Vascular Ehlers-Danlos Syndrome Long-Term Observational Study

Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study

Vascular Ehlers-Danlos (ED) syndrome is a genetic connective tissue disorder secondary to pathogenic variants within the COL3A1 gene. This rare disease is characterized by a deficiency of synthesis, secretion, and structure of procollagen type III affecting the entire arterial tree, together with the skin, the uterus and the intestine. The diagnosis is usually made at young age, when a first serious and potentially fatal event, such as arterial (splenic, carotid, aorta) dissection and/or rupture, uterus rupture or spontaneous perforation of the intestine occurs.

The outcome of surgical or vascular interventions performed in an acute setting is not good. Elective vascular procedure are not indicated because of the arterial walls fragility and high risk of complications.

Some years ago the BBEST Trial (Beta-Blockers in Ehlers-Danlos Syndrome Treatment) trial suggested that treatment with the beta-blocker celiprolol, could prolong the survival free of vascular events. This multicenter, open-label, and randomized study was stopped prematurely because of the treatment benefit in patients receiving celiprolol as compared to those untreated with the beta-blocker the drug.

Celiprolol is a betablocker with beta1 antagonist and beta2 partial agonist and beta2 weak antagonist activity, with vasodilating  properties and no adverse effects on metabolic or polmunary function. The drug is indicated for the treatment of hypertension and angina pectoris and potentially in patients with concomitant chronic obstructive pulmonary disease; celiprolol may also act on beta3 receptors  leading to coronary vasorelaxation and stimulation of nitric oxide release. The hemodynamic effects are a decrease in systolic and diastolic BP, with a lesser bradycardia, as compared to other beta-blockers

It is available in Europe, but not in the USA and in Canada

The present study reports the outcomes of a large cohort of vEDS patients followed in the French referral center in Paris. One hundred forty seven patients (91 index patients and 56 family members) with vascular ED syndrome, confirmed by a genetic molecular analysis , were examined a first time with an extensive vascular evaluation, were prescribed celiprolol, titrated to 400 mg /daily)  and  scheduled for an yearly follow-up visit. All vEDS-related events and deaths were collected and recorded for each patient. During the 17 years follow –up (2000 to 2017), 144 patients aged more than 18 years, were included in the retrospective analysis

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.

During this long-term survey, vascular ED 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.

The observation that  in the longterm follow-up study the majority of patients remained clinically silent, including those with a previous event at the molecular diagnosis, is promising, taking into account that in the BBEST trial the lack of celiprolol treatment was associated to the occurrence of 17 events in a 36 months period of follow-up in the group of untreated 28 patients. In the future, attention should be given to younger patients, both index and relatives, in consideration of the. high mortality reported in children, with a greater prevalence in males; the ideal age to start treatment should be clearly established.

It is still not clear which mechanism could explain the beneficial effect observed in both the BBEST trial and this long term observational follow up. It was suggested that celiprolol could counteract the actvity of TGbeta, and stimulate endothelial nitric oxide synthase activity, in addition to a “traditional” beta-receptor blockade. A recent experimental study in mouse model of vascular ED suggest that celiprolol or doxycycline, but not losartan, can improve the biomechanical integrity of the aortic wall, thereby potentially reducing the risk of dissection and rupture.

Authors have followed the patients with a rigorous clinical and scientific approach, based on the structured and multidisciplinary approach of the internationally recognized Paris center, and have further confirmed the goodness of celiprolol treatment. These results are reassuring for all the scientific community and support the value of the Reference Network, for a wider contribution to the assessment and management of rare disease, and in particular of those affected by such a  dreadful disease as vascular Ehlers Danlos syndrome.