Raynaud Phenomenon 

  • Author: Heather Hansen-Dispenza, MD; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: Sep 22, 2011
 

Background

Raynaud phenomenon manifests as recurrent vasospasm of the fingers and toes and usually occurs in response to stress or cold exposure. The phenomenon is named for Maurice Raynaud, who, as a medical student, defined the first case in 1862 as "episodic, symmetric, acral vasospasm characterized by pallor, cyanosis, suffusion, and a sense of fullness or tautness, which may be painful."[1]

Secondary Raynaud phenomenon should be distinguished from primary Raynaud phenomenon (Raynaud disease). They are distinct disorders that share a similar name. Raynaud disease is characterized by the occurrence of the vasospasm alone, with no association with another illness. Secondary Raynaud phenomenon is a designation usually used in the context of vasospasm associated with another illness, most commonly an autoimmune disease.

There are several diagnostic criteria for primary Raynaud phenomenon, including attacks triggered by exposure to cold and/or stress, symmetric bilateral involvement, an absence of necrosis, no detectable underlying cause, normal capillaroscopy findings, normal laboratory findings for inflammation, and an absence of antinuclear factors.[2]

Young female patients who have had Raynaud phenomenon alone for more than 2 years and have not developed any additional manifestations are at low risk for developing an autoimmune disease. The same should not be said for older patients and male patients with Raynaud phenomenon, as vasospastic symptoms may predate systemic disease by as many as 20 years. In some studies, 46%-81% of affected patients have secondary Raynaud phenomenon.

Although Raynaud phenomenon has been described with various autoimmune diseases, the most common association is with progressive systemic sclerosis (90% in individuals with scleroderma) and mixed connective-tissue disease (85% prevalence). Raynaud phenomenon has also been described with such diverse diseases as systemic lupus erythematosus and other disorders not classified as autoimmune, including frostbite, vibration injury, polyvinyl chloride exposure, and cryoglobulinemia.

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Pathophysiology

In individuals with Raynaud phenomenon, one or more body parts experience intense vasospasm with associated color change and subsequent hyperemia. Patients often describe 3 phases of change with intial white (vasoconstriction), followed by blue (cyanosis), and then red (rapid blood reflow). The affected body parts are usually those most susceptible to cold injury. A clear line of demarcation exists between the ischemic and unaffected areas (see the image below).

A 9-year-old with Raynaud phenomenon. Notice the dA 9-year-old with Raynaud phenomenon. Notice the discoloration of the fingers.

These effects are reversible, and they must be distinguished from irreversible causes of ischemia such as vasculitis or thrombosis. Rarely, tissue necrosis occurs distal to the affected vessel, usually in the periphery of the vasculature. It most commonly affects the digits of the fingers but may affect the toes, nose, and ears. Occasionally, even the tongue is involved.

Despite several years of research, the full understanding of the pathophysiology of Raynaud phenomenon remains to be elucidated.

Primary Raynaud phenomenon is related to functional alterations alone. In contrast, secondary Raynaud phenomenon also reflects structural microvascular abnormalities. Herrick (2005) reviewed the pathogenesis of Raynaud phenomenon and describes the mechanisms under 3 categories: vascular, neural, and intravascular abnormalities.[3]

Vascular abnormalities

  • Endothelial dysfunction
    • A deficiency of vasodilatory mediators, including nitric oxide, has been implicated in the pathogenesis of Raynaud phenomenon.[4]
    • Endothelin-1, a potent vasoconstrictor found in the endothelium, has been found to be circulating in high levels in patients with secondary Raynaud phenomenon.[5]
    • Release of endothelin-1 is triggered by vasoactive stimuli, including angiotensin, vasopressin, and transforming growth factor-beta (TGF-beta).[6]
    • A study by Rajagopalan et al reported increased levels of circulating endothelin-1 in patients with secondary Raynaud phenomenon.[4]
    • Conflicting results regarding the levels of endothelin-1 in patients with primary Raynaud phenomenon are noted.
    • Angiotensin also has vasoconstrictive and profibrotic effects.[7]
    • A study by Kawaguchi et al revealed higher levels of angiotensin II in patients with diffuse cutaneous systemic sclerosis.[8]
  • Structural abnormalities
    • In patients with systemic sclerosis, Raynaud phenomenon differs from primary Raynaud disease.[9]
    • It is related to fibrotic proliferation of the vasculature leading to reduced blood flow to the digits.

Neural abnormalities

  • Central mechanisms
    • Edwards et al performed a series of experiments showing that patients with primary Raynaud phenomenon do not habituate to stressful stimuli in the same way as healthy control subjects. The ability to habituate is described as vasodilation in forearm muscles and vasoconstriction in the cutaneous circulation of skin.
    • Based on these data, it is presumed that patients with Raynaud phenomenon repeatedly undergo cutaneous vasoconstriction to many stressful stimuli. Healthy individuals are able to habituate, thus not displaying these responses.[10]
  • Impaired vasodilation
    • An important neuropeptide, calcitonin gene-related peptide, is a potent vasodilator secreted by nerves that supply blood vessels.[11]
    • A diminished number of calcitonin gene-related peptide–releasing neurons has been found in skin biopsy samples of patients with primary Raynaud and systemic sclerosis.[12]
    • Neuropeptide Y, a potent vasoconstrictor, has been found in increased levels in Raynaud phenomenon secondary to systemic sclerosis.
  • Impaired vasoconstriction
    • α2C -adrenoreceptors overactivity: α2C -adrenoreceptors have been found to enable cold-induced vasoconstriction of the blood vessels.[13]
    • Two studies by Furspan et al showed that the enhanced contractile response to α2 -adrenergic agonists and cooling in patients with primary Raynaud phenomenon may be linked to increased protein tyrosine kinase activity.[14]
    • These data provide information regarding the possible benefits of protein tyrosine kinase inhibitors in the treatment of Raynaud phenomenon.

Intravascular abnormalities

  • In primary Raynaud and systemic sclerosis, increased platelet activation and aggregation has been demonstrated.[15]
  • An increased production of platelet thromboxane A2, a potent vasoconstrictor, has been found in patients with Raynaud phenomenon.
  • In patients with systemic sclerosis, an impaired fibrolytic system has been reported, probably contributing to vascular obstruction.[16]
  • Oxidative stress by reactive oxygen species has also been implicated in the pathogenesis of Raynaud phenomenon.
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Epidemiology

Frequency

United States

A 7-year study of Raynaud phenomenon in whites in the United States showed baseline prevalence rates of 11% in women and 8% in men and yearly incidence rates of 2.2% in women and 1.5% in men.[17]

International

The prevalence of primary Raynaud phenomenon varies among different populations, from 4.9%-20.1% in women to 3.8%-13.5% in men.

As in the United States, the prevalence of secondary Raynaud phenomenon depends on the underlying disorder.

Mortality/Morbidity

Primary Raynaud phenomenon does not usually cause death or serious morbidity. However, in very rare cases, ischemia of the affected body part can result in necrosis.

Secondary Raynaud phenomenon is important as a possible marker for other diseases that may lead to morbidity and mortality. Examples of this include scleroderma (progressive systemic sclerosis), systemic lupus erythematosus, and hyperviscosity syndromes.

Race

Primary Raynaud phenomenon has no racial predilection.

Secondary Raynaud phenomenon approximates the racial prevalence of the underlying disease, if any.

Sex

The prevalence of primary Raynaud phenomenon varies in different populations, ranging from 4.9%-20.1% in women to 3.8%-13.5% in men.

Age

Primary Raynaud phenomenon usually occurs in the second or third decade of life.

Secondary Raynaud phenomenon begins in accordance with the underlying disorder.

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Contributor Information and Disclosures
Author

Heather Hansen-Dispenza, MD  Rheumatology Fellow, University of Arizona College of Medicine

Heather Hansen-Dispenza, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Nothing to disclose.

Coauthor(s)

S Anita Narayanan, MD  Fellow in Rheumatology, University of Arizona College of Medicine

S Anita Narayanan, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and American Medical Association

Disclosure: Nothing to disclose.

Jeffrey R Lisse, MD, FACP  Professor, Department of Internal Medicine, Chief, Section of Rheumatology, University of Arizona School of Medicine

Jeffrey R Lisse, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American College of Rheumatology, American Geriatrics Society, and Sigma Xi

Disclosure: Genentech Consulting fee Consulting; Centacor Consulting fee Consulting; Novartis Consulting fee Review panel membership

Mayra Oberto-Medina, DO  Fellow, Section of Rheumatology, University of Arizona

Disclosure: Nothing to disclose.

Specialty Editor Board

John Varga, MD  Professor, Department of Internal Medicine, Division of Rheumatology, Northwestern University

John Varga, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Central Society for Clinical Research, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Elliot Goldberg, MD  Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Alex J Mechaber, MD, FACP  Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD  Adjunct Professor of Medicine, Division of Rheumatology, University of Pittsburgh School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa

Disclosure: Merck Ownership interest Other; Smith Kline Ownership interest Other; Zimmer Ownership interest Other

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A 9-year-old with Raynaud phenomenon. Notice the discoloration of the fingers.
Photo of a patient with Raynaud phenomenon that resulted from working with a jackhammer. Courtesy of the CDC.
 
 
 
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