In patients with PXE, etidronate reduced arterial calcification and subretinal neovascularization events but did not lower femoral fluoride sodium positron emission tomography activity compared with placebo, without important safety issues. (Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum; NTR5180).
Visual impairment and blindness are frequent in PXE, particularly in patients older than 50 years. Although choroidal neovascularization is associated with the majority of vision loss, macular atrophy is also common. The proportion of visual impairment in PXE is comparable with late age-related macular degeneration but manifests earlier in life.
Background and aims: Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. Methods: ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. Results: 158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (β: 0.39, 95%CI:-0.62;-0.17) and total (β: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. Conclusions: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability.
PURPOSE: To investigate whether the extent of Bruch's membrane calcification is associated with choroidal neovascularization (CNV) and macular atrophy in patients with pseudoxanthoma elasticum (PXE) by using the extent of angioid streaks as a surrogate marker for the degree of Bruch's membrane calcification.DESIGN: Retrospective cross-sectional study. METHODS: We investigated 301 patients with PXE (median age, 52 years; range, 9-79 years) in a tertiary referral center. For both eyes, we graded the extent of angioid streaks, that is, their distance from the optic disc, into 5 groups. Imaging was systematically assessed for signs of CNV and macular atrophy. Associations between the extent of angioid streaks and CNV or macular atrophy were investigated using regression analysis.RESULTS: CNV was present in 148 patients (49%) and retinal atrophy in 71 patients (24%). The extent of angioid streaks was associated with older age (P for trend ¼ 1.92 3 10 L15 ) and a higher prevalence of CNV and/or macular atrophy (P for trend [ 4.22 3 10 L10 and P for trend [ 5.17 3 10 L6 , respectively). In addition, the extent of angioid streaks was associated with the presence of CNV when adjusted for age and sex (odds ratio, 1.9; 95% confidence interval, 1.3-2.9) and with more severe macular atrophy (proportional odds ratio, 2.3; 95% confidence interval, 1.5-3.6).CONCLUSIONS: In patients with PXE, longer angioid streaks are associated with an increased risk of CNV and macular atrophy, even after adjustment for age. These findings are relevant when counseling PXE patients on their visual prognosis.
Purpose: To describe the natural history of Bruch's membrane (BM) calcification in patients with pseudoxanthoma elasticum (PXE).Design: Retrospective cohort study.Participants: Both eyes of 120 PXE patients younger than 50 years, 78 of whom had follow-up imaging after more than 1 year.Methods: All patients underwent multimodal imaging, including color fundus photography, near-infrared reflectance (NIR) imaging, and late phase indocyanine green angiography (ICGA). We determined the distance from the optic disc to the central and temporal border of peau d'orange on NIR, expressed in horizontal optic disc diameter (ODD). The length of the longest angioid streak was classified into 5 zones.Main Outcome Measures: Age-specific changes of peau d'orange, angioid streaks, and ICGA hypofluorescence as surrogate markers for the extent of BM calcification.Results: In cross-sectional analysis, longer angioid streaks were associated with increasing age (P < 0.001 for trend). The temporal border of peau d'orange showed a weak association with increasing age (b ¼ 0.02; 95% confidence interval [CI], 0.00e0.04), whereas the central border showed a strong association (b ¼ 0.12; 95% CI, 0.09e0.15). Longitudinal analysis revealed a median shift of the central border to the periphery of 0.08 ODD per year (interquartile range [IQR], 0.00e0.17; P < 0.001). This shift was more pronounced in patients younger than 20 years (0.12 ODD per year [IQR, 0.08e0.28]) than in patients older than 40 years (0.07 ODD per year [IQR, e0.05 to 0.15]). The temporal border did not shift during follow-up (P ¼ 0.69). New or growing angioid streaks were detected in 39 of 156 eyes (25%). The hypofluorescent area on ICGA was visible only in the fourth or fifth decade and correlated with longer angioid streaks.Conclusions: In PXE patients, the speckled BM calcification slowly confluences during life. The location of the temporal border of peau d'orange remains rather constant, whereas the central border shifts to the periphery. This suggests the presence of a predetermined area for BM calcification. A larger ICGA hypofluorescent area correlates with older age and longer angioid streaks, which implies that it depends on the degree of BM calcification.
Progressive calcification of Bruch's membrane (BM) causes considerable visual morbidity in patients with pseudoxanthoma elasticum (PXE). Since calcification is hyperreflective on optical coherence tomography (OCT), our aim was to measure BM calcification with OCT imaging. Methods: Case-control study with 45 patients with PXE under 40 years (range, 11-39) and 25 controls (range, 14-39). Spectralis HRA-OCT imaging consisted of seven macular B-scans with 250-μm spacing. Retinal segmentation was performed with the IOWA Reference Algorithms. MATLAB was used to extract and average z-axis reflectivity profiles. Layer reflectivities were normalized to the ganglion cell and inner plexiform layers. Both median and peak layer reflectivities were compared between patients with PXE and controls. The discriminative value of the retinal pigment epithelium (RPE)-BM peak reflectivity was analyzed using receiver operating characteristic analysis. Results: The reflectivity profile of patients with PXE differed from controls in the outer retinal layers. The normalized median RPE-BM reflectivity was 41.1 (interquartile range [IQR], 26.3-51.9) in patients with PXE, compared with 22.5 (IQR, 19.3-29.5) in controls (P = 2.09 × 10 −3). The normalized RPE-BM peak reflectivity was higher in patients with PXE (67.5; IQR, 42.1-84.2) than in controls (32.7; IQR, 25.7-38.9; P = 2.43 × 10 −5) and had a high discriminative value with an area under the curve of 0.85 (95% confidence interval, 0.76-0.95). In patients with PXE under 40 years, increasing age did not have a statistically significant effect on the RPE-BM peak reflectivity (patients under 20 years: 44.
To assess the effect of the bisphosphonate etidronate on choroidal neovascular (CNV) activity in patients with pseudoxanthoma elasticum (PXE). Methods This is an ancillary study in a single center, randomized, double-blind placebo-controlled trial (RCT) in which 74 patients with PXE were assigned to either one-year etidronate or placebo treatment. Spectral domain optical coherence tomography (SD-OCT) imaging and color fundus photography were performed every three months for one year and were systematically assessed on signs of CNV activity. Results In the etidronate group, 11 (30%) of the patients had CNV activity at baseline, compared to 25 (67%) of the patients in the placebo group (P = 0.005). The proportion of eyes with CNV activity during the study ranged from 18-33% in the etidronate group and 42-56% in the placebo group and no significant difference in improvement or worsening of CNV activity was found (P = 0.168). Using a generalized mixed model for repeated measures, there was a protective effect of etidronate in crude analysis (RR 0.86, 95% CI 0.75-0.98) that disappeared when adjusting for baseline CNV activity (RR 0.97, 95% CI 0.84-1.13). Conclusion In this post-hoc RCT analysis we did not observe a protecting or deteriorating effect of etidronate on CNV activity in patients with PXE after adjustment for baseline CNV.
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