eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Raynaud Phenomenon

Author: S Anita Narayanan, MD, Fellow in Rheumatology, University of Arizona College of Medicine
Coauthor(s): Jeffrey R Lisse, MD, FACP, Professor, Department of Internal Medicine, Chief, Section of Rheumatology, University of Arizona School of Medicine; Mayra Oberto-Medina, DO, Fellow, Section of Rheumatology, University of Arizona
Contributor Information and Disclosures

Updated: Jun 3, 2009

Introduction

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.

Pathophysiology

In individuals with Raynaud phenomenon, one or more body parts experience intense vasospasm with associated pallor and, often, cyanosis. This is often followed by a hyperemic phase with associated erythema. The affected body parts are usually those most susceptible to cold injury. A clear line of demarcation exists between the ischemic and unaffected areas. 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 (2003) reported increased levels of circulating endothelin-1 in patients with secondary Raynaud phenomenon.⁴
    • There have been conflicting results regarding the levels of endothelin-1 in patients with primary Raynaud phenomenon.
  • Angiotensin also has vasoconstrictive and profibrotic effects.⁷
    • A 2004 study by Kawaguchi et al revealed higher levels of angiotensin II in patients with diffuse cutaneous systemic sclerosis.⁸
    • Based on these results, treatment with angiotensin-converting enzyme (ACE) inhibitors needs further investigation.
• 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 (1998) 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
  • α_2C -adrenoreceptors overactivity: α_2C -adrenoreceptors have been found to enable cold-induced vasoconstriction of the blood vessels.¹³
  • Two studies by Furspan et alshowed 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.

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.

Clinical

History

• Numbness and pain in the affected area or areas may be present.
• Affected areas show at least two color changes: white (pallor), blue (cyanosis), and red (hyperemia).
  • The color changes are usually in the order noted, but not always.
  • These changes should be reversible but may, in severe cases, lead to local ischemia and ulceration.
• Any history of associated symptoms should raise suspicion of an underlying disorder. History of other vasospastic symptoms such as migraines may be useful.
• Obtain occupational history.
  • Secondary Raynaud phenomenon has been associated with the frequent use of vibrating tools such as jackhammers and sanders.
    
    

    

    Photo of a patient with Raynaud phenomenon that resulted from working with a jackhammer. Courtesy of the CDC.

    [ CLOSE WINDOW ]

    

    Photo of a patient with Raynaud phenomenon that resulted from working with a jackhammer. Courtesy of the CDC.

  • Industrial exposure to polyvinyl chloride has been implicated.
  • Any history of injury or frostbite may leave the involved limb vulnerable to vasospasm.
• Syndromes associated with Raynaud phenomenon include the following:
  • Autoimmune disorders
    • Progressive systemic sclerosis (scleroderma) including the diffuse and limited (formerly called CREST syndrome)
    • Systemic lupus erythematosus
    • Mixed connective-tissue disease (and other overlap syndromes)
    • Dermatomyositis and polymyositis
    • Rheumatoid arthritis
    • Sjögren syndrome
    • Vasculitis
    • Primary pulmonary hypertension
  • Infectious syndromes
    • Hepatitis B and C infections (especially associated with mixed or type 3 cryoglobulinemia)
    • Mycoplasma infections (with cold agglutinins)
  • Neoplastic syndromes
    • Lymphoma
    • Leukemia
    • Myeloma
    • Waldenström macroglobulinemia
    • Polycythemia
    • Monoclonal or type 1 cryoglobulinemia
    • Lung adenocarcinoma
    • Other paraneoplastic disorders
  • Environmental associations
    • Vibration injury
    • Vinyl chloride exposure
    • Frostbite
    • Lead exposure
    • Arsenic exposure
  • Metabolic/endocrine syndromes
    • Acromegaly
    • Myxedema
    • Diabetes mellitus
    • Pheochromocytoma
    • Fabry disease
  • Hematologic syndromes
    • Paroxysmal nocturnal hemoglobinuria
    • Polycythemia
    • Cryofibrinogenemia
  • Drug-related associations
    • Oral contraceptives
    • Ergot alkaloids
    • Bromocriptine
    • Beta-adrenergic blocking drugs
    • Antineoplastics (eg, vinca alkaloids, bleomycin, cisplatin)
    • Cyclosporine
    • Alfa-interferon
• Syndromes that may be confused with Raynaud phenomenon are as follows:
  • Anatomic syndromes
    • Carpal tunnel syndrome
    • Reflex sympathetic dystrophy syndromes
    • Thoracic outlet syndrome
  • Miscellaneous circulatory syndromes
    • Atherosclerosis
    • Thromboangiitis obliterans
    • Vasculitis
    • Thromboembolic disease
  • Vasospastic syndromes
    • Livedo reticularis
    • Acrocyanosis
    • Chilblains

Physical

• Carefully examine digits if either primary or secondary Raynaud is suspected.
  • Observe for sclerodactyly, calcinosis, or digital ulcers.
  • Examine nailfold capillaries under magnification from a dissecting microscope or ophthalmoscope to help diagnose underlying autoimmune disorders.
  • Abnormalities often appear in patients with early scleroderma. The normally regular pattern of capillary loops is replaced with abnormally large loops, alternating with areas without any capillaries.
• Evaluate any signs or symptoms of other syndromes associated with secondary Raynaud.
  • Bone pain may suggest a paraneoplastic syndrome associated with a hyperviscosity syndrome.
  • The presence of nephritis, malar erythema, and arthritis suggests systemic lupus erythematosus.
• Persistent cyanosis or necrotic distal tissue suggests an underlying disorder or permanent ischemia. Livedo reticularis suggests an autoimmune disorder or coagulation abnormality.
• Carpal tunnel syndrome has been associated with an increased frequency of Raynaud phenomenon.

Causes

• The cause of primary Raynaud phenomenon remains unknown.
• Possible causes for secondary Raynaud can be divided into several broad categories, including the following:
  • Occupational
  • Hematologic
  • Collagen-vascular (autoimmune)
  • Medication-induced
  • Miscellaneous syndromes such as Fabry disease, pheochromocytoma, lung adenocarcinoma, acromegaly, carpal tunnel syndrome, and myxedema
• Although the following entities do not usually have the same inciting causes, nor do they encompass the usual color changes associated with Raynaud phenomenon, they can easily be mistaken for Raynaud phenomenon:
  • Vasculitis
  • Carpal tunnel syndrome
  • Reflex sympathetic dystrophy
  • Thromboembolic disease
  • Thoracic outlet syndrome

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