin thickness and tissue architecture were quantitatively assessed by ultrasound. As an exploratory biomarker of the tissue response to the therapeutic agent, we developed and implemented an artificial intelligence pipeline to assess qualitative changes in cutaneous ultrasound images. Bioimpedance measurements were used to evaluate detectable extracellular fluid excess, and three quality-of-life questionnaires assessed subjective well-being among participants. Outcomes were compared between visits using linear mixed-effect models. Oral selective leukotriene B 4 antagonism was associated with significant reductions in lymphedematous limb volume 1012.3 mL [95% C.I.: -1457.9 to -565.9, P < 0.0001. Skin thickness was also significantly reduced, with most prominent reductions occurring at the proximal calf and midthigh (-1.1 mm [95% C.I.: -1.8 to -0.4], P = 0.004 and -1.6 mm [95% C.I.: -2.6 to -0.7], P < 0.001, respectively). Ultrasonographic and bioimpedance analyses revealed changes that would support a favorable impact on affected tissue architecture and extracellular fluid accumulation (R 0 13.8 [95% C.I.: 1.8 to 25.8], P = 0.03). These findings were accompanied by significant improvements in quality-of-life parameters throughout the course of treatment. Selective leukotriene B 4 antagonism is associated with improvement in overall objective and subjective measures of lymphedema. This study provides the first evidence in support of acebilustat as a novel oral therapeutic for chronic lymphedema.