Two faces of the same coin: Raynaud phenomenon and digital ulcers in systemic sclerosis

doi:10.1016/j.autrev.2010.09.008

Autoimmunity Reviews

Volume 10, Issue 5, March 2011, Pages 241-243

https://doi.org/10.1016/j.autrev.2010.09.008 Get rights and content

Abstract

Systemic sclerosis (SSc) is characterized by wide-spread fibrosis, activation of immune system with production of autoantibodies and extensive vascular damage. Raynaud's phenomenon (RP) and digital ulcers (DU) represent two faces of the same coin in SSc vasculopathy. RP, the earliest manifestation of the vascular involvement, is due to an excessive vasospasm of digital arteries, precapillary arterioles and cutaneous arteriovenous shunts, usually in response to cold exposure or other stimuli. DU are a severe complication of microvessel involvement and also of the persistent vasospasm of RP. Thus, the management of RP and DU requires a multimodal approach using a combination of pharmacological, non-pharmacological, and surgical treatments. Currently, the treatment of these complications represents a great challenge for all physicians.

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

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Digital ulcers (DU) are one of the most common complication of Systemic Sclerosis (SSc)-related vasculopathy and represent an important burden for the patients as well as for the society. Still today there is no agreement on the definition, classification and cathegorization of DU even if they are of pivotal importance in clinical practice, for treatment choice and prognostic outcomes, as well as for clinical trials. DU management requires a dedicated multidisciplinary team, that must remain ever vigilant for the development of infective complications and gangrene throughout their disease course, as well as patient education that is crucial to obtain the best compliance to assure the success of the treatment. Currently several drugs are available for DU treatment but in the future, more investigations will be needed to ameliorate the approach and the systemic and local therapies.
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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].
Ischemic digital ulcers (DU) represent a major complication of systemic sclerosis (SSc). We investigated the impact of controlling the ulcerative disease on disability, pain, and quality of life in SSc patients receiving bosentan.
ECLIPSE (Study AC-052-517) is a 2-year prospective, multicenter, and observational study. Patients with SSc who experienced at least 1 DU in the previous year and received bosentan were included between October 2009 and March 2011. Disability scores [Cochin Hand Function Scale (CHFS) and Health Assessment Questionnaire Disability Index (HAQ-DI)], pain scores (visual analog scale), and quality-of-life scores (SF-36) were collected at inclusion and 1 year later (primary endpoint). A controlled ulcerative disease was defined by the absence of ongoing/new DU episode between inclusion and 1-year follow-up.
Data were available at 1 year for 120 patients out of 190 included. During follow-up, 46 (38.3%) patients experienced a new DU episode. The number of DU per patient decreased from 1.4 ± 1.8 at inclusion to 0.6 ± 1.6 (p < 0.0001) at 1 year. Disability scores decreased from 1.0 ± 0.7 to 0.9 ± 0.7 (p = 0.04) for the HAQ-DI and from 29 ± 20 to 25 ± 20 (p = 0.005) for the CHFS; the pain score decreased from 4.3 ± 3.1 to 2.9 ± 2.8 (p < 0.0001).
This improvement was attributed to patients with a controlled ulcerative disease (48.3%), who significantly improved HAQ-DI (p = 0.04), CHFS (p = 0.04), and pain score (p = 0.046).
In patients with SSc, control of the ulcerative disease for 1 year was associated with significant attenuation of hand disability.
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Raynaud's phenomenon is a common clinical disorder characterized by recurrent vasospasm episodes of digital arteries, arterioles, pre-capillary and post-capillary venules triggered by exposure to cold or emotional stress. RP can be classified as primary (idiopathic), or secondary to several diseases or conditions. The pathogenesis of RP is still not entirely clear or understood, but recent insights into the pathogenic mechanisms underlying Raynaud's phenomenon include vascular, neuronal and intravascular abnormalities which may identify crucial key points and potential targets for therapeutic intervention.
In this review we summarize the epidemiology, pathogenesis, clinical manifestations and assessments as well as the recent advances in therapeutic approaches.
An extensive review of recent literature was conducted, according to the guidelines proposed at the PRISMA statement. MEDLINE database (PubMed) and Thomson Reuters Web of Knowledge platform were searched for articles published in peer-reviewed journals and published in English language. The keyword search terms included: Raynaud phenomenon, epidemiology, pathogenesis, thermoregulation, endothelium dysfunction, risk factors, clinical features, nailfold videocapillaroscopy and treatment.
Inclusion criteria were: (1) Randomized controlled trials (2) Reviews, systematic reviews and meta-analysis of randomized controlled trials (3) English language. Studies lacking clinical end points of relief, case reports and open label trials were excluded.
Management of Systemic Sclerosis-Related Skin Disease: A Review of Existing and Experimental Therapeutic Approaches
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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
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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
Therapeutic hypothermia favorably impacts neurologic outcomes in patients after cardiopulmonary arrest, although the appropriate target temperature is less clear. Its safety profile in patients with systemic sclerosis (SSc) and Raynaud phenomenon (RP), who may be at increased risk for ischemic complications, has not been addressed in the literature, to our knowledge. Digital lesions are commonly seen in patients with SSc, and cold-induced myocardial ischemia has also been reported. We describe a case of a man with SSc, RP, and digital ulcers who underwent therapeutic hypothermia after cardiopulmonary arrest. He regained full neurologic function, and except for digital necrosis, no hypothermia-associated adverse events were observed. Other risk factors for ischemia, such as cocaine use, may have contributed to the development of the digital necrosis. However, clinicians should be aware of the risk for ischemic complications in patients with SSc and RP when considering the appropriate target temperature after cardiopulmonary arrest.

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ReviewTwo faces of the same coin: Raynaud phenomenon and digital ulcers in systemic sclerosis

Abstract

Introduction

Section snippets

First face: Raynaud's phenomenon

Second face: digital ulcers

The management

Conclusion

Take-home messages

Autoimmun Rev

Autoimmun Rev

J Am Acad Dermatol

J Hand Surg Am

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

Br J Dermatol

The pathogenesis of systemic sclerosis revisited

Clin Rev Allergy Immunol

Vascular involvement in systemic sclerosis

Clin Exp Rheumatol

Raynaud's phenomenon and the role of capillaroscopy

Arthritis Rheum

Overview of pathogenesis of systemic sclerosis

Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis

Arthritis Rheum

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

Review
Two faces of the same coin: Raynaud phenomenon and digital ulcers in systemic sclerosis