Diagnosis and Management of Scleroderma Peripheral Vascular Disease

doi:10.1016/j.rdc.2007.11.006

Rheumatic Disease Clinics of North America

Volume 34, Issue 1, February 2008, Pages 89-114

https://doi.org/10.1016/j.rdc.2007.11.006 Get rights and content

The manifestations of peripheral vascular disease in patients who have systemic sclerosis (SSc) range from episodic Raynaud's phenomenon to irreversible tissue injury with ulceration and gangrene. Structural and functional changes may occur in the microvessels, digital arteries, and sometimes more proximal vessels. This article discusses the assessment of patients who have Raynaud's phenomenon in whom an underlying scleroderma-spectrum disorder is suspected and patients who have SSc with critical digital ischemia/ulceration. Different imaging techniques, including capillaroscopy and angiography, complement the history and examination, and developments in vascular imaging should facilitate future studies of pathogenesis and treatment response. New vasoactive treatments are currently being researched and older treatments revisited; therefore new approaches to therapy will likely be developed over the next 5 to 10 years.

Section snippets

Microvascular versus macrovascular disease

Vascular abnormalities have long been recognized as being central to the pathogenesis of SSc, and SSc has been suggested to be primarily a vascular disease [4], [5]. Both structural and functional changes occur, which interrelate [6]. Structural changes affect digital microcirculation (well demonstrated with nailfold capillaroscopy) (Fig. 1) and the digital arteries, in which the most characteristic histologic lesion is marked intimal hyperplasia/fibrosis (Fig. 2) [7].

Although involvement of

Diagnosis

Two aspects of the approach to diagnosis are considered: (1) diagnosis of an underlying scleroderma-spectrum disorder in patients who present with Raynaud's phenomenon/digital ischemia and (2) diagnosis/assessment of severe digital ischemia/ulceration in patients who have an established diagnosis of SSc. Although the main contributor to disease pathogenesis is a noninflammatory microangiopathy in most patients who have SSc-related peripheral vascular disease, other possibilities should always

Imaging of peripheral vascular disease

Different imaging modalities are complementary because they examine different aspects of vascular structure and function. Those selected for further discussion are relevant to the rheumatologist because they inform management or are important research tools. These modalities include (1) nailfold capillaroscopy, which assesses microvascular structure; (2) thermography, which gives an indirect assessment of small and large vessel function; (3) conventional (radiographic), MRI, and CT angiography,

Management

The first principle of management is to establish the diagnosis. Raynaud's phenomenon in the patient who has SSc is almost invariably part of the disease process (vasospasm against the background of a noninflammatory microangiopathy), but in the context of severe/critical peripheral ischemia, other possibilities should be considered, especially proximal vessel disease but also vasculitis or a coagulopathy. Although this section provides a broad overview of management, it will emphasize recent

Summary

Diagnosis and management of peripheral vascular disease in patients who have SSc present different challenges according to the clinical context. In patients presenting with Raynaud's phenomenon, whether an underlying scleroderma-spectrum disorder exists must be established. If not, the patient can be reassured, but if so, the patient is likely to require long-term follow-up. In patients who have SSc and severe/critical ischemia, treatable contributory causes, especially proximal vessel disease,

Acknowledgment

I am grateful to Dr. Charles Hutchinson for the radiology images.

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Cited by (57)

Photoacoustic Oxygenation Quantification in Patients with Raynaud's: First-in-Human Results
2018, Ultrasound in Medicine and Biology
Citation Excerpt :
RP is almost a universal finding in patients with scleroderma and is driven by endothelial dysfunction, intimal fibro-proliferation and vessel lumen occlusion (Maricq et al. 1996). It is present in more than 90% of patients with scleroderma (Herrick 2008; Maricq et al. 1996). RP can be seriously disabling, leading to digital ulcers, finger necrosis and amputation or associated complications, such as infection and osteomyelitis.
The purpose of this study was to investigate the use of photoacoustic imaging for quantifying fingertip oxygenation as an approach to diagnosing and monitoring Raynaud's phenomenon. After 30 min of acclimation to room temperature, 22 patients (7 patients with secondary Raynaud's associated to Scleroderma and 15 healthy controls) provided informed consent to undergo fingertip Doppler imaging and high-frequency photoacoustic imaging before and 5, 15 and 30 min after cold stimulus (submerged hand in a 15 °C water bath for 1 min). High-frequency ultrasound and photoacoustic imaging was performed on the nail bed of each patient's second through fifth finger on their dominant hand, using a Vevo 2100 LAZR system with an LZ-250 probe (Fujifilm VisualSonics, Toronto, ON, Canada) in oxy-hemoglobin quantification mode. During each exam, volumetric data across a 3-mm span of data was acquired to produce a volumetric image of percent oxygenation and hemoglobin concentration. Changes in fingertip oxygenation between Raynaud's patients and healthy volunteers were compared, using receiver operator characteristic (ROC) analysis. Photoacoustic signal was detected in both the nail bed and nailfold in all study participants. Doppler ultrasound resulted in poor differentiation of Raynaud's patients from healthy volunteers, with an area under the ROC curve (A_z) of 0.51. Photoacoustic imaging demonstrated improved accuracy at baseline (A_z = 0.72), which improved when quantifying normalized changes after cold stimulus (A_z = 0.89 5-min post stimulus, A_z = 0.91 15-min post stimulus, and A_z = 0.85 after stimulus). Oxygenation levels derived using photoacoustic imaging are able to identify patients with Raynaud's and safely evaluate their response to a cold stimulus over time.
Plasma endothelial microparticles reflect the extent of capillaroscopic alterations and correlate with the severity of skin involvement in systemic sclerosis
2017, Microvascular Research
Citation Excerpt :
However, the pathogenesis of SSc-related microangiopathy is not well understood and reliable assessment of endothelial state in vivo in SSc patients still remains a challenge. In fact, neither molecule among commonly used soluble markers (e.g. sICAM-1, sVCAM-1, sE-selectin, von Willebrand factor) is derived specifically from dysfunctional endothelium and cannot distinguish between endothelial damage and activation (Blann et al., 2005; Herrick, 2008; Kahaleh et al., 2003; McHugh et al., 2003). In the last decade, endothelial microparticles (EMPs) have emerged as a new useful marker of ECs status in vascular diseases (Horstman et al., 2004a, 2004b).
Endothelial microparticles (EMPs) are membrane-coated vesicles shed from endothelial cells and are considered markers of the endothelial state. It has been shown that total numbers of circulating EMPs are increased in patients with systemic sclerosis (SSc), but their clinical correlations have not yet been investigated in detail. We aimed to assess possible relationships between circulating EMPs and clinical as well as laboratory features among SSc patients with special attention to possible association with alteration in microvascular morphology objectified on nailfold videocapillaroscopy and clinical signs of microvascular complications.
The study included 47 SSc patients and 27 age- and sex-matched healthy controls. EMPs were identified with flow cytometry after staining platelet-poor plasma with combinations of fluorescent cell-specific monoclonal antibodies (anti-CD31, -51, -42b, -62E and Annexin V). The following types of EMPs were evaluated: total EMPs (CD31 +/CD42b −), activated EMPs (CD62E +/AnnV −,) and apoptotic EMPs (CD62E +/AnnV + or CD51 +). Clinical evaluation of patients was obtained, including nailfold videocapillaroscopy.
All types of EMPs were significantly elevated in SSc patients as compared with healthy controls. We found significant inverse correlation between severity of skin involvement and values of total EMPs (r = − 0.32; p = 0.02) and their levels tended to be lower in SSc patients with digital ulcers when compared to those without ischaemic skin lesions (p = 0.09). Total EMPs and activated EMPs showed correlations with the number of ramified capillaries (r = − 0.40 and r = 0.37, respectively, p < 0.05 for both). Moreover, total EMPs inversely correlated with the severity of capillary loss (r = − 0.35, p < 0.05) and their levels were significantly lower in patients with late NVC pattern with respect to those with early microangiopathy (p < 0.05). On the other hand, active NVC pattern was characterized by strongly elevated levels of activated EMPs when compared to an early vascular alteration (p < 0.05).
Our results suggest that quantity and phenotype of circulating EMPs might indicate on molecular vascular damage with endothelial dysfunction and to reflect progressive loss of capillaries consequencing in microvascular insufficiency in SSc patients.
Differential diagnosis of critical digital ischemia in systemic sclerosis: Report of five cases and review of the literature
2016, Seminars in Arthritis and Rheumatism
Critical digital ischemia is a rare, but serious complication of systemic sclerosis (SSc) and is not always due solely to the non-inflammatory angiopathy that characterizes the SSc disease process. Our objective was to illustrate the range of presentations and causes of critical digital ischemia in patients with SSc in order to highlight how optimal management is dependent upon establishing the correct diagnosis.
Five cases exemplifying differential diagnoses were identified and their case notes reviewed in order to extract clinically relevant data and images. A review of the literature was performed in PubMed in English.
Causes of critical digital ischemia included typical micro-angiopathic changes and proximal (large vessel) disease. One case highlighted the difficulty of ascertaining whether an inflammatory cause is also present in SSc/SLE overlap syndrome. Two cases demonstrated embolic causes (thromboembolism due to atrial fibrillation and septic emboli).
Critical digital ischemia in patients with SSc requires thorough investigation in order to avoid missing additional potentially modifiable causes including large vessel disease, inflammation, embolism, infection, and paraneoplastic syndromes. A firm evidence base for current medical and surgical interventions is lacking, highlighting the need for further research into the optimum management of this rare, but painful, debilitating, and limb-threatening complication of SSc.
Macrovascular complications of systemic sclerosis: Prospective descriptive Doppler ultrasound study in 20 patients
2016, Journal des Maladies Vasculaires
La sclérodermie systémique est caractérisée par une sclérose cutanée, une atteinte vasculaire et une dysfonction immunologique. La prévalence de l’atteinte macrovasculaire reste controversée.
Il s’agit d’une étude descriptive prospective monocentrique réalisée dans le service de médecine vasculaire du CHU de Bordeaux du 1^er juillet au 1^er septembre 2015. L’ensemble des patients sclérodermiques hospitalisés dans le service était inclus. Chaque patient a bénéficié d’un échodoppler des troncs supra-aortiques, des artères des membres supérieurs, des artères digitales, de l’aorte et des artères des membres inférieurs. L’objectif de notre étude est de décrire la présence et la localisation des lésions artérielles chez les patients sclérodermiques.
Sur les vingt patients inclus, il y avait 13 femmes et 7 hommes, la moyenne d’âge était de 58 ± 16 ans. Au total, 16 patients (80 %) avaient un épaississement pariétal, 10 (50 %) des plaques calcifiées, 3 (15 %) des sténoses hémodynamiquement significatives et 12 (60 %) des occlusions artérielles. L’indice de pression systolique (IPS) moyen était de 0,98 ± 0,16 à droite et 0,99 ± 0,21 à gauche. Deux patients avaient des IPS inférieurs à 0,8. La pression artérielle systolique brachiale moyenne était de 113 ± 14 mmHg. Les données de la cartographie artérielle (860 sites artériels) ont trouvé 93 artères présentant un épaississement pariétal (10 %), 47 des plaques calcifiées (5 %), 7 sténoses hémodynamiquement significatives et 22 occlusions. Les occlusions artérielles étaient localisées au niveau des artères ulnaires (n = 2), des artères digitales (n = 18), de l’artère tibiale postérieure (n = 1) et de l’artère pédieuse (n = 1).
Les données de notre étude sont corrélées avec l’atteinte macrovasculaire décrite dans la littérature. Cette constatation permet de poser deux questions. Comment intégrer cette notion avec la sévérité du phénomène de Raynaud, le risque d’ulcères digitaux et les variations du paysage capillaroscopique des patients au cours du suivi ? Quelle est la cause de ces anomalies vasculaires, dont certaines sont très différentes de ce que l’on observe dans l’athérosclérose ?
Systemic sclerosis is characterized by cutaneous sclerosis, vascular disease and immunological dysfunction. The prevalence of macrovascular disease remains controversial.
This was a descriptive prospective single-center study conducted in the vascular medicine department of the University Hospital of Bordeaux from July 1 to September 1, 2015. All inpatients followed for systemic scleroderma were included. Each patient had a Doppler ultrasound of the supra-aortic, upper and lower limb, and digital arteries as well as the aorta. The main objective of the study was to describe the presence and location of arterial lesions in patients with systemic sclerosis.
Of the twenty patients included, there were 13 women and 7 men; mean age was 58 ± 16 years. Patients exhibited wall thickening (n = 16, 80%), calcified plaques (n = 10, 50%), hemodynamically significant stenoses (n = 3, 15%) and arterial occlusions (n = 12, 60%). Ankle brachial pressure index (ABPI) was 0.98 ± 0.16 on the right and 0.99 ± 0.21 on the left. Two patients had ABPI < 0.8. The mean brachial systolic blood pressure was 113 ± 14 mmHg. Arterial mapping (860 arterial sites) found wall thickening (n = 93 arteries, 10%), calcified plaques (n = 47, 5%), hemodynamically significant stenoses (n = 7) and occlusions (n = 22). Arterial occlusions were located in the ulnar arteries (n = 2), the digital arteries (n = 18), the posterior tibial artery (n = 1) and the dorsalis pedis artery (n = 1).
The data of our study correlate with macrovascular disease described in the literature. This finding raises two questions: how does this concept integrate with the severity of Raynaud's phenomenon and the risk of digital ulcers and changes in patients’ capillaroscopic landscape during follow-up? What is the cause of these vascular anomalies, some of which are very different from what is observed in atherosclerosis?
Correlations between skin blood perfusion values and nailfold capillaroscopy scores in systemic sclerosis patients
2016, Microvascular Research
Citation Excerpt :
Systemic sclerosis (SSc) is characterized by early impairment of the microvascular system and decreased peripheral blood perfusion together with progressive tissue fibrosis (Cutolo et al., 2010a,b; Herrick, 2008; Rosato et al., 2011).
To correlate blood perfusion (BP) values assessed by laser speckle contrast analysis (LASCA) in selected skin areas of hands and face with nailfold capillary damage scores in systemic sclerosis (SSc) patients.
Seventy SSc patients (mean SSc duration 6 ± 5 years) and 70 volunteer healthy subjects were enrolled after informed consent. LASCA was performed at different areas of the face (forehead, tip of nose, zygomas and perioral region) and at dorsal and volar regions of hands. Microvascular damage was assessed and scored by nailfold videocapillaroscopy (NVC) and the microangiopathy evolution score (MES) was calculated.
SSc patients showed a significantly lower BP than healthy subjects at fingertips, periungual areas and palm of hands (p < 0.0001), but not at the level of face and dorsum of hands. A gradual decrease of BP at fingertips, periungual and palm areas, was found in SSc patients with progressive severity of NVC patterns of microangiopathy (“early”, “active”, or “late”) (p < 0.01). A negative correlation was observed between MES and BP values, as well as between loss of capillaries and BP, at the same areas (p < 0.001 and p < 0.01, respectively). Patients with diffuse cutaneous SSc (dcSSc) showed lower BP than those with limited cutaneous SSc (p < 0.04).
LASCA detects a significant reduction of BP only in those areas usually affected by Raynaud's phenomenon (fingertips, periungual and palm areas), especially in dcSSc patients, and BP values significantly correlate with the nailfold capillaroscopy scores of microangiopathy.
Botulinum toxin for the treatment of chronic pain. Review of the evidence
2014, Revista Colombiana de Anestesiologia
El dolor crónico es una de las principales causas de consulta médica, produce limitación funcional, altera el estado del ánimo y disminuye el rendimiento laboral. En muchas ocasiones es de difícil manejo y pobre respuesta a terapias farmacológicas, generando un reto para el equipo interdisciplinario que trata esta enfermedad. Cada día se investigan más métodos enfocados a aliviar el dolor, entre ellos la aplicación de sustancias como la toxina botulínica en los puntos dolorosos.
Realizar una revisión narrativa no sistemática sobre la evidencia científica disponible acerca del uso de la toxina botulínica en el tratamiento del dolor crónico.
Se realizó una búsqueda en la base de datos PUBMED, que incluyó artículos de metaanálisis, revisiones sistemáticas, revisiones de Cochrane, ensayos clínicos, revisiones narrativas y series de casos, entre 1997 y 2013, para la realización de una revisión narrativa no sistemática.
Se tuvieron en cuenta un total de 66 artículos para la realización de la actualización en el tema propuesto.
La toxina botulínica presenta propiedades que posiblemente puedan tener algún beneficio en el área del dolor crónico. Sin embargo, no existe suficiente evidencia que soporte su uso en la mayoría de sus indicaciones en este grupo de pacientes. Se requieren más estudios para recomendar su uso. La guía ultrasonográfica es considerada una herramienta útil en su aplicación.
Chronic pain is one of the primary reasons why people seek medical help. It produces functional limitation, affects mood, and impairs job performance. Many times it is difficult to manage and responds poorly to pharmacological therapies, posing a challenge for the multidisciplinary team in charge of treating this disorder. A number of approaches to relieve pain are the subject of growing research, including the application of agents such as botulinum toxin on painful points.
To carry out a non-systematic narrative review of the scientific evidence available on the use of botulinum toxin for the treatment of chronic pain.
A search was conducted in the PUBMED database, including meta-analyses, systematic reviews, Cochrane reviews, clinical trials, narrative reviews and case series, published between 1997 and 2013, in order to carry out a non-systematic narrative review.
Overall, 66 articles were considered for an update on the proposed topic.
Botulinum toxin has certain properties that might have a beneficial effect on chronic pain. However, there is not sufficient evidence supporting its use in the majority of indications in this group of patients. Additional studies are required to recommend its use. Ultrasound is considered a useful tool to guide its application.

View all citing articles on Scopus

: Dr. Herrick has consulted for and spoken at meetings sponsored by Actelion Pharmaceuticals Ltd.

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Diagnosis and Management of Scleroderma Peripheral Vascular Disease

Section snippets

Microvascular versus macrovascular disease

Diagnosis

Imaging of peripheral vascular disease

Management

Summary

Acknowledgment

Semin Arthritis Rheum

Rheum Dis Clin North Am

Am J Med

Rheum Dis Clin North Am

Semin Arthritis Rheum

J Dermatol Sci

Microvasc Res

Eur J Vasc Surg

Microvasc Res

Rheum Dis Clin North Am

Am J Med

Am J Med

Am Heart J

Lancet

Lancet

Raynaud's phenomenon: a proposal for classification

Clin Exp Rheumatol

Preliminary criteria for the classification of systemic sclerosis (scleroderma)

Arthritis Rheum

Pathogenesis of Raynaud's phenomenon

Rheumatology

Vascular function in systemic sclerosis

Curr Opin Rheumatol

Morphological changes in the digital arteries of patients with progressive systemic sclerosis (scleroderma) and Raynaud phenomenon

Medicine

Increased prevalence of symptomatic macrovascular disease in systemic sclerosis

Ann Rheum Dis

Macrovascular disease and systemic sclerosis

Ann Rheum Dis

Limited scleroderma is associated with increased prevalence of macrovascular disease

J Rheumatol

Ankle brachial pressure index in systemic sclerosis: influence of disease subtype and anticentromere antibody

Rheumatology

Angiotensin-converting enzyme I/D polymorphism and macrovascular disease in systemic sclerosis

Rheumatology

Arteriographic evaluation of vascular changes of the extremities in patients with systemic sclerosis

Br J Dermatol

Digital arteries in patients with scleroderma: arteriographic and plethysmographic study

Arch Intern Med

Arteries of the hand in patients with scleroderma

Diagn Imaging Clin Med

Macroangiopathy of the upper extremities in progressive systemic sclerosis

Eur J Med Res

Distribution of macrovascular disease in scleroderma

Ann Rheum Dis

Ulnar artery involvement in systemic sclerosis (scleroderma)

J Rheumatol

Vasculitis in systemic sclerosis: association with Sjögren's syndrome and the CREST syndrome

J Rheumatol

Giant cell arteritis in a patient with limited cutaneous systemic sclerosis

Rheumatology

Large vessel arterial thrombosis in systemic sclerosis associated with antiphospholipid antibodies

J Rheumatol

Validity and reliability of three methods used in the diagnosis of Raynaud's phenomenon

Br J Rheumatol

Diagnosis of Raynaud's phenomenon assisted by color charts

J Rheumatol

Outcomes in primary Raynaud phenomenon. A meta-analysis of the frequency, rates, and predictors of transition to secondary diseases

Arch Intern Med

Intermittent claudication

N Engl J Med

Anticentromere antibody as a predictor of digital ischemic loss in patients with systemic sclerosis

Arthritis Rheum

Anticardiolipin, anticentromere and anti-Scl-70 antibodies in patients with systemic sclerosis and severe digital ischaemia

Ann Rheum Dis

Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon

Arthritis Rheum

A disease severity scale for systemic sclerosis: development and testing

J Rheumatol

Quantifying digital vascular disease in patients with primary Raynaud's phenomenon and systemic sclerosis

Ann Rheum Dis

Raynaud phenomenon and finger systolic pressure during cooling