Discussion
dysphagia, fatigue, abdominal pain, IVH, anemia, PNH, erectile dysfunction
DYSPHAGIA, ANEMIA, NA DEFICIENCY, REGRESSION, PNH, ERECTILE DYSFUNCTION
This Individuals with PNH frequently experience symptoms of fatigue, which contribute to impaired QoL [PNH is characterized by a deficiency of cell surface glycosylphosphatidylinositol-anchored proteins, including the complement regulatory proteins CD55 and CD59. The absence of CD55 and CD59 causes uncontrolled terminal complement activity that leads to IVH, which is indicated by increased LDH levels. IVH releases large amounts of free Hb causing nitric oxide depletion which manifests clinically as symptoms of fatigue, dysphagia, abdominal pain, and erectile dysfunction [In study 301, C5 inhibition with eculizumab or ravulizumab demonstrated significant improvements in key clinical parameters associated with PNH, with 219 patients (90.5%) achieving LDH < 1.5 × ULN at day 183. The improvement seen in LDH levels was associated with improvements in patient fatigue and QoL, as assessed by FACIT-F and EORTC QLQ-C30 GH, respectively. In other studies, improvements in Hb levels associated with C5 inhibition have previously been reported to be associated with QoL outcomes in patients with PNH [To understand the interaction between LDH and Hb in study 301, a regression analysis was performed. The interaction of LDH response with improvements in Hb level was a significant predictor of improvement in fatigue in the current study, demonstrating the significance of LDH level in driving PROs. This is similar to a previous multivariate analysis of data from TRIUMPH, a phase 3 trial of eculizumab and placebo, which demonstrated that a reduction in IVH was better than improvements in anemia in predicting improvements in fatigue [There are limitations to this study that must be considered. Although study 301 collected data covering both physical functioning and fatigue subscales of the EORTC QLQ-C30, only the GH subscale was used for this analysis. Future research may benefit from incorporating additional domains to describe the interactions between clinical outcomes and PROs further. The use of PNH-specific PRO and QoL tools may also be considered in future studies once further validation and psychometric properties have been established. The changes in LDH levels linked to improvements in fatigue and QoL beyond 26 weeks remain unknown. Additionally, study 301 was a controlled trial and may not be reflective of real-world clinical practice.