AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Raynaud phenomenon refers to reversible ischemia of peripheral arterioles. This can be in response to various stimuli but is most commonly caused by exposure to cold or stress.

Raynaud phenomenon (secondary Raynaud) should be distinguished from Raynaud disease (primary Raynaud). They are distinct disorders that share a similar name. Raynaud disease is the occurrence of the vasospasm alone, with no association with another illness. Raynaud phenomenon is usually used in the context of vasospasm associated with another illness, most commonly an autoimmune disease. Other terms used for this distinction are primary Raynaud (disease) and secondary Raynaud (phenomenon).

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. Most of these patients are considered to have primary Raynaud. These patients do not exhibit capillary nailfold changes. If such changes are noted on nailfold capillaroscopy, other autoimmune diseases should be considered in the differential diagnoses. The same should be said for older and male patients who have Raynaud phenomenon, as vasospastic symptoms may predate systemic disease by as much as 20 years. In some studies, 46-81% of patients have secondary Raynaud.

Although Raynaud phenomenon has been described with various autoimmune diseases, the most common association is with progressive systemic sclerosis (scleroderma; 90% prevalence) 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

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. This usually happens 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.

Evidence exist that, even under normal conditions, patients with primary or secondary Raynaud have abnormal blood flow to the affected digits and an abnormal recovery to cold stimuli. The decreased blood flow may be a result of increased blood viscosity, abnormalities of the vasculature (specifically the endothelium), or unusually intense vessel constriction. Patients with cryoglobulins or Waldenström macroglobulinemia have hyperviscosity syndromes that make blood flow in their peripheral vessels even more difficult, leading to this manifestation. Release of von Willebrand factor, nitric oxide synthesis, and local inflammation and cytokine production have all been implicated.

In patients with scleroderma, secondary Raynaud is associated with narrowing of the blood vessels from proliferation in the subintimal area. This fixed lesion causes a certain amount of baseline ischemia and hypoxia. The endothelial cell has been implicated as one of the early targets for scleroderma. Vasospasm occurs on top of the background hypoxia. It has also been associated with an increase in endothelin-1, a vasoconstrictor substance. Endothelin-1 has not been noted in patients with primary or secondary Raynaud that is not associated with scleroderma. It is believed to be a product of abnormal endothelial cells that are present in the skin of these patients.

Medications have been associated with exacerbations of primary or secondary Raynaud. Most of these medications promote vasoconstriction and include ergot alkaloids, nonspecific beta-adrenergic antagonists, and birth control pills. Some chemotherapeutic agents that are associated with fibrosis and may decrease blood flow, specifically bleomycin and the vinca alkaloids, have been associated with the development of secondary Raynaud.

Frostbite leads to vasomotor instability that may last for many years after the freezing episode. Patients with primary Raynaud have successfully been treated by blocking alpha2-adrenergic receptors, but the precise mechanism for this positive response is unclear.

U1-RNP antibodies may represent a marker for the vascular process that causes Raynaud phenomenon. It can also be considered a marker for associated structural vasculopathy. Originally, anti–U1-RNP was mostly associated with MCTD; however, subsequent studies have revealed that up to 29 % of patients may have undifferentiated connective-tissue disease (UCTD). Patients with scleroderma may express this in up to 21% of cases, while patients with SLE may develop antibodies up to 30% of the time. Neurologic influences, both locally and systemically, have been implicated.

Frequency

United States

One survey reported an incidence of primary Raynaud at 5-10% in persons who are nonsmokers. However, the more accepted figure is 3-4%.

The frequency of secondary Raynaud depends on the underlying disorder. For example, it is almost universal in patients with scleroderma (progressive systemic sclerosis). Secondary Raynaud may occur in up to 50% of individuals who regularly use vibrating equipment.

International

The prevalence of primary Raynaud varies among different populations, from 4.9-20.1% in women to 3.8-13.5% in men. The commonly accepted rate remains about 3-4%.

As in the United States, prevalence of secondary Raynaud is dependent on the underlying disorder.

Mortality/Morbidity

• Primary Raynaud does not usually cause death or serious morbidity. However, ischemia of the affected body part can result in necrosis. This is a very rare occurrence.
• Secondary Raynaud 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 shows no racial predilection.
• Secondary Raynaud approximates the racial prevalence of the underlying disease.

Sex

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

Age

• Primary Raynaud usually occurs in the second or third decade of life.
• Secondary Raynaud simultaneously begins with the underlying disorder.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Numbness and pain in the affected area(s) may be present.
• Affected areas show at least 2 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 has been associated with the frequent use of vibrating tools such as jackhammers and sanders.
  • 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 (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.

Causes

• The cause of primary Raynaud remains unknown.
• Possible causes for secondary Raynaud can be divided into several broad categories that include 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(s)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Acrocyanosis
Alfa-interferon
Antineoplastics (eg, vinca alkaloids, bleomycin, cisplatin)
Beta-adrenergic blocking drugs
Bromocriptine
Carpal Tunnel Syndrome
Chilblains
Cryoglobulinemia, mixed or type 3, associated with hepatitis B and C
Cryoglobulinemia, monoclonal or type I
Cyclosporine
Ergot alkaloids
Fabry disease
Leukemia
Livedo reticularis
Lymphoma
Mycoplasma with cold agglutinins
Myeloma
Oral contraceptives
Overlap syndromes
Peripheral Vascular Disease
Scleroderma, diffuse and localized (CREST syndrome)
Thoracic Outlet Syndrome
Thromboembolic disease
Vasculitis
Vibration injury
Vinyl chloride exposure
Waldenström macroglobulinemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Complete blood cell count - To evaluate polycythemic disorders, underlying malignancies, or autoimmune disorders
• Blood urea nitrogen - To evaluate possible renal impairment or dehydration
• Creatinine - To evaluate possible renal impairment
• Prothrombin time - To observe for any evidence of hepatic dysfunction
• Activated partial thromboplastin time - To observe for any evidence of antiphospholipid antibody disorder or hepatic dysfunction
• Serum glucose - To evaluate patient for diabetic disease
• Thyroid-stimulating hormone - To observe for thyroid disorders
• Optional laboratory tests
• • Antinuclear antibody - May be positive in autoimmune disorders and should be ordered in patients with features of these disorders
  • Serum viscosity - Elevated in hyperviscosity syndromes such as paraproteinemias
  • Serum creatine kinase - Elevated in muscle damage such as polymyositis and dermatomyositis
  • Rheumatoid factor - May be elevated in rheumatoid arthritis, other autoimmune disorders, and some forms of cryoglobulinemia (monoclonal proteins in multiple myeloma and Waldenström macroglobulinemia have an increased frequency of rheumatoid factor activity)
  • Hepatitis panel - Positive for B or C infection in many patients with cryoglobulinemia
  • Cold agglutinins - Present in Mycoplasma infections and lymphomas
  • Heavy metal screen - To observe for patients with neuropathic pain from poisoning
  • Growth hormone - To evaluate patients for acromegaly
  • Serum vanillylmandelic acid - To evaluate for pheochromocytoma
  • Metanephrine - To observe for pheochromocytoma in appropriate patients
  • Catecholamines - To observe for pheochromocytoma
  • Leukocyte alkaline phosphatase - To evaluate for leukemias in appropriate patients
  • Antiphospholipid antibodies studies - Including dilute Russell viper venom studies, anticardiolipin antibodies, and anti-beta-1-glycoprotein-2 antibodies.

Imaging Studies

• Thermography, isotope studies, and arteriography have all been used, but none has proven superior to clinical assessment in office practice.
• A fixed, nonreversible, cyanotic lesion requires further evaluation of the vasculature.

Other Tests

• Acid hemolysis test
• Sucrose lysis test

Procedures

• Serum protein electrophoresis
• Liver or kidney biopsy
• Measurement of digital blood pressures before and after immersion in cold water (The difference should be less than 30 mm Hg.).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• General measures: These include education, warming of local body part, and cessation of vasoconstricting agents such as nicotine.
• Primary Raynaud
• • Use calcium channel blockers, especially those that cause vasodilation. The most commonly used drug is nifedipine. Use the lowest dose of a long-acting preparation and titrate up as tolerated. If adverse effects occur, decrease dosage or use another agent such as nicardipine, amlodipine, or diltiazem.
  • Angiotensin-converting enzyme inhibitors and intravenous prostaglandins have been advocated, and clinical trials have indicated some benefit. The selective serotonin uptake inhibitor fluoxetine has also been shown effective in at least one study.
  • Therapy with antiplatelet agents has been tried but has not been proven effective, and anticoagulation is not indicated. The angiotensin-receptor antagonist losartan at 50 mg/d has been found effective in patients with primary Raynaud and scleroderma.
• Secondary Raynaud
• • Therapy must be tailored to the underlying disorder.
  • If associated with occupational or toxic exposure, the patient should avoid the inciting environment.
  • Patients with hyperviscosity syndromes and cryoglobulinemia improve with treatments that decrease the viscosity and improve the rheologic properties of their blood (eg, plasmapheresis).
  • Unfortunately, patients with autoimmune disorders and associated Raynaud phenomenon do not usually respond well to therapy.
  • Infections such as hepatitis B, hepatitis C, and Mycoplasma infections need to be addressed.
  • In older patients with new-onset Raynaud and no obvious underlying cause, malignancy must be considered.

Surgical Care

• Cervical sympathectomy still is considered controversial and may offer only temporary relief.
• Digital sympathectomy has been gaining support for patients with severe or tissue-threatening disease. This may be used in patients with either primary or secondary disease, but it is more commonly necessary with the secondary forms.

Consultations

• Typically, primary Raynaud does not require any consultations.
• Secondary Raynaud can require consultations.
• • Consult a rheumatologist or hematologist to delineate associated syndromes.
  • Fixed (nonreversible) lesions are not Raynaud phenomenon and may require referral to a rheumatologist, vascular surgeon, orthopedist, or other specialist.

Diet

Fish oils containing omega-3-fatty acids may be beneficial to some patients with primary Raynaud.

Activity

• Nondrug therapy may be all that is required for mild cases of primary Raynaud phenomenon. Therapies can include the following:
• • Biofeedback and relaxation
  • Avoiding inciting environmental factors such as direct contact with frozen foods or cold drinks
  • Insulation against cold and local warming, including electric and chemical warming devices
  • Removing any drugs from the medical regimen that may provoke vasospasm
  • Avoiding smoking
• With time, most patients learn to incorporate these therapies on their own.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drugs should be used to vasodilate the affected circulation, as long as other tissues and systemic blood pressure are not compromised.

Sildenafil has shown in some case reports to be effective in Raynaud phenomenon; however, no formal clinical trials have been reported.

Drug Category: Calcium channel blockers

Used for vasodilation and possible antiplatelet effects. The dihydropyridine class of agents are potent vasodilators and first line of treatment after nondrug therapy.

Drug Category: Angiotensin-converting enzyme inhibitors

Used for vasodilation and possible antifibrotic and anti-inflammatory properties.

Drug Category: Angiotensin II receptor antagonists

Used for vasodilation and for their possible antifibrotic and anti-inflammatory effects.

Drug Category: Endothelin inhibitors

Inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 (ET-1) receptors ETA and ETB in endothelium and vascular smooth muscle.

Drug Category: Serotonin reuptake inhibitors

Serotonin is a potent vasoconstrictor that is released from nerve endings and during platelet activation. This is the reason that these medications are believed to be helpful in the treatment of Raynaud phenomenon. Fluoxetine (20 mg) versus nifedipine (40 mg) in patients with primary and secondary Raynaud phenomenon showed that fluoxetine statistically improved the frequency and severity of Raynaud attacks, while nifedipine did not reach statistical significance. A better response was seen in patients with Raynaud disease versus patients with Raynaud phenomenon.

Drug Category: Prostaglandins

Agents in this class have potent vasodilatory effects.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Primary Raynaud phenomenon is usually treatable on an outpatient basis.
• Although the same drugs and maneuvers are used for the phenomenon itself, treatment of secondary Raynaud phenomenon depends on the underlying disease.

Further Outpatient Care

• Patients should check their systemic blood pressure regularly and may want to keep a log of the number and severity of attacks. This may help in evaluating the efficacy of therapeutic management.

Transfer

• Transfer is not usually necessary.

Deterrence/Prevention

• Avoid cold and stressful situations that precipitate attacks.

Complications

• Rarely, digital ulceration and tissue loss may result from primary Raynaud phenomenon.
• The complications associated with secondary Raynaud are usually related to the underlying disease. The direst of these are loss of tissue pulp in the distal phalanx, ulceration, and digital gangrene.
• Critical digital ischemia necessitates aggressive management. It is considered a medical emergency that requires hospitalization. Warm temperature and bed rest are used to decrease trauma and activity and to control pain.
• • Local infiltration of lidocaine or bupivacaine at the base of the involved digits decreases sympathomimetic input, reduces ischemic pain, and improves blood flow.
  • Rapidly advancing ischemic tissue anticoagulant therapy may be necessary. No algorithms or studies exist for the use of heparin.
  • Intravenous iloprost, alprostadil, or epoprostenol can be used if anticoagulant therapy fails or if the ischemia rapidly worsens.
  • Failure of all these therapies might warrant surgical intervention with distal digital sympathectomy and arterial reconstruction.
  • Further workup for vasculitis, thrombosis, arthrosclerosis, among other conditions, must be performed while treatment is in place.

Prognosis

• Prognosis of primary Raynaud is usually very good, with no mortality and little morbidity.
• Prognosis of secondary Raynaud is related to the underlying disease. Prognosis for the involved digit in these patients is related to the severity of the ischemia and the effectiveness of maneuvers to restore blood flow.

Patient Education

• Patients should avoid situations that precipitate their attacks, and they should insulate their hands from the cold.
• Smoking should be prohibited.
• If ulcerations develop, patients need to keep them sterile and to treat any infections aggressively that may intercede. All of this should be done under the supervision of a physician.
• If ulcerations or gangrene occur, a consultation with a wound care specialist may be useful.
• For excellent patient education resources, visit eMedicine's Circulatory Problems Center. Also, see eMedicine's patient education article Raynaud Phenomenon.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to appropriately diagnose a secondary disorder

Special Concerns

• Caution should be taken to not overlook an underlying disorder.
• Wounds need to be treated appropriately.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Apr 5, 2006