Elsevier

Autoimmunity Reviews

Volume 13, Issue 6, June 2014, Pages 655-667
Autoimmunity Reviews

Review
Raynaud's phenomenon: From molecular pathogenesis to therapy

https://doi.org/10.1016/j.autrev.2013.12.001Get rights and content

Abstract

Raynaud's phenomenon (RP) is a well defined clinical syndrome characterized by recurrent episodes of digital vasospasm triggered by exposure to physical/chemical or emotional stress. RP has been classified as primary or secondary, depending on whether it occurs as an isolated condition (pRP) or is associated to an underlying disease, mainly a connective tissue disease (CTD-RP). In both cases, it manifests with unique “triple” (pallor, cyanosis and erythema), or “double” color changes. pRP is usually a benign condition, while sRP can evolve and be complicated by acral digital ulcers and gangrene, which may require surgical treatment. The pathogenesis of RP has not yet been entirely clarified, nor is it known whether autoantibodies have a role in RP. Even so, recent advances in our understanding of the pathophysiology have highlighted novel potential therapeutic targets. The aim of this review is to discuss the etiology, epidemiology, risk factors, clinical manifestations, recently disclosed pathogenic mechanisms underlying RP and their correlation with the available therapeutic options, focusing primarily on pRP and CTD-RP.

Introduction

Raynaud's phenomenon (RP) is a vascular acro-syndrome characterized by recurrent, reversible episodes of vasospasm, involving peripheral small vessels (arteries, arterioles, pre-capillary and post-capillary venules). They are triggered by exposure to physical [1], chemical [2] and/or emotional stress [3], [4]. RP is classified as primary RP (pRP) when it occurs as an isolated condition, accounting for 80% of cases [5], and secondary RP (sRP) if it is associated to other diseases, mainly connective tissue diseases (CTD) (CTD-RP). RP may also occur in other non CTD (Table 1). While in pRP no structural changes, or only minimal alterations of the vessel walls occur [5], in sRP (especially in CTD-RP) the vasospasm is more sustained, long-lasting and highly recurrent, and is associated with structural alterations of the vessel walls mainly due to the underlying CTD [6]. The clinical severity of RP varies greatly, ranging from a simple but uncomfortable condition to severe symptoms that seriously affect the patient's quality of life [6].

Although 150 years have passed since the identification of RP as a clinical entity, its etiology and pathogenesis still has not been fully clarified.

The first part of this review summarizes the etiology, epidemiology, risk factors and the clinical manifestations of pRP and sRP, highlighting the relationship with CTD. Then, a critical evaluation of recent insights into the pathogenic mechanisms underlying RP is discussed, laying a particular emphasis on vascular, neuronal and intravascular abnormalities to highlight the crucial key points and potential targets for therapeutic intervention. Finally, the results of the most salient clinical trials are illustrated, highlighting the drugs that have been successfully employed in this clinical condition.

Section snippets

Methods

We conducted a literature search in the MEDLINE database through the PubMed interface, using the following terms: Raynaud's phenomena (primary Raynaud's phenomenon or secondary Raynaud's phenomenon) and/or systemic sclerosis, in combination with epidemiology, risk factors, clinical features, pathogenesis, connective tissue diseases, vasculitis, atherosclerosis, hand arm vibration syndrome, digitals ulcers (DUs), nailfold videocapillaroscopy (NFVC), autoantibodies, and therapy. Additional

Epidemiology and risk factors

RP has a prevalence of 3–5% in the general population [6], and the mean age of affected patients ranges from 47.2 years in Europe [7] to 53.5 years in the US [8]. In Italy, the prevalence rate ranges from 3.4% in women to 0.5% in men [9], while in the US it ranges from 9.6% in women to 5.8% in men [10]. In a recent randomized clinical trial performed in California in 162 RP patients of various ethnic origins, RP was more frequent in non-Hispanic white people (80.2%) than in American Indian/Alaska

Clinical features

RP can manifest as a unique “triple” color change featuring pallor (ischemic phase), cyanosis (deoxygenation phase) and erythema (reperfusion phase); or a “double” color change, usually consisting of pallor and cyanosis or cyanosis and erythema [18] (Fig. 1). The latter stage may sometimes be associated with pain and paresthesia [19].

RP most frequently involves the hands and toes [6] (Fig. 2), but only 5% of patients have initial symptoms in the toes [20]. Less frequently, the nose and the

Pathogenesis

Vasculature consists of endothelial, smooth muscle and fibroblast cell types with an integrated system of paracrine/autocrine and nervous system interactions [19]. Vascular tone is the result of a delicate balance between vasodilator and vasoconstrictor factors. A perturbation of this equilibrium can be observed in healthy individuals following exposure to physical (cold, heat), mechanical (vibration) or emotional stress, resulting in either vasoconstriction and/or vasodilation of peripheral

Role of autoantibodies in RP

Clinical evidence suggests that ANA may have a role in the pathogenesis of RP [39], [143], [144]. Firstly, pRP patients express, albeit at low titers, ANA in their sera. Secondly, ANA were found to be independent predictive factors for the progression of pRP to SSc [145]; thirdly, the high prevalence of ANA in CTD presenting RP is noteworthy [146]. One possibility to test whether ANA contribute to RP is to search for their ability to react with and block vasodilator agonists and/or their

Therapy

The aim of medical therapy in RP is to counteract vasoconstriction in order to prevent or cure all possible arrays of clinical manifestations and their complications. In sRP, the success of the treatment will also depend on the underlying disease, in that RP is more easily controlled when associated to CTD which are more responsive to immune suppressive therapy (i.e., SLE or rheumatoid arthritis). By contrast, RP associated to the poorly responsive SSc or MCTD pose a real therapeutic challenge

Conclusions

RP remains an incurable disease with a complex pathophysiology, even if research during the last ten years has yielded further insights into the pathogenic mechanism(s). Indeed, the identification of novel mediators, their receptors, and the corresponding intracellular pathway-associated molecules has raised much enthusiasm and hope for novel possible future therapeutic applications. As expected, clinical studies have been mostly focused on pRP and on CTD-RP, which are poorly responsive to

Take-home messages

  • Raynaud's phenomenon (RP) remains an incurable disease.

  • Recent insights into the pathogenetic mechanisms have disclosed novel key points for therapeutic intervention.

  • Calcium channel blockers and prostacyclin analog are currently used in RP and in its severe forms.

  • Endothelin receptor antagonist and type V phosphodiesterase inhibitors offer promising therapeutic perspective.

Acknowledgments

This work was supported by a 2013 grant from the Italian Group for Systemic Sclerosis (GILS), Milan, Italy.

Dr. Favoino was supported by a 2013 grant from the Italian Group for Systemic Sclerosis (GILS).

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