Spotlight on the vascular zebras

The National Organization of Rare Diseases (NORD) estimates that 25–30 million Americans and 350 million individuals worldwide have a rare disease, which the organization defines as prevalence of 200,000 or fewer affected individuals in the United States. ¹ Rare vascular diseases encompass the spectrum of vascular medicine, including arterial, venous, and lymphatic disorders, and many vascular rare diseases involve multiple organ systems beyond the vasculature. As a physician who focuses her clinical practice and research on a currently recognized rare disease (fibromuscular dysplasia, FMD), and who has spent many years speaking to hundreds of afflicted patients who complain of feeling like a ‘zebra,’ a ‘medical anomaly,’ or a ‘freak of nature’ that other health care providers know little or nothing about (or pull out a textbook or open a search engine in office for some minimal background), developing the 2024 focused issue of Vascular Medicine has been on my Editor’s wish list for the past decade, and I am delighted to see it come to fruition.

A rare disease is as real, relevant, and important to the afflicted patient as a more common condition, like venous thromboembolism, atherosclerotic carotid artery stenosis, and peripheral artery disease. Patients afflicted with rare vascular diseases hope and deserve to receive quality, compassionate, and informed longitudinal medical care, even if their rare disease is one of the 90% estimated by NORD to have no FDA-approved specific treatment. ¹

Another aspect of this topic that is particularly exciting to me as Editor of Vascular Medicine is the role vascular medicine specialists have played in championing awareness and research of these rare conditions and providing a medical home for some of this patient population. ² For example, in the case of FMD, vascular medicine specialists have served as national leaders in establishing a network of clinical centers and developing a coordinated North American research registry to study the disorder in partnership with a patient advocacy organization, the FMD Society of America. ³

The articles contained in this special issue of Vascular Medicine reflect the broad and heterogeneous spectrum of rare vascular diseases. Through original research articles and letters, reviews, and image vignettes, this issue provides up to date information on the natural history of specific rare vascular diseases and approach to their management. Further, these articles provide hope for patients and the providers who care for them in the form of clinical research studies of potential new diagnostic and therapeutic approaches.

Three state-of-the-art review articles are included in this issue, which demonstrate the tremendous diversity of the rare vascular disease spectrum. Wong and colleagues review cardiovascular manifestations of Erdheim–Chester disease; Pantic and colleagues discuss the approach to a rare congenital anomaly of the inferior vena cava which is associated with venous thrombosis (KILT syndrome); and finally Hausman-Kedem and colleagues provide a comprehensive review of the approach to stroke in children, an uncommon but devastating occurrence, and its underlying arteriopathies with focus on pediatric FMD.^{4 –6}

Two articles in this issue focus on a rarest of rare vascular disease, the recently described arterial calcification due to deficiency of CD73 (ACDC). Baral and Hussaini and colleagues from the National Heart, Lung, and Blood Institute of the National Institutes of Health present CT images from two patients with ACDC with progressive upper and lower-extremity calcifications over time. ⁷ These images demonstrate the extensive vascular and extra-vascular calcification that has been reported in these patients and provides a perfect segue to a report of a pilot, open-label, clinical trial of the bisphosphonate etidronate, led by investigators at the same institution. ⁸ Though this study only enrolled seven patients with a genetically confirmed diagnosis of ACDC, it did demonstrate safety of the study drug and a potential signal in terms of stabilizing peripheral vascular calcium deposition with treatment, providing data to inform future treatment trials. ⁸

Buso and colleagues report on patients seen at their rare vascular disease referral center with a genetically confirmed diagnosis of vascular Ehlers–Danlos syndrome (vEDS), a most aggressive arteriopathy associated with aortic and arterial aneurysm, dissection, and rupture. ⁹ Their analysis focuses on outcomes among patients treated with celiprolol, dosed up to 400 mg daily, over an average follow-up of approximately 6 years. In this series of patients, 20 of whom had longitudinal follow-up, they reported high adherence to celiprolol but, unfortunately, a high incidence of new vascular events during follow-up in 60% of patients (12/20), with an estimated yearly risk of symptomatic vascular events of 8.8%. ⁹ The authors were unable to identify clinical features associated with the higher risk of vascular events, though the study was likely underpowered to do so. This study provides a reminder of the high vascular risk associated with vEDS, even among those treated with the best current medical therapy (though celiprolol is not currently available in the United States), and reminds us of the need for vigilance in managing these patients.

From a diagnostic perspective, Goudot and colleagues studied the use of a highly advanced ultrasound imaging technique with microbubble contrast (ultrasound localization microscopy) to assess disease activity among patients with Takayasu arteritis. ¹⁰ They report on visualization of complex vasa vasorum networks in the carotid wall among patients with active disease, including vasa vasorum interna, which are small vessels that communicate with the artery lumen. ¹⁰

Beyond diagnostics and medical therapy, this issue includes both endovascular and surgical management of rare vascular diseases. Bobadilla-Rosado and colleagues report on their center’s evolving surgical technique for the management of carotid body tumors. ¹¹ Sharifi and colleagues share their center’s experience with endovascular therapy for 10 patients with external iliac artery endofibrosis, a rare nonatherosclerotic cause of claudication. ¹² Additional research articles and letters provide new insights on spontaneous coronary artery dissection (SCAD), superior mesenteric artery dissection, and FMD. The issue rounds out with a series of Images in Vascular Medicine providing classic and atypical examples of several other rare vascular diseases, a patient information page on popliteal artery aneurysm, and a Society for Vascular Medicine ‘blue page’ on how to support patients with aortic disease.^13,14

If you are a vascular clinician or investigator, I hope you are able to download a few of the articles in this year’s focused issue of Vascular Medicine and expand your knowledge of one or multiple rare vascular diseases and perhaps be prepared for the next patient to walk through your clinic door. If you are a patient struggling with a rare vascular disease, I applaud your search for knowledge and answers, and although this collection of articles only represents a minute fraction of the work that needs to be done in the field of rare vascular diseases . . . and may not include an article on YOUR disease . . . I do hope you know there is a community of clinicians and researchers worldwide who see you and all of the beautiful vascular zebras. And this community is working hard on finding more answers and cures.