Vascular Ehlers-Danlos Syndrome (vEDS)
Vascular Ehlers-Danlos Syndrome (vEDS, previously known as EDS Type IV or EDS IV) is a subtype of Ehlers-Danlos Syndrome (EDS), a disorder of collagen production. Collagen is the main protein in connective tissue such as skin, bones, blood vessels, and many other organs and tissues.
Unlike other subtypes of EDS, people with vEDS often do not have the typical symptoms of EDS, which include skin hyperextensibility (skin that is easily stretched) and hypermobility of the joints (unusually large joint range of motion). Because of the lack of other symptoms associated with EDS, the first symptom a person with vEDS may experience is often related to a catastrophic complication, such as colonic perforation, when the tissue of the colon tears, or an arterial rupture, when the wall of an artery tears.1
Vascular EDS is considered the most severe EDS subtype. The average lifespan is 50 years, with 70% of people with vEDS experiencing a major complication by the age of 30 years. There are approximately 2,000 people in the U.S. diagnosed with vEDS, though experts estimate as many as 5,000 people may be affected.1
Vascular EDS should be suspected in the presence of the following major symptoms:2
- Characteristic facial features (thin lips, narrow nose, undersized jaw, protruding eyes)
- Easy bruising
- Thin skin with visible veins (especially on the chest or abdomen)
- Rupture or tearing of the arteries, intestines or uterus
- Family history of vEDS
Other less obvious symptoms that may also help raise suspicion of vEDS include:2
- Acrogeria (an aged appearance, especially of the hands and feet)
- Carotid-cavernous sinus arteriovenous fistula (an abnormal connection between an artery in the neck and a set of veins behind the eye)
- Joint hypermobility
- Rupture of muscles or tendons
- Early-onset varicose veins
- Collapsed lung (with possible buildup of blood in the chest cavity)
- Chronic joint dislocations
- Dislocated hips or clubfoot (in infants born with the disorder)
- Receding gums
Clinical suspicion of vEDS is confirmed through genetic testing of COL3A1 and/or biochemical analysis of fibroblasts, the cells that produce collagen, as a means of detecting abnormalities in type III collagen.1
There is currently no approved treatment option for vEDS. In 2015, the U.S. Food and Drug Administration (FDA) granted EDSIVOTM (celiprolol) orphan drug designation for the potential treatment of vEDS.
EDSIVOTM (celiprolol) for vEDS
EDSIVO™ (celiprolol) is being evaluated for the treatment of vascular Ehlers-Danlos syndrome (vEDS) in the United States. The FDA has reviewed our NDA for EDSIVO™ for the treatment of vEDS in patients with a confirmed type III collagen (COL3A1) mutation. The FDA also granted a priority review of the NDA. Priority review is a designation granted by the FDA to accelerate the review process for drugs that offer a significant improvement in treatment or provide treatment where no satisfactory alternative therapy exists. On June 25, 2019 we announced receipt of a Complete Response Letter from the FDA stating that it will be necessary to conduct an adequate and well-controlled trial to determine whether celiprolol reduces the risk of clinical events in patients with vEDS. Acer plans to request a meeting to discuss the FDA’s response and remains committed to working closely with the Agency to fully understand its response.
Prospective Randomized, Open-Label, Blinded-Endpoints Trial (BBEST)
In a well-controlled study of people with vEDS in eight centers in France and one in Belgium, 53 people with vEDS were randomized to either a treatment group or non-treated control group. Celiprolol was administered twice daily to patients in the celiprolol group, starting at 100 milligrams (mg) per day. The dosage was then up-titrated every six months by 100 mg per day to a maximum of 400 mg per day. Patients assigned to the control group received the same attention as those assigned to the celiprolol group but did not receive celiprolol or any beta blocker. The trial was stopped at 47-months for perceived treatment benefit. The study investigators concluded that these data demonstrated a significant reduction in risk for arterial events in the group being treated when compared to the non-treated control group. In addition, very few adverse events or side effects of treatment were reported; treatment with celiprolol was well tolerated, and the target dose of 400 mg twice a day was reached in all but two patients and only one had to stop taking celiprolol because of fatigue.6
Long-Term Observational Study
In April 2019, long-term data from a cohort of COL3A1-positive vEDS patients were published in the Journal of the American College of Cardiology (JACC). This published study described outcomes in 144 COL3A1-positive vEDS patients clinically monitored and treated at the French National Referral Center for Rare Vascular Diseases (Paris, France) between the years 2000 and 2017. Patients were followed for a median of 5.3 years, and up to 20 years. At the initial work up, 50% of patients were not treated regularly and only 33.3% were taking celiprolol; by the end of the study period, the majority (90.3%) were treated with celiprolol alone or in combination with other medications. Once the maximum tolerated dose of celiprolol was reached, 90 (62.5%) patients remained at this dose throughout their follow-up. Only 5 (3.5%) patients required dose reduction due to fatigue, and no serious drug-related adverse event was recorded.
The median rate of arterial events was 1.6 (IQR: 0.9 to 3.0 events) per 5 years and was not significantly different between celiprolol-treated and untreated groups. Also, majority of patients (72.7%) remained quiescent (i.e., asymptomatic) despite 51% having previous arterial events, lesions, or molecular diagnosis. Survival curve analysis showed that those not treated with celiprolol had a significantly worse outcome than celiprolol-treated patients: survival was 80.7% (95% CI 67.8%–93.6%) in those treated with celiprolol versus 48.5% (95% CI 19.7%–77.4%) in those not treated (p<0.001) after 11.1 years of follow-up. Survival was significantly higher in patients treated with celiprolol of 400mg/day (n=83) vs. patients treated with 100 to 300 mg/day (n=27), suggesting a dose effect and that 400mg/day should be considered the optimal dose. The authors also observed a relative decrease in hospitalization rates for acute arterial events during the time period in which the majority of patients were on celiprolol, suggesting a positive effect of celiprolol on the incidence and/or severity of new arterial events.
The authors concluded that in this large, long-term cohort study, vEDS patients had a higher survival rate than expected relative to the known natural history of the disease and a lower annual occurrence of arterial complications, and that celiprolol use was potentially associated with these significant improvements in clinical outcomes.9
- Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342:673-680.
- Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology. Am J Med Genet. 1998;77(31):31-37.
- Milne RJ, Buckley MT. Celiprolol An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cardiovascular disease. Drugs. 1991;41(6):941-969.
- Ferre FC, et al. Oral phenotype and scoring of Vascular Ehlers-Danlos syndrome: A case-control study. British Medical Journal (BMJ) Open Science. 2012;2(2).
- Oderich GS, et al. . The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience. J Vasc Surg. 2005;42(1):98-106.
- Ong KT, Perdu J, De Backer J, et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet.2010;376(9751):1476-1484.
- Shalhub S, et al. Molecular diagnosis in vascular Ehlers-Danlos syndrome predicts pattern of arterial involvement and outcomes. J Vasc Surg. 2014;60(1):160-9.
- Shimaoka Y, et al. Clinical and genetic features of 20 Japanese patients with vascular-type Ehlers-Danlos syndrome British J Dermatol. 2010;163(4):704-710.
- Frank, M, et al. Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study. JAm Coll Cardiol 2019; 73(15):1948–57.