Pseudoxanthoma Elasticum and Arterial Calcification

Abstract

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by mutations in the ABCC6 gene, leading to calcification of elastic fibers in the skin, Bruch’s membrane, and arteries. It affects approximately 1 in 25,000 to 1 in 56,000 individuals. Key manifestations include skin lesions (pseudoxanthomas), retinal degeneration due to Bruch’s membrane involvement (causing vision loss), and vascular calcifications leading to early-onset claudication. The ABCC6 transporter, primarily in the liver, regulates an unknown substrate but is linked to reduced circulating pyrophosphate levels, a key inhibitor of calcification. Currently, PXE treatments focus on symptom management, such as anti-VEGF therapy for vision loss and cardiovascular risk management. More targeted approaches, such as the bisphosphonate etidronate—a pyrophosphate analog—have shown potential in reducing arterial calcification. Given PXE’s rarity and slow progression, surrogate markers for disease progression are crucial for clinical trials. Arterial calcification, as observed on CT scans, is a promising marker, but should be further evaluated. This thesis explores various aspects of PXE and arterial calcification. Part I examines potential PXE manifestations. Part II assesses arterial calcification’s impact via CT imaging in PXE and peripheral artery disease (PAD) patients. Part III evaluates potential treatments for PXE-related arterial calcification. Part I investigates whether certain conditions are part of the PXE phenotype. Chapter 2 examines kidney stone prevalence in PXE (n=273) versus controls (n=125), finding no significant difference (6.9% vs. 5.6%, p=0.6), suggesting kidney stones are not PXE-related. Chapter 3 explores PXE patients’ (n=312) plasma lipid levels compared to the general population and non-PXE controls (n=44), refuting prior claims that ABCC6 mutations directly affect lipid metabolism. Chapter 4 highlights breast arterial calcification (BAC) in PXE women (n=125), showing an 82% prevalence, supporting PXE’s high calcification burden and its effect on the tunica media. Part II focuses on arterial calcification’s progression and its link to cardiovascular events. Chapter 5 tracks arterial calcification in 311 PXE patients over 3.8 years, revealing a 15.9% annual increase, most rapid in the legs. Some arteries exhibit nonlinear calcification growth. Chapter 6 follows 326 PXE patients for 6 years, showing that higher arterial calcification volumes at baseline predict first-time cardiovascular events (adjusted HR: 1.87, 95% CI: 1.14–3.09), though no association was found in those with pre-existing cardiovascular disease. Chapter 7 systematically reviews 48 studies on peripheral arterial calcification in PAD patients, finding a trend linking higher calcification scores to major adverse limb events, amputations, cardiovascular events, and mortality, though heterogeneity precluded meta-analysis. Part III examines etidronate as a potential treatment. Chapter 8 assesses 73 PXE patients over a median 3.6 years without etidronate and 2.8 years with it. The annual calcification progression rate decreased from 11.7% to 5.3% with etidronate (p<0.001). Chapter 9 details the ongoing TEMP-PREVENT trial, a 24-month randomized, double-blind, placebo-controlled study investigating etidronate’s effect on arterial calcification in younger PXE patients, with results expected in 2027.