Despite celiprolol therapy, patients with vascular Ehlers-Danlos syndrome remain at risk of vascular events: A 12-year experience in an Italian referral center.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol has been suggested to significantly reduce rates of vascular events in this setting, though real-world evidence is limited. The aim of this study was to report our experience with celiprolol therapy in vEDS management. METHODS: Patients with a genetically confirmed diagnosis of vEDS who were referred for outpatient consultation at the Brescia University Hospital between January 2011 and July 2023 were included. At each visit, patients' medical history, results of vascular imaging, and office blood pressure measurements were recorded. Celiprolol therapy was progressively titrated to the maximum tolerated dose of up to 400 mg daily, according to the patients' tolerance. RESULTS: Overall, 26 patients were included. Female sex was prevalent (62%). Mean (SD) age was 37 (16) years. Follow-up duration was 72 (41) months. At the last follow-up visit, all patients were on celiprolol therapy, 80% of whom were taking the maximum recommended dose. The yearly risk of symptomatic vascular events was 8.8%, the majority of which occurred after reaching the maximum recommended dose of celiprolol. No significant predictor of symptomatic vascular events was identified among patients' clinical characteristics. CONCLUSION: In our cohort, rates of celiprolol use were high and the drug was well tolerated overall. Nonetheless, the risk of symptomatic vascular events remained nonnegligible. Future studies should identify reliable predictors of major adverse events and explore additional therapeutic strategies that could further lower the risk of life-threatening events in this population.

Manejo odontológico de pacientes con el síndrome de Ehlers-Danlos: revisión narrativa / Dental management in patients with Ehlers-Danlos syndrome: a narrative review

El síndrome de Ehlers-Danlos es una enfermedad heredita- ria, producida por mutaciones cromosómicas que pueden llegar a tener un comportamiento autosómico dominante, recesivo o ligado al cromosoma X. Se caracteriza por defectos en las enzi- mas encargadas de la estructura y síntesis de colágeno. En vista de los 20 tipos de colágeno que existen, este síndrome es extre- madamente heterogéneo tanto en su presentación clínica como en su progresión y evolución. Dentro de los signos y síntomas habituales encontramos la hiperlaxitud articular, hiperelastici- dad de la piel e hiperequimosis de los vasos sanguíneos. Con relación a las complicaciones que pueden presentar es- tos pacientes, encontramos dislocaciones articulares, fragilidad en la piel, dolor articular, ruptura de grandes vasos sanguíneos, dificultad en la cicatrización y, en consecuencia, mayor inci- dencia de procesos infecciosos y de cicatrices poco estéticas. Presenta una incidencia de 1 caso cada 2.500-5.000 na- cidos vivos. Por ello, es fundamental que el odontólogo se encuentre familiarizado con el manejo médico-dental de estos pacientes, a fin de estar preparado para brindarles un trata- miento adecuado y responder ante las posibles complicacio- nes que se pueden presentar. En esta revisión se emplearon resultados extraídos manual- mente de artículos, indexados en las bases de datos PUBMED y EBSCO, que respondían a la búsqueda de los términos Ehlers-Danlos syndrome, dental management y oral surgery. El objetivo fue describir el manejo médico-odontológico del paciente con síndrome de Ehlers-Danlos hasta la fecha (AU)

Ehlers-Danlos syndrome is a hereditary disease, produced by chromosomal mutations that can have an autosomal behavior, which can be dominant, recessive or X-linked. It is characterized by defects in the enzymes responsible for the structure and syn- thesis of collagen. In view of the 20 existent types of collagen, this syndrome is extremely heterogeneous in its clinical presentation, as well as in its progression and evolution. Within the usual signs and symptoms, we find joint hyperlaxity, skin hyperelasticity and hyper-ecchymosis of the blood vessels. Regarding the complications that these patients can pres- ent, we find joint dislocations, skin fragility, joint pain, rupture of large blood vessels, difficulty in healing and, consequently, a higher incidence of infectious processes and unsightly scars. It presents an incidence of 1 case every 2.500-5.000 live births. Therefore, it is essential that the dentist is familiar with the medical-dental management of these patients, in order to be prepared to provide them with adequate treatment and re- spond to possible complications that may arise. In this review, results were manually extracted from ar- ticles, indexed in the PUBMED and EBSCO databases, that respond to the search for the terms Ehlers-Danlos syndrome, dental management and oral surgery. The aim was describing the medical-dental management of patients with Ehlers-Dan- los syndrome to date (AU)

Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1+/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1+/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vascular Ehlers-Danlos syndrome.

A case-control study of respiratory medication and co-occurring gastrointestinal prescription burden among persons with Ehlers-Danlos syndromes.

We previously reported increased pain and gastrointestinal (GI) medication prescription claims among persons with Ehlers-Danlos syndromes (EDS) and peripubertal increase in opioid and anti-emetic claims among women with EDS. Herein, we hypothesized a higher proportion of respiratory and co-occurring respiratory and GI medication prescription claims among persons with EDS compared to their matched controls with increases among peripubertal women with EDS. We compared the proportions of respiratory and co-occurring respiratory and GI medication prescription claims among persons with EDS (aged 5-62) against their age-, sex-, state of residence-, and earliest claim date-matched controls using 10 years of private prescription claims data. Prescription claims among persons with EDS versus matched controls were increased for eight medication classes (p < .0001): intranasal/inhaled corticosteroids (ICS) (30.8% vs. 19.0%), oral steroids (30.0% vs. 16.5%), H1-antihistamines (26.2% vs. 12.2%), short-acting beta agonists (22.7% vs. 11.6%), decongestants (21.6% vs. 15.9%), leukotriene modifiers (8.9% vs. 3.6%), ICS/long-acting beta agonists (5.7% vs. 2.9%), muscarinic antagonists (2.5% vs. 0.9%), and co-occurring prescriptions (29% vs. 10%). Our results suggest a critical time window for peripubertal intervention and research and a need to focus on the pathogenesis and clinical evaluation of EDS-specific respiratory and aerodigestive disorders.

The Effect of Low Dose OnabotulinumtoxinA on Cervical Dystonia in Hypermobile Ehlers-Danlos Syndrome.

Background: Many patients with hypermobile Ehlers-Danlos Syndrome (EDS) suffer from cervical dystonia. Intramuscular injection of botulinum toxin may exacerbate myeloradiculopathy or atlantoaxial subluxation in this patient population. Case: Three patients with hypermobile EDS underwent low-dose OnabotulinumtoxinA injections for cervical dystonia into myofascial sites selected using Fascial Manipulation diagnostic sequencing technique. All patients improved in clinical symptoms without complications. Results: Patients clinically improved on the TWSTRS by 16 points with demonstrated changes in deep fascia thickness decrease of 0.28 mm. Discussion: Low-dose OnabotulinumtoxinA injections into carefully selected sites is a safe and effective treatment in hypermobile EDS patients suffering from cervical dystonia.

Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare monogenetic disease caused by pathogenic variants in procollagen 3A1. Arterial rupture is the most serious clinical manifestation. A randomised controlled trial, the Beta-Blockers in Ehlers-Danlos Syndrome Treatment (BBEST) trial, reported a significant protective effect of the beta blocker celiprolol. The aim was to study the outcome of celiprolol treatment in a cohort of Swedish patients with vEDS. METHODS: Uppsala is a national referral centre for patients with vEDS. They are assessed by vascular surgeons, angiologists, and clinical geneticists. Family history, previous and future clinical events, medication, and side effects are registered. Celiprolol was administered twice daily and titrated up to a maximum dose of 400 mg daily. Logistic regression was used to analyse predictors of vascular events. RESULTS: Forty patients with pathogenic sequence variants in COL3A1 were offered treatment with celiprolol in the period 2011-2019. The median follow up was 22 months (range 1-98 months); total follow up was 106 patient years. In two patients, uptitration of the dose is ongoing. Of the remaining 38, 26 (65%) patients reached the target dose of 400 mg daily. Dose uptitration was unsuccessful in six patients because of side effects; one died before reaching the maximum dose, and five terminated the treatment. Five major vascular events occurred; four were fatal (ruptured ascending aorta; aortic rupture after type B dissection; ruptured cerebral aneurysm; and ruptured pulmonary artery). One bled from a branch of the internal iliac artery, which was successfully coiled endovascularly. The annual risk of a major vascular event was 4.7% (n = 5/106), similar to the treatment arm of the BBEST trial (5%) and lower than in the control arm of the same trial (12%). No significant predictor of vascular events was identified. CONCLUSION: Treatment with celiprolol is tolerated in most patients with vEDS. Despite fatal vascular events, these observations suggest that celiprolol may have a protective effect in vEDS.

The first experience of denosumab therapy on patients with Ehlers-Danlos syndrome and osteoporosis: detailed observation of two patients.

Previous studies have shown decreased bone mineral density (BMD) due to an unknown mechanism in Ehlers-Danlos Syndrome (EDS) patients and described approaches to treatment for osteoporosis in EDS. To date, however, there is no established method of treatment. In this study, we investigated two patients with EDS to clarify the efficacy and safety of denosumab treatment in EDS patients with osteoporosis. We retrospectively enrolled two EDS patients with osteoporosis who underwent denosumab therapy. Patient 1 was a 59-year-old male with classical EDS and osteoporosis who received a 48-month course of denosumab therapy. His lumbar BMD and total hip BMD were 1.335 g/cm2 and 0.762 g/cm2 before treatment, respectively. Forty-eight months later, the lumbar and total hip BMD showed gains of 1.6% and 11.4%, respectively. Patient 2 was a 42-year-old male with vascular EDS and osteoporosis who received an 18-month course of denosumab therapy. His lumbar BMD and total hip BMD were 0.763 g/cm2 and 0.583 g/cm2 before treatment, respectively. Eighteen months later, the lumbar and total hip BMD showed gains of 5.0% and 1.8%, respectively. No fractures or other complications were recorded during the observational period in both cases. This is the first experience of denosmab therapy on patients with EDS and osteoporosis. Denosumab, administered safely with no serious adverse effects such as fractures, exerted a fluctuating but probably positive effect regarding BMD and could be a treatment option on these patients.

The first case report of Kyphoscoliotic Ehlers-Danlos syndrome of chinese origin with a novel PLOD1 gene mutation.

BACKGROUND: Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disorder characterized by progressive kyphoscoliosis, congenital muscular hypotonia, marked joint hypermobility, and severe skin hyperextensibility and fragility. Deficiency of lysyl hydroxylase 1 (LH1) due to mutations of PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1) gene has been identified as the pathogenic cause of kEDS (kEDS-PLOD1). Up to now, kEDS-PLOD1 has not been reported among Chinese population. CASE PRESENTATION: A 17-year-old Chinese male patient presenting with hypotonia, joint hypermobility and scoliosis was referred to our hospital. After birth, he was found to have severe hypotonia leading to delayed motor development. Subsequently, joint hypermobility, kyphoscoliosis and amblyopia were found. Inguinal hernia was found at age 5 years and closed by surgery. At the same time, he presented with hyperextensible and bruisable velvety skin with widened atrophic scarring after minor trauma. Dislocation of elbow joint was noted at age of 6 years. Orthopedic surgery for correction of kyphoscoliosis was performed at age 10 years. His family history was unremarkable. Physical examination revealed elevated blood pressure. Slight facial dysmorphologies including high palate, epicanthal folds, and down-slanting palpebral fissures were found. He also had blue sclerae with normal hearing. X-rays revealed severe degree of scoliosis and osteopenia. The Echocardiography findings were normal. Laboratory examination revealed a slightly elevated bone turnover. Based on the clinical manifestations presented by our patient, kEDS was suspected. Genetic analysis revealed a novel homozygous missense mutation of PLOD1 (c.1697 G > A, p.C566Y), confirming the diagnosis of kEDS-PLOD1. The patient was treated with alfacalcidol and nifedipine. Improved physical strength and normal blood pressure were reported after 12-month follow-up. CONCLUSIONS: This is the first case of kEDS-PLOD1 of Chinese origin. We identified one novel mutation of PLOD1, extending the mutation spectrum of PLOD1. Diagnosis of kEDS-PLOD1 should be considered in patients with congenital hypotonia, progressive kyphoscoliosis, joint hypermobility, and skin hyperextensibility and confirmed by mutation analysis of PLOD1.

An old drug for a rare disease: The example of celiprolol for vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (OMIM 130050, 1/150,000 birth) is caused by mutations in collagen 3A1 gene. It is associated with severe phenotype associating early arterial dissection and rupture, digestive and uterine perforations, and skin and joints fragility. Until recently, no treatment was available. Celiprolol, a beta1 antagonist with beta2 partial antagonist properties betablocker was tested in a randomized, controlled trial. We could show that this compound was associated with a 3-fold decrease in major events related to the disease. This effect was similar in molecular-proven patients. Administration of celiprolol in a cohort of patients followed routinely in France was accompanied to similar benefit. Celiprolol is unavailable in the USA. The ACER Therapeutics company applied for new drug application (NDA) to the Food and Drug Administration.

Celiprolol but not losartan improves the biomechanical integrity of the aorta in a mouse model of vascular Ehlers-Danlos syndrome.

AIMS: Antihypertensive drugs are included in the medical therapy of vascular Ehlers-Danlos syndrome (vEDS). The ß-blocker celiprolol has been suggested to prevent arterial damage in vEDS, but the underlying mechanism remains unclear. It is also unknown whether the widely used angiotensin II receptor type 1 antagonist losartan has a therapeutic effect in vEDS. Here, we evaluated the impact of celiprolol and losartan on the biomechanical integrity of the vEDS thoracic aorta. METHODS AND RESULTS: We established a new approach to measure the maximum tensile force at rupture of uniaxially stretched murine thoracic aortic rings. In a vEDS model, which we (re-)characterized here at molecular level, heterozygous mice showed a significant reduction in the rupture force compared to wild-type mice, reflecting the increased mortality due to aortic rupture. For the assessment of treatment effects, heterozygous mice at 4 weeks of age underwent a 4-week treatment with celiprolol, losartan, and, as a proof-of-concept drug, the matrix metalloproteinase inhibitor doxycycline. Compared to age- and sex-matched untreated heterozygous mice, treatment with doxycycline or celiprolol resulted in a significant increase of rupture force, whereas no significant change was detected upon losartan treatment. CONCLUSIONS: In a vEDS model, celiprolol or doxycycline, but not losartan, can improve the biomechanical integrity of the aortic wall, thereby potentially reducing the risk of dissection and rupture. As doxycycline is a broad-spectrum antibiotic with considerable side effects, celiprolol may be more suitable for a long-term therapy and thus rather indicated for the medication of patients with vEDS.

Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene, which encodes the pro-α 1 chain of collagen III. Loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including spontaneous arterial dissection and/or rupture, the major cause of mortality. We created 2 mouse models of vEDS that carry heterozygous mutations in Col3a1 that encode glycine substitutions analogous to those found in patients, and we showed that signaling abnormalities in the PLC/IP3/PKC/ERK pathway (phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal-regulated kinase) are major mediators of vascular pathology. Treatment with pharmacologic inhibitors of ERK1/2 or PKCß prevented death due to spontaneous aortic rupture. Additionally, we found that pregnancy- and puberty-associated accentuation of vascular risk, also seen in vEDS patients, was rescued by attenuation of oxytocin and androgen signaling, respectively. Taken together, our results provide evidence that targetable signaling abnormalities contribute to the pathogenesis of vEDS, highlighting unanticipated therapeutic opportunities.

Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic connective tissue disorder secondary to pathogenic variants within the COL3A1 gene, resulting in exceptional arterial and organ fragility and premature death. The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality. OBJECTIVES: The authors herein describe the outcomes of a large cohort of vEDS patients followed ≤17 years in a single national referral center. METHODS: All patients with molecularly confirmed vEDS were included in a retrospective cohort study. After an initial work-up, patients were treated or recommended for treatment with celiprolol (≤400 mg/day) in addition to usual care and scheduled for yearly follow-up. vEDS-related events and deaths were collected and recorded for each patient. RESULTS: Between 2000 and 2017, 144 patients (median age at diagnosis 34.5 years, 91 probands) were included in this study. After a median follow-up of 5.3 years, overall patient survival was high (71.6%; 95% confidence interval: 50% to 90%) and dependent on the type of COL3A1 variant, age at diagnosis, and medical treatment. At the end of the study period, almost all patients (90.3%) were treated with celiprolol alone or in combination. More than two-thirds of patients remained clinically silent, despite a large number (51%) with previous arterial events or arterial lesions at molecular diagnosis. Patients treated with celiprolol had a better survival than others (p = 0.0004). The observed reduction in mortality was dose-dependent: the best protection was observed at the dose of 400 mg/day versus <400 mg/day (p = 0.003). During the period surveyed, the authors observed a statistically significant difference in the ratio of hospitalizations for acute arterial events/hospitalizations for regular follow-up before and after 2011. CONCLUSIONS: In this long-term survey, vEDS patients exhibited a low annual occurrence of arterial complications and a high survival rate, on which the overall medical care seems to have a positive influence.

Aortic treatment in connective tissue disease.

Connective tissue disease (CTD) represents a group of genetic conditions characterized by disruptive matrix remodeling. When this process involves aortic and vascular wall, patients with CTD have a high risk of developing arterial aneurysms, dissections and ruptures. Open surgical repair is still the gold standard therapy for patients with CTD with reasonable morbidity and mortality risk. The surgical treatment of CTD often requires multiple operations. In the endovascular era, fenestrated and branched stent grafts may play a role in reducing the complications of multiple open operations. Although the long-term results of endovascular treatment in the setting of CTD are unknown, it is generally accepted that endovascular treatment is restricted to selected patients with high surgical risk. In an emergency setting, endovascular intervention can serve as a lifesaving bridge to elective open aortic repair. Aortic centers performing a large volume of complex open and endovascular aortic repairs have started to combine these two techniques in a staged fashion. The goal is to reduce the morbidity and mortality associated with extensive aortic repairs in CTD patients. For this reason, recommend endovascular therapy when a "graft-to-graft" approach is possible. In this scenario, the surgeon who performs the open repair must take into consideration future interventions. Surgical repair in any aortic segment should allow creation of proximal and distal landing zones over 4 cm to secure the sealing of a future stent graft. Connective tissue disease should be treated with a multidisciplinary approach, in high volume centers. Endovascular treatment represents a potential option in patients at high risk for open repair. Staged hybrid procedures have emerged as a way to reduce spinal cord ischemia and avoid multiple open surgeries. The aim of this article is to discuss the management of aortic diseases in CTD, focusing on to the role of standard open surgery and emerging endovascular treatment, and to give an overview of the few series published regarding this topic with a small number of patients.

Skeletal fragility: an emerging complication of Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome (EDS) is an emerging cause of skeletal fragility. Mechanism of bone damage are probably multifactorial in line with the different skeletal phenotypes that can be found in clinical practice. A structured approach to clinical management of bone metabolic complication in EDS is proposed.

A case of vascular Ehlers-Danlos Syndrome with a cardiomyopathy and multi-system involvement.

Ehlers-Danlos Syndrome comprises a heterogeneous group of heritable connective tissue disorders resulting from various gene mutations. We present an unusual case of vascular Ehlers-Danlos Syndrome with distinctive physical characteristics and a cardiomyopathy with features suggesting isolated left ventricular non-compaction. The cardiac features represent the first report of a cardiomyopathy associated with a mutation in the COL3A1 gene. This case also illustrates the multi-system nature of Ehlers-Danlos Syndrome and the complexity of managing patients with the vascular subtype.

[EHLERS-DANLOS SYNDROME OF THE HYPERMOBILE TYPE: A MULTISYSTEMIC DISORDER. CONTRIBUTION OF SKIN ULTRASTRUCTURE TO INDIVIDUAL MANAGEMENT]. / SYNDROME D'EHLERS-DANLOS DE TYPE HYPERMOBILE : UNE ATTEINTE MULTI-SYSTÉMIQUE. Apport de l'ultrastructure cutanée pour une prise en charge personnalisée.

Ehlers-Danlos syndrome (EDS) represents a heterogeneous group of disorders of the connective tissue structure. Currently, several types are distinguished following a limited set of clinical signs and genetic mutations. However, there is a lack of specificity of most recognized genetic alterations with the current clinical typing. In addition, the criteria from dermatopathology, ultrastructure and biomechanics are not considered. In addition, the established EDS frontiers are hazardous because a series of anatomo-clinical signs are not considered in the classical EDS concept. The hypermobile type EDS represents an example of the diagnostic uncertainties. It results that guidelines based on evidence-based medicine cannot be established. Only an individual management can be offered to the concerned patients.

The Ehlers-Danlos syndrome.

The Ehlers-Danlos Syndromes comprise a heterogeneous group of diseases, which are characterized by fragility of the soft connective tissues and widespread manifestations in skin, ligaments and joints, blood vessels and internal organs. The clinical spectrum varies from mild skin and joint hyperlaxity to severe physical disability and life-threatening vascular complications. The current Villefranche classification recognizes six subtypes, most of which are linked to mutations in one of the genes encoding fibrillar collagen proteins or enzymes involved in post-translational modification of these proteins. Establishing the correct EDS subtype has important implications for genetic counselling and management and is supported by specific biochemical and molecular investigations. Over the last years, the characterisation of several new EDS variants has broadened insights into the molecular pathogenesis of EDS by implicating genetic defects in the biosynthesis of other extracellular matrix molecules, such as proteoglycans and tenascin-X, or genetic defects in molecules involved in intracellular trafficking, secretion and assembly of extracellular matrix proteins.