ReviewTwo faces of the same coin: Raynaud phenomenon and digital ulcers in systemic sclerosis
Introduction
Systemic sclerosis (SSc) is a severe multiorgan disease characterized by wide-spread fibrosis, activation of immune system with production of autoantibodies and extensive vascular damage [1]. The vascular involvement is clinically evident with Raynaud's phenomenon (RP) and digital ulcers (DU) that represent two faces of the same coin.
In SSc, microvessels, endothelial cell injury in microvessels and in small and medium arteries [2], [3] may be triggered by vasculotropic viruses, inflammatory cytokines, granzymes, endothelial cell-specific autoantibodies or elevated levels of reactive oxygen species due to oxidative stress [4]. Vascular injury leads to structural changes, loss of capillaries (well demonstrated with nailfold capillaroscopy [5]), remodelling of the vessel wall with intimal and median layers hyperplasia and adventitial fibrosis resulting in progressive luminal narrowing and eventually occlusion. This proliferative intimal vasculopathy is mediated by molecules that regulate mainly cell apoptosis, proliferation and vasoconstriction including an increase production of endothelin (ET), a reduction of prostacyclin release and a reduced production of nitric oxide synthase. Moreover, there is an overexpression of adhesion molecules (E-selectin, P-selectin, VCAM-1, ICAM-1) [6]. The loss of capillaries in SSc is not compensated because of defective angiogenesis and vasculogenesis [7], [8].
Section snippets
First face: Raynaud's phenomenon
The earliest manifestation of the vascular involvement is RP, the clinical expression of SSc in the acral parts characterized by episodic colour changes of the digits that classically turn white (ischemia), then blue (cyanosis) and red (reperfusion). RP is essentially due to an excessive vasospasm of digital arteries, precapillary arterioles and cutaneous arteriovenous shunts, usually in response to cold exposure or other stimuli resulting in impaired oxygenation of the distal extremities.
Second face: digital ulcers
DU are a frequent complication that affects almost half of the SSc patients, and about 75% of the affected patients have their first DU episode within 5 years from their first non-Raynaud symptom [11], [12]. DU are persistent, difficult to heal and extremely painful, can cause tissue loss, autoamputation and impaired hand function, heavily impairing quality of life [13]. Moreover, DU are frequently infected and, if not treated early, may lead eventually to osteomyelitis, gangrene and
The management
Currently, there are several pharmacological therapies for the treatment and prevention for both RP and DU, including calcium channel blockers, antiplatelet and anticoagulant therapies, endothelin receptor antagonist, phosphodiesterase inhibitors and statins.
In Europe, although the high impact on patients’ quality of life, there are no guidelines for the therapy of DU and only iloprost was approved for severe RP.
The management of DU include non pharmacological therapy, with the avoidance of all
Conclusion
Currently, the treatment of RP and DU represents a great challenge for all physicians. First, we must recognize that both RP and DU are a sign of the result of underlying different processes. Second, vascular injury is itself a complex process mediated by many factors that can, in different ways, contribute to the dysregulation of the vascular tone and of the repair and regeneration processes. Thus, vascular structure and function are involved in SSc and both play a key role in the mechanism of
Take-home messages
- •
The vascular involvement is clinically evident with Raynaud's phenomenon and digital ulcers that represent two faces of the same coin in SSc.
- •
Secondary RP has a severe course in SSc and is frequently associated with DU and tissue necrosis.
- •
DUs are a frequent and extremely painful complication heavily affecting patient's quality of life.
- •
The aetiology of DU is multifactorial and may differ depending on the DU localization.
- •
The management of DU includes non-pharmacological therapy with the avoidance
References (40)
- et al.
Vascular complications of scleroderma
Autoimmun Rev
(2007) - et al.
Digital ulcers in patients with systemic sclerosis
Autoimmun Rev
(2006) - et al.
A pilot trial of treprostinil for the treatment and prevention of digital ulcers in patients with systemic sclerosis
J Am Acad Dermatol
(2006) - et al.
Botulinum toxin type A: a treatment option for digital ischemia in patients with Raynaud's phenomenon
J Hand Surg Am
(2009) - et al.
Arteriographic evaluation of vascular changes of the extremities in patients with systemic sclerosis
Br J Dermatol
(2006) - et al.
The pathogenesis of systemic sclerosis revisited
Clin Rev Allergy Immunol
(Jan 20 2010) Vascular involvement in systemic sclerosis
Clin Exp Rheumatol
(2004)- et al.
Raynaud's phenomenon and the role of capillaroscopy
Arthritis Rheum
(2003) - et al.
Overview of pathogenesis of systemic sclerosis
- et al.
Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis
Arthritis Rheum
(2000)
Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers
Arthritis Res
Raynaud's phenomenon: a proposal for classification
Clin Exp Rheumatol
Pathogenesis of Raynaud's phenomenon
Rheumatology
Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study
J Rheumatol
Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database
Ann Rheum Dis
Impact of digital ulcers on disability and health-related quality of life in systemic sclerosis
Ann Rheum Dis
Scleroderma: a treatable disease
Cleve Clin J Med
Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis
Ann Rheum Dis
Digital ulceration and critical digital ischemia in scleroderma
Scleroderma Care Res
Cited by (42)
Human mesenchymal stem cells for the management of systemic sclerosis. Systematic review
2021, Autoimmunity ReviewsDigital Ulcers in Systemic Sclerosis
2021, Presse MedicaleControlling the digital ulcerative disease in systemic sclerosis is associated with improved hand function
2017, Seminars in Arthritis and RheumatismCitation Excerpt :As vascular damage progresses, reduced perfusion of the skin and visceral microvascular beds leads to a state of chronic ischemia favoring fibroblast activation and extracellular matrix synthesis. Raynaud’s phenomenon and digital ulcers (DUs) are typical manifestations of the underlying vasculopathy that characterizes SSc [3]. About 44–60% of patients with SSc experience one or more digital ulcers (DU) at some point in their disease course [4–8].
Raynaud phenomenon
2016, Reviews in Vascular MedicineManagement of Systemic Sclerosis-Related Skin Disease: A Review of Existing and Experimental Therapeutic Approaches
2015, Rheumatic Disease Clinics of North AmericaCitation Excerpt :Selective serotonin reuptake inhibitor, such as fluoxetine,70 and While the etiology of ischemic ulcerations is multifactorial and often depends on the ulcer location, DU are in part attributable to persistent vasospasm from RP, plus an underlying vasculopathy associated with SSc.72,73 In addition to avoiding precipitating factors, bosentan may reduce the number of new ulcerations, especially in patients with an increased number of ulcers.74
Therapeutic hypothermia after cardiac arrest in a patient with systemic sclerosis and raynaud phenomenon
2015, ChestCitation Excerpt :However, even in healthy subjects, mild accidental hypothermia is associated with an increased risk of local cold injuries.6 Digital ulcers may be attributable to underlying vasculopathy from SSc, as well as persistent vasospasm associated with RP.7 Intraluminal platelet activation with clot formation and thromboxane release has been proposed as another mechanism for digital ulcers in patients with SSc and RP, who are believed to have underlying endothelial dysfunction.8, 9