Anti-VEGF treatment for secondary neovascularization in pseudoxanthoma elasticum - age of onset, treatment frequency and visual outcome.

PURPOSE: To assess the onset, treatment frequency, and visual outcome of anti-vascular endothelial growth factor (anti-VEGF) treatment due to secondary choroidal neovascularization (CNV) in patients with pseudoxanthoma elasticum (PXE). DESIGN: Retrospective cohort study METHODS: One-hundred six eyes of 53 patients with PXE were analyzed. The assessment of CNV activity relied on hemorrhage visible on funduscopy and intra- / subretinal fluid on optical coherence tomography (OCT), individually defining a shortening or extension of treatment interval. Best-corrected visual acuity (BCVA) at baseline, age at anti-VEGF therapy initiation, and BCVA-drop events at exudation onset (worsening of BCVA of 2 or more lines) were documented. Further, we assessed the number of injections during the first year and the total number of injections, the time to treatment initiation of the fellow eye, and BCVA over time. RESULTS: During a median observation period of 77 months (IQR 49; 126) patients received a median number of 28.0 anti VEGF-injections (IQR 9.8; 43.5). Eight patients received no injection (median age at baseline 38.1 years), 11 patients underwent anti-VEGF treatment in one eye (median age 47.2 years) and 34 patients in both eyes (median age 51.8 years). The median age at the first anti-VEGF treatment was 52.80 years (IQR 47.2 - 57.6). Applying Cox regression models, the median 'survival' time of fellow eye until treatment initiation was 16.8 months. In the group of bilateral treated patients, the median time difference was 9.6 months (IQR 2.1 - 32.4, range 0 - 122) The median number of injections was 5.5 per eye in the first year of treatment (IQR 3 - 7) and was associated with the total number of injections in the observation period (2.33, CI 1.22 - 3.44, p<0.001). A better BCVA at the last follow-up visit was associated with a better baseline BCVA (p<0.001, R2=0.318) and with the absence of a BCVA drop at the onset of exudation (p=0.035, R2=0.339). CONCLUSIONS: The results of this study indicate that anti-VEGF treatment is required for most PXE patients at a relatively young age. Once treatment in one eye is initiated, the time to fellow eye treatment is relatively short. A BCVA drop before treatment initiation is a risk factor for worse visual outcomes, suggesting that treatment is prudent before exudation affects the central retina. Given the young age of onset and intensive treatment needs, patients with PXE might particularly benefit from longer-acting anti-VEGF therapeutics.

Pseudoxanthoma elasticum-associated angioid streaks near a scleral buckle.

Purpose: We report a patient with pseudoxanthoma elasticum (PXE) with angioid streaks near a scleral buckle site. Observations: A 46-year-old male with PXE presented for evaluation of blurry vision and was found to have classic PXE findings in both eyes and angioid streaks adjacent to the site of a scleral buckle in his left eye. He underwent multimodal imaging, genetic testing, and intravitreal aflibercept in the right eye. Conclusions and importance: Bruch's membrane is known to be fragile in PXE, and patients are often counseled about the heightened risk of playing contact sports. This report raises the question of whether tension from a scleral buckle in the setting of a calcified and brittle BM may increase the likelihood of angioid streaks near the buckle site. In the setting of retinal detachment, it may be worthwhile to carefully weigh the pros and cons of vitrectomy versus buckle for PXE patients.

Angioid Streaks Remain a Challenge in Diagnosis, Management, and Treatment.

Aim: Angioid streaks (ASs) are a rare retinal condition and compromise visual acuity when complicated with choroidal neovascularization (CNV). They represent crack-like dehiscences at the level of the Bruch's membrane. This objective narrative review aims to provide an overview of pathophysiology, current treatment modalities, and future perspectives on this condition. Materials and Methods: A literature search was performed using "PubMed", "Web of Science", "Scopus", "ScienceDirect", "Google Scholar", "medRxiv", and "bioRxiv." Results: ASs may be idiopathic, but they are also associated with systemic conditions, such as pseudoxanthoma elasticum, hereditary hemoglobinopathies, or Paget's disease. Currently, the main treatment is the use of anti-vascular endothelial growth factors (anti-VEGF) to treat secondary CNV, which is the major complication observed in this condition. If CNV is detected and treated promptly, patients with ASs have a good chance of maintaining functional vision. Other treatment modalities have been tried but have shown limited benefit and, therefore, have not managed to be more widely accepted. Conclusion: In summary, although there is no definitive cure yet, the use of anti-VEGF treatment for secondary CNV has provided the opportunity to maintain functional vision in individuals with AS, provided that CNV is detected and treated early.

Bruch's Membrane Calcification in Pseudoxanthoma Elasticum: Comparing Histopathology and Clinical Imaging.

Purpose: To investigate the histology of Bruch's membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging. Design: Experimental study with clinicopathological correlation. Subjects and Controls: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison. Methods: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient. Main Outcome Measures: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease. Results: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole. Conclusions: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Pseudoxanthoma elasticum and retinitis pigmentosa in a patient with a novel mutation in the ABCC6 gene.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an autosomal recessive condition caused by mutations in the ABCC6 gene. Ocular features include angioid streaks, peau d'orange fundus, and drusen. We report a novel ABCC6 mutation causing PXE in a patient with a mixed phenotype of PXE and retinitis pigmentosa (RP). CASE: A 37-year-old female presented with decreased peripheral vision and nyctalopia. Ocular imaging revealed angioid streaks emanating from the optic nerve as well as peripheral pigmentary changes and bone spicules. Genetic testing revealed two mutations in ABCC6 in trans. No other mutation was identified. CONCLUSION: We present a rare case with ocular findings of PXE and RP in a patient with a novel ABCC6 mutation. The patient presented both with peripheral pigmentary changes and angioid streaks. Further investigation into this novel mutation would be beneficial to determine if the mutation is involved in the RP phenotype.

Do pseudoxanthoma elasticum patients have higher prevalence of kidney stones on computed tomography compared to hospital controls?

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by diminished inorganic plasma pyrophosphate (PPi), a strong calcification inhibitor. In addition to more typical calcification of skin, retina and arterial wall a diminished plasma PPi could lead to other ectopic calcification, such as formation of kidney stones. OBJECTIVE: To compare the prevalence of kidney stones between PXE patients and hospital controls on computed tomography (CT). METHOD: Low-dose CT images of PXE patients and controls were assessed by one radiologist, who was blinded for the diagnosis PXE. The number of kidney stones, and the size of the largest stone was recorded. Odds ratios (ORs) for having kidney stone were calculated using multivariable adjusted logistic regression. RESULTS: Our study comprised 273 PXE patients and 125 controls. The mean age of PXE patients was 51.5 ± 15.9 years compared to 54.9 ± 14.2 in the control group (p = 0.04) and PXE patients more often were women (63 vs. 50%, p = 0.013). The prevalence of kidney stones on CT was similar: 6.9% in PXE patients, compared to 5.6% in controls (p = 0.6). In the multivariate analysis adjusting for age and sex, there was no significantly higher odds for PXE patients on having stones, compared to controls: OR 1.48 (95% CI 0.62-3.96). CONCLUSION: There is no significant difference in the prevalence of incidental kidney stones on CT in PXE patients versus controls.

ENPP1 in Blood and Bone: Skeletal and Soft Tissue Diseases Induced by ENPP1 Deficiency.

The enzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) codes for a type 2 transmembrane glycoprotein that hydrolyzes extracellular ATP to generate pyrophosphate (PPi) and adenosine monophosphate, thereby contributing to downstream purinergic signaling pathways. The clinical phenotypes induced by ENPP1 deficiency are seemingly contradictory and include early-onset osteoporosis in middle-aged adults and life-threatening vascular calcifications in the large arteries of infants with generalized arterial calcification of infancy. The progressive overmineralization of soft tissue and concurrent undermineralization of skeleton also occur in the general medical population, where it is referred to as paradoxical mineralization to highlight the confusing pathophysiology. This review summarizes the clinical presentation and pathophysiology of paradoxical mineralization unveiled by ENPP1 deficiency and the bench-to-bedside development of a novel ENPP1 biologics designed to treat mineralization disorders in the rare disease and general medical population.

Pseudoxanthoma elasticum veiled as vasculitis: shedding light on an uncommon disorder and an in-depth review of the literature.

Pseudoxanthoma Elasticum (PXE) is a rare genetic disorder caused by an autosomal recessive mutation in the ABCC6 gene. It manifests with distinctive clinical symptoms impacting the skin, eyes, and cardiovascular system, along with an elevated risk of cardiovascular diseases. We present a case of a 34-year-old male patient who was initially referred to the rheumatology clinic for evaluation due to suspected large vessel vasculitis. The patient's primary complaint was severe hemifacial pain radiating to the neck and upper limb. Radiological imaging studies unveiled substantial vascular narrowing and collateral vessel formation, prompting further investigation to exclude systemic vasculitis. Intriguingly, the patient also exhibited cutaneous manifestations, which were later confirmed via skin biopsy as consistent with PXE. An ophthalmological examination further revealed the presence of the classic PXE findings of angioid streaks. Given the rarity of PXE and its multifaceted clinical presentation, it can be particularly challenging to diagnose and manage. As such, cases like the one presented here may necessitate a referral to a rheumatologist for evaluation of potential systemic involvement. To provide a comprehensive perspective on PXE, we conducted a systematic review of case reports published in the past decade in English, collected from PubMed, Scopus, and the Directory of Open Access databases. The analysis of these cases will be discussed to shed light on the diversity of PXE's clinical features and the diagnostic and management dilemmas it poses and to facilitate ongoing exploration and research into this intricate condition, ultimately leading to improved care for individuals affected by PXE.

Macular neovascularization in inherited retinal diseases: A review.

Inherited retinal diseases (IRDs) are the most common cause of blindness in working-age adults. Macular neovascularization (MNV) may be a presenting feature or occurs as a late-stage complication in several IRDs. We performed an extensive literature review on MNV associated with IRDs. MNV is a well-known complication of Sorsby fundus dystrophy and pseudoxanthoma elasticum. Those with late-onset Stargardt disease may masquerade as exudative age-related macular degeneration (AMD) when MNV is the presenting feature. Peripherinopathies may develop MNV that responds well to a short course of anti-vascular endothelial growth factor (anti-VEGF) therapy, while bestrophinopathies tend to develop MNV in the early stages of the disease without vision loss. Enhanced S-cone syndrome manifests type 3 MNV that typically regresses into a subfoveal fibrotic nodule. MNV is only a rare complication in choroideraemia and rod-cone dystrophies. Most IRD-related MNVs exhibit a favorable visual prognosis requiring less intensive regimens of anti-vascular endothelial growth factor therapy compared to age-related macular degeneration. We discuss the role of key imaging modalities in the diagnosis of MNV across a wide spectrum of IRDs and highlight the gaps in our knowledge with respect to the natural history and prognosis to pave the way for future directions of research.

Identification of a DBA/2 Mouse Sub-strain as a Model for Pseudoxanthoma Elasticum-Like Tissue Calcification.

Ectopic calcification in the cardiovascular system adversely affects life prognosis. DBA/2 mice experience calcification owing to low expression of Abcc6 as observed in pseudoxanthoma elasticum (PXE) patients; however, little is known about its characteristics as a calcification model. In this study, we explore the suitability of a DBA/2 sub-strain as a PXE-like tissue calcification model, and the effect of a bisphosphonate which prevents calcification of soft tissues in hypercalcemic models was evaluated. The incidence of calcification of the heart was compared among several sub-strains and between both sexes of DBA/2 mice. mRNA expression of calcification-related genes was compared with DBA/2 sub-strains and other mouse strains. In addition, progression of calcification and calciprotein particle formation in serum were examined. Among several sub-strains of DBA/2 mice, male DBA/2CrSlc mice showed the most remarkable cardiac calcification. In DBA/2CrSlc mice, expression of the anti-calcifying genes Abcc6, Enpp1 and Spp1 was lower than that in C57BL/6J, and expression of Enpp1 and Spp1 was lower compared with other sub-strains. Calcification was accompanied by accelerated formation of calciprotein particle, which was prevented by daily treatment with bisphosphonate. A model suitable for ectopic calcification was identified by choosing a sub-strain of DBA/2 mice, in which genetic characteristics would contribute to extended calcification.

Pseudoxanthoma Elasticum With Comedones in a 12-Year-Old Female Patient: A Case Report.

Pseudoxanthoma elasticum (PXE) is a rare multisystem disease characterized by progressive calcification and disintegration of elastic fibers. The disorder is attributed to a genetic mutation occurring in the ABCC6 gene, which encodes for the ATP-binding cassette transporter C6. This gene is located on chromosome 16. Patients commonly present with cutaneous, ophthalmic, and cardiovascular manifestations. However, there is a significant degree of phenotypic diversity. The diagnosis is determined by clinical manifestations, histological analysis of the lesions, and genetic analysis. The present study includes a case report of a 12-year-old female patient who presented with a chief complaint of painless, mildly pruritic yellow papules located on her neck for a period of one year. These papules were accompanied by comedones.

The Activation of JAK/STAT3 Signaling and the Complement System Modulate Inflammation in the Primary Human Dermal Fibroblasts of PXE Patients.

Previous studies revealed a link between inflammation and overactivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in syndromes associated with aging. Pseudoxanthoma elasticum (PXE), a rare autosomal-recessive disorder, arises from mutations in ATP-binding cassette subfamily C member 6 (ABCC6). On a molecular level, PXE shares similarities with Hutchinson-Gilford progeria syndrome, such as increased activity of senescence-associated- beta-galactosidase or high expression of inflammatory factors. Thus, this study's aim was the evaluation of activated STAT3 and the influence of JAK1/2-inhibitor baricitinib (BA) on inflammatory processes such as the complement system in PXE. Analysis of activation of STAT3 was performed by immunofluorescence and Western blot, while inflammatory processes and complement system factors were determined based on mRNA expression and protein level. Our results assume overactivation of JAK/STAT3 signaling, increased expression levels of several complement factors and high C3 protein concentration in the sera of PXE patients. Supplementation with BA reduces JAK/STAT3 activation and partly reduces inflammation as well as the gene expression of complement factors belonging to the C1 complex and C3 convertase in PXE fibroblasts. Our results indicate a link between JAK/STAT3 signaling and complement activation contributing to the proinflammatory phenotype in PXE fibroblasts.

Dermoscopic Patterns of Genodermatoses: A Comprehensive Analysis.

(1) Background: Genodermatoses are a clinically and genetically heterogenous group of inherited skin disorders. Diagnosing inherited skin diseases is a challenging task due to their rarity and diversity. Dermoscopy is a non-invasive, easily accessible, and rapid tool used in dermatology not only for diagnostic processes but also for monitoring therapeutic responses. Standardized terminologies have been published for its proper use, reproducibility, and comparability of dermoscopic terms. (2) Methods: Here, we aimed to investigate dermoscopic features in various genodermatoses by conducting a systematic review and comparing its results to our own findings, data of patients diagnosed with genodermatoses at the Department of Dermatology, Venereology and Dermatooncology, Semmelweis University. (3) Results: Our systematic search provided a total of 471 articles, of which 83 reported both descriptive and metaphoric dermoscopic terminologies of 14 genodermatoses. The literature data were then compared to the data of 119 patients with 14 genodermatoses diagnosed in our department. (4) Conclusion: Dermoscopy is a valuable tool in the diagnosis of genodermatoses, especially when symptoms are mild. To enable the use of dermoscopy as an auxiliary diagnostic method, existing standardized terminologies should be extended to more genodermatoses.

Novel Treatments for PXE: Targeting the Systemic and Local Drivers of Ectopic Calcification.

Pseudoxanthoma elasticum (PXE) is a heritable multisystem ectopic calcification disorder. The gene responsible for PXE, ABCC6, encodes ABCC6, a hepatic efflux transporter regulating extracellular inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. Recent studies demonstrated that in addition to the deficiency of plasma PPi, the activated DDR/PARP signaling in calcified tissues provides an additional possible mechanism of ectopic calcification in PXE. This study examined the effects of etidronate (ETD), a stable PPi analog, and its combination with minocycline (Mino), a potent inhibitor of DDR/PARP, on ectopic calcification in an Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 4 weeks of age, before the development of ectopic calcification, were treated with ETD, Mino, or both for 18 weeks. Micro-computed tomography, histopathologic examination, and quantification of the calcium content in Abcc6-/- mice treated with both ETD and Mino revealed further reduced calcification than either treatment alone. The effects were associated with reduced serum alkaline phosphatase activity without changes in plasma PPi concentrations. These results suggest that ETD and Mino combination therapy might provide an effective therapeutic approach for PXE, a currently intractable disease.

Pseudoxanthoma Elasticum With Detailed Analyses of Coronary Artery Disease.

A 60-year-old woman with pseudoxanthoma elasticum (PXE) underwent thorough coronary artery disease assessments. Intravascular imaging tests suggested fragmented and calcified elastic fibers in the internal elastic lamina, suggesting a possible pathophysiology of coronary artery disease in PXE. Our case report would allow clinicians to acknowledge the clinical picture of PXE. (Level of Difficulty: Intermediate.).

Recent Advances in Clinical Research on Rare Intractable Hereditary Skin Diseases in Japan.

Our Research Group for Rare and Intractable Skin Diseases operates within the Project for Research on Intractable Diseases of the Ministry of Health, Labour, and Welfare of Japan and is conducting research on eight rare intractable skin diseases. Five of these are monogenic disorders (epidermolysis bullosa, congenital ichthyoses, oculocutaneous albinism, pseudoxanthoma elasticum, and hereditary angioedema), and for a sixth [generalized pustular psoriasis (GPP)], genetic predisposing factors are important. This review introduces our activities for raising public awareness of these six intractable hereditary skin diseases and summarizes our recent achievements in clarifying the situation of medical treatments for these diseases in Japan. We note our current progress in elucidating the pathogeneses of these diseases and in developing new treatment methods, and we discuss our progress in establishing clinical practice guidelines. A nationwide survey on epidermolysis bullosa and a clinical survey on congenital ichthyoses are progressing. The Angioedema Activity Score and the Angioedema Quality-of-Life Questionnaire, the latter of which is a quality-of-life evaluation tool, have been established for hereditary angioedema. Registries of patients with oculocutaneous albinism and pseudoxanthoma elasticum have been created, and the registry for the latter has achieved its target of 170 cases. For GPP, the results of our survey on clinical practice were published in 2021. Information regarding all six of these hereditary skin diseases has been disseminated to academic societies, medical professionals, patients, and the general public.

Pseudoxanthoma elasticum is associated with cardiocirculatory inefficiency.

Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease characterized by dystrophic calcification of elastic fibres in the skin, retina and vascular wall. Data on cardiac involvement are inconsistent. Hence, we aimed to evaluate cardiorespiratory response to incremental cardiopulmonary exercise testing (CPET) in PXE. A total of 30 PXE patients (54.0 ± 11.2 years, 40.0% male) and 15 matched controls underwent symptom-limited incremental CPET. PXE patients presented an impaired peak work rate as compared to controls (84.2 ± 16.0% vs. 94.7 ± 10.4%, p = 0.03) that was accompanied by a lower peak oxygen uptake (in % predicted and mL/min/kg), reduced increments in oxygen uptake per increments of work rate (ΔV´O2/ΔWR, 8.4 ± 3.0 mL/min/W vs. 11.3 ± 4.9 mL/ min/W, p = 0.02), lower peak oxygen pulse (78.0 ± 12.3% vs. 90.6 ± 19.6%, p = 0.01) and reduced minute ventilation at peak exercise (V´E, 66.2 ± 16.8% vs. 82.9 ± 25.2%, p = 0.02). To summarize, we presently observed impairment in mainly cardiocirculatory parameters, whilst no substantial ventilatory limitation was detected. The potential implications of this finding for PXE management warrant further study.

Pseudoxanthoma-elasticum-like changes on the soft palate.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive genetic disorder characterized by aberrant fragmentation and calcification of elastic fibers, leading to characteristic cutaneous, ophthalmic, and cardiovascular manifestations. PXE demonstrates significant phenotypic variability; involvement of the oral mucosa may be the only clue to the diagnosis. Reports on mucous membrane involvement in PXE are scarce. Here, we present a case of PXE-like changes in the oral cavity. A 70-year-old male patient presented with a painless leukoplakic lesion on the soft palate. Biopsy revealed numerous degenerated fibers in the lamina propria. Verhoeff-van Gieson and von Kossa staining confirmed their identity as calcified elastic fibers. A histopathological diagnosis of PXE-like changes was made; the patient was referred to ophthalmology where angioid streaks were visualized fundoscopically. PXE-like changes in the absence of the characteristic genetic mutation have also been reported with or without systemic manifestations. Furthermore, PXE-like changes have been reported in up to 10% of oral biopsy specimens undertaken without clinical suspicion for PXE. Therefore, the significance of such changes in isolation is unclear. Clinicians and pathologists should be aware of the potential oral manifestations of PXE to facilitate prompt diagnosis and subspecialist referral.

Matrix Metalloproteinases Contribute to the Calcification Phenotype in Pseudoxanthoma Elasticum.

Ectopic calcification and dysregulated extracellular matrix remodeling are prominent hallmarks of the complex heterogenous pathobiochemistry of pseudoxanthoma elasticum (PXE). The disease arises from mutations in ABCC6, an ATP-binding cassette transporter expressed predominantly in the liver. Neither its substrate nor the mechanisms by which it contributes to PXE are completely understood. The fibroblasts isolated from PXE patients and Abcc6-/- mice were subjected to RNA sequencing. A group of matrix metalloproteinases (MMPs) clustering on human chromosome 11q21-23, respectively, murine chromosome 9, was found to be overexpressed. A real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescent staining confirmed these findings. The induction of calcification by CaCl2 resulted in the elevated expression of selected MMPs. On this basis, the influence of the MMP inhibitor Marimastat (BB-2516) on calcification was assessed. PXE fibroblasts (PXEFs) exhibited a pro-calcification phenotype basally. PXEF and normal human dermal fibroblasts responded with calcium deposit accumulation and the induced expression of osteopontin to the addition of Marimastat to the calcifying medium. The raised MMP expression in PXEFs and during cultivation with calcium indicates a correlation of ECM remodeling and ectopic calcification in PXE pathobiochemistry. We assume that MMPs make elastic fibers accessible to controlled, potentially osteopontin-dependent calcium deposition under calcifying conditions.