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The pathogenesis, diagnosis and treatment of Raynaud phenomenon

Abstract

The past 10 years have seen the publication of results from several multicentre clinical trials in primary and systemic sclerosis (SSc)-related Raynaud phenomenon. The publication of these studies has occurred as a result of new insights into the pathogenesis of Raynaud phenomenon, which are directing new treatment approaches, and increased international collaboration between clinicians and scientists. Although the pathogenesis of Raynaud phenomenon is complex, abnormalities of the blood vessel wall, of neural control mechanisms and of intravascular (circulating) factors are known to interact and contribute. Key players relevant in drug development include nitric oxide, endothelin-1, alpha adrenergic receptor activation, abnormal signal transduction in vascular smooth muscle, oxidative stress and platelet activation. The main advances in diagnosis have been a clearer understanding of autoantibodies and of abnormal nailfold capillary patterns as independent predictors of SSc, and widespread use and increased availability of capillaroscopy. The ultimate aim is to translate the advances made in the pathophysiology and early diagnosis into development of treatments to prevent and reverse digital vascular dysfunction and injury. This Review provides an update of the pathogenesis, diagnosis and treatment of Raynaud phenomenon. Current and future treatment approaches are discussed, and some key unanswered questions are highlighted.

Key Points

  • When a patient presents with Raynaud phenomenon, the clinician should first decide whether the condition is primary (idiopathic) or secondary to an underlying cause, which might require specific treatment

  • Primary Raynaud phenomenon is vasospastic and does not progress to irreversible tissue injury; conversely, systemic sclerosis (SSc)-related Raynaud phenomenon can lead to digital ulceration and gangrene, which require urgent medical intervention

  • Although the pathogenesis of Raynaud phenomenon is complex and incompletely understood, progress is being made and new insights are directing novel approaches to treatment

  • Abnormalities of the blood vessel wall, of neural control mechanisms, and of intravascular (circulating) factors can all contribute to the pathogenesis of Raynaud phenomenon

  • In patients with Raynaud phenomenon, presence of SSc-specific autoantibodies and abnormal nailfold capillary pattern are independent predictors of an underlying SSc-spectrum disorder

  • New treatment approaches for Raynaud phenomenon include phosphodiesterase inhibitors and, for patients with SSc and recurrent digital ulcers, endothelin-1 receptor antagonists

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Figure 1: Schematic representation of some of the key elements and mechanisms contributing to the pathogenesis of Raynaud phenomenon.
Figure 2: Nailfold capillaroscopy images for the assessment of Raynaud phenomenon.
Figure 3: Histological hematoxylin and eosin staining (magnification: 100×) of a digital artery from a patient with limited cutaneous systemic sclerosis, showing intimal thickening.
Figure 4: Thermograms from a patient with primary Raynaud phenomenon (upper panels) and a patient with systemic sclerosis (SSc; lower panels).
Figure 5: Flow chart of the treatment strategies for Raynaud phenomenon.
Figure 6: Images showing fingertip ulceration (healing, left panel) and critical digital ischaemia (right panel) in patients with systemic sclerosis.

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The author declares that she has been a consultant for and received honoraria from Actelion and Pfizer. She has also been an investigator in clinical trials supported by Actelion, MediQuest, Orion Pharma and United Therapeutics.

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Herrick, A. The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nat Rev Rheumatol 8, 469–479 (2012). https://doi.org/10.1038/nrrheum.2012.96

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