Raynaud Phenomenon

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Practice Essentials

Raynaud phenomenon manifests as recurrent vasospasm of the fingers and toes and usually occurs in response to stress or cold exposure.[1] 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."[2] See the image below.



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

See Cutaneous Clues to Accurately Diagnosing Rheumatologic Disease, a Critical Images slideshow, to help recognize cutaneous manifestations of rheumatologic diseases.

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.

Diagnostic criteria for primary Raynaud phenomenon include the following[1] :

Young women 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.

For primary Raynaud phenomenon, the first line of therapy consists of lifestyle measures. If these prove inadequate, the patient may benefit from pharmacologic treatment. Therapy for secondary Raynaud phenomenon must be tailored to the underlying disorder. Patients with secondary Raynaud phenomenon are more likely to require pharmacologic therapy. A variety of drugs are used off-label for treatment; the most commonly used drug is nifedipine. See Treatment and Medication.

For discussion of Raynaud phenomenon in children, see Pediatric Raynaud Phenomenon.

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 initial 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).



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Raynaud phenomenon showing demarcation of color difference.

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.[3]

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.[4]

Vascular abnormalities

A deficiency of vasodilatory mediators, including nitric oxide, has been implicated in the pathogenesis of Raynaud phenomenon.[5] In addition, 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] Conflicting results regarding the levels of endothelin-1 in patients with primary Raynaud phenomenon are noted.

Angiotensin 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]

In patients with systemic sclerosis, structural abnormalities related to fibrotic proliferation of the vasculature leading to reduced blood flow to the digits have been found. This differs from primary Raynaud disease.[9]

Neural abnormalities

Edwards et al proposed that primary Raynaud's disease involves abnormal function of brain stem areas that integrate the cardiovascular components of the response to acute stress. These researchers found that initially, both patients with Raynaud phenomenon and healthy individuals responded to sound stimuli with vasodilation in forearm muscles and vasoconstriction in the skin of the digit. Over 5 days, however, healthy individuals showed habituation to the stimuli, while patients with primary Raynaud phenomenon did not.[10]

Impaired vasodilation may be involved in Raynaud phenomenon. 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]

Enhanced vasoconstriction in Raynaud phenomenon may involve overactivity of α2C -adrenoreceptors; these 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 suggest that protein tyrosine kinase inhibitors may be beneficial in the treatment of Raynaud phenomenon.

In patients with Raynaud phenomenon secondary to systemic sclerosis, increased levels of neuropeptide Y have been found. Neuropeptide Y is a potent vasoconstrictor.

Intravascular abnormalities

Raynaud phenomenon has been associated with the following intravascular abnormalities:

Etiology

The cause of primary Raynaud phenomenon remains unknown. Ascherman et al propose an autoimmune etiology, with cytokeratin 10 (K10) as a candidate autoantigen; their study in mice showed that anti-K10 antibodies can mediate ischemia similar to that seen in Raynaud phenomenon.[17]

Possible causes for secondary Raynaud can be divided into several broad categories, including the following:

Epidemiology

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.[20] Internationally, 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.

Racial, sexual, and age-related demographics

Primary Raynaud phenomenon has no racial predilection. Secondary Raynaud phenomenon approximates the racial prevalence of the underlying disease, if any.

Primary Raynaud phenomenon occurs more frequently in women than in men. The prevalence by sex varies in different populations, ranging from 4.9%-20.1% in women to 3.8%-13.5% in men.

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

Prognosis

The prognosis for patients with primary Raynaud phenomenon is usually very good, with no mortality and little morbidity. In very rare cases, however, ischemia of the affected body part can result in necrosis.

However, a study in 830 participants of the Charleston Heart Study cohort identified a potentially significant relationship between Raynaud phenomenon and all-cause mortality, especially in elderly subjects. In addition, in whites the presence of Raynaud phenomenon (when broadly defined as including both blanching and cyanotic color changes) was associated with a 1.6-fold higher risk of death related to cardiovascular disease.[21]

In a study by Mueller et al of 2958 consecutive patients with incipient Raynaud phenomenon without previously known connective tissue disease, survival during a median follow-up period of 9.3 years was poorer than in a demographically matched standard population (log-rank test P < 0.0001). Mortality was higher in men than in women (P< 0.0001). In women, but not in men, the presence of abnormal nailfold capillaries, antinuclear antibodies, and anti-Scl-70 antibodies were associated with all-cause mortality.[22]

The prognosis for patients with secondary Raynaud phenomenon is related to the underlying disease. The prognosis for the involved digit or digits in these patients is related to the severity of the ischemia and the effectiveness of maneuvers to restore blood flow.

Patient Education

Patients with Raynaud phenomenon 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 aggressively treat any infections that may develop. All of this should be done under the supervision of a physician; consultation with a wound care specialist may be useful.

For patient education information, see Raynaud Phenomenon.

History

Patients with Raynaud phenomenon report vasospastic episodes provoked by cold temperatures or emotional stress. Episodes usually affect the fingers and toes but may rarely affect the nose, ears, nipples, or lips.

Numbness and pain in the affected area or areas may be present. Affected areas also 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 are usually reversible but may, in severe cases, lead to local ischemia and ulceration.

Any history of associated symptoms should raise suspicion of an underlying disorder. A history of other vasospastic symptoms such as migraines may be useful.

Obtain a history of injury or frostbite, as this may leave the involved limb vulnerable to vasospasm. Also obtain an occupational history, with consideration of the following:

Autoimmune disorders associated with secondary Raynaud phenomenon include the following:

Infectious syndromes associated with secondary Raynaud phenomenon include the following:

Neoplastic syndromes associated with secondary Raynaud phenomenon include the following:

Environmental associations with Raynaud phenomenon include the following:

Metabolic/endocrine syndromes associated with secondary Raynaud phenomenon include the following:

Hematologic syndromes associated with secondary Raynaud phenomenon include the following:

Drugs associated with Raynaud phenomenon include the following:

Physical Examination

Carefully examine the 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.[27]

A cold challenge test can trigger Raynaud phenomenon in the office setting. However, it is not usually necessary to make the diagnosis.

A sharp demarcation of the border between the affected and unaffected areas is required for diagnosis. Many patients do not have classic triphasic color changes.

Evaluate any signs or symptoms of other syndromes associated with secondary Raynaud phenomen, as follows:

Approach Considerations

Raynaud phenomenon can be diagnosed on clinical grounds. Imaging studies, including thermography, isotope studies, and arteriography, have all been used, but none has proven superior to clinical assessment in office practice. However, patients with a fixed, nonreversible, cyanotic lesion require further evaluation of the vasculature.

Laboratory testing may be performed to assess for conditions that can mimic Raynaud phenomenon or cause secondary Raynaud phenomenon. The selection of tests should be guided by the clinical findings.

Laboratory Studies

The following laboratory studies may be considered in patients with Raynaud phenomenon:

Optional laboratory tests are as follows:

Magnetic Resonance Imaging

Smitaman and colleagues report that magnetic resonance imaging (MRI) scans of the feet of patients with Raynaud phenomenon demonstrate a progressive distal-to-proximal pattern of phalangeal bone marrow edema. They suggest that this finding may allow early diagnosis and treatment of rheumatologic disorders that may be associated with Raynaud phenomenon.[28]

Visceral Raynaud phenomenon may exist in patients with systemic sclerosis. Using cardiac MRI, Quarta et al demonstrated the presence of cold-induced cardiac ischemia in patients with systemic sclerosis and secondary Raynaud phenomenon, and showed that therapy with iloprost can reduce episodes of cardiac Raynaud phenomenon.[29]

Approach Considerations

General measures for Raynaud phenomenon include education, warming of the affected body part, and cessation of vasoconstricting agents such as nicotine. A number of pharmacologic treatments have been studied, but none provide a cure and none has been approved for this indication in the United States. In an international study of patients with self-reported Raynaud phenomenon, 82% reported that at least one currently used medication was tolerated, but only 16% reported that at least one current medication was effective.[30]

For primary Raynaud phenomenon, the first line of therapy consists of lifestyle measures, such as avoidance of precipitating factors and use of gloves. If these prove inadequate, the patient may be considered for calcium channel blocker treatment; nifedipine is the usual choice. Topical nitroglycerin (1% or 2%) has been found to help if applied locally.[31, 32]

Therapy for secondary Raynaud phenomenon must be tailored to the underlying disorder. If the disorder is 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 Raynaud phenomenon associated with autoimmune disorders do not usually respond well to therapy. Hepatitis B, hepatitis C, and Mycoplasma infections need to be addressed, if present.

Patients with secondary Raynaud phenomenon should also use lifestyle measures. However, these patients are more likely to require pharmacologic therapy than are patients with primary Raynaud phenomenon.

Pharmacologic options for secondary Raynaud phenomenon include calcium channel blockers and prostacyclin analogues. Other agents may be considered; however, in a meta-analysis of interventions for secondary Raynaud phenomenon by Huisstede et al, solid evidence for therapies beyond calcium channel blockers and the prostacyclin analogue iloprost was lacking.[33]

Nonpharmacologic Therapy

Nondrug therapy may be all that is required for mild cases of primary Raynaud phenomenon. With time, most patients learn to incorporate these therapies on their own. Such therapies can include the following:

Laser therapy may result in less frequent, less severe attacks. However, this therapy needs more study.[35]

Studies of acupuncture have been limited, but have suggested some benefit. Biofeedback and relaxation have shown no difference in frequency or severity of attacks.[35, 36]

Physical maneuvers for alleviating acute attacks that involve the hands have been proposed. In the so-called windmill maneuver, the affected person rotates the arms backward, in a motion similar to a softball pitcher; the resulting centrifugal force enhances blood flow through the distal arteries. More recently, a "Frisbee" maneuver has been suggested for paitents unable or reluctant to perform the windmill maneuver. This maneuver begins with the forearm flexed at a 90-dgree angle and internally rotated across the chest. The patient then rotates the forrearm laterally, in a snapping motion, while maintaining digital extension, and repeats this movement rapidly.[37]

 

 

Pharmacologic Therapy

Calcium channel blockers are the class of drugs most widely used for treatment of Raynaud syndrome—especially the dihydropyridines (eg, nifedipine, nicardipine), which are the most potent vasodilators.[38] Nifedipine is the customary first choice. The usual dosage is 30-120 mg of the extended-release formulation taken once daily. Start with the lowest dose and titrate up as tolerated. If adverse effects occur, decrease the dosage or use another agent, such as nicardipine, or a non-dihydropyridine calcium channel blocker such as such as diltiazem.

Patients should check their 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.

Other medications that have been studied in Raynaud phenomenon include the following[39] :

Topical nitroglycerin (1% or 2%) has been found to help if applied locally.[31, 32] Side effects include headache and dizziness.

Improvement in Raynaud phenomenon has been reported in patients treated with the SSRIs fluoxetine, sertraline, and escitalopram. However, exacerbation of Raynaud phenomenon has also been reported with SSRI treatment.[39]

Therapy with antiplatelet agents has been attempted but has not been proved effective. A randomized controlled trial by Gliddon et al showed no significant difference in attack frequency or severity between the angiotensin-converting enzyme inhibitor quinapril and placebo.[41] High-quality, well-designed, randomized controlled trials are needed to study the effect of other pharmacotherapy. Anticoagulation is not indicated, except in rare cases of rapidly advancing digital ischemia.

Treatment of Critical Digital Ischemia

Critical digital ischemia, which is more likely to occur in secondary Raynaud phenomenon, 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.

In patients with rapidly advancing ischemia, 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.[45]

While treatment is proceeding, further workup for underlying conditions must be performed. Conditions to consider include vasculitis, thrombosis, and atherosclerosis.

Consultations

Typically, primary Raynaud phenomenon does not require any consultations. Secondary Raynaud phenomenon may require consultation with a rheumatologist or hematologist to delineate associated syndromes.

Fixed (nonreversible) lesions are not Raynaud phenomenon. These patients may require referral to a rheumatologist, vascular surgeon, orthopedist, or other specialist.

Diet

Fish oils containing omega-3-fatty acids may be beneficial in some patients with primary Raynaud phenomenon; however, this has not been validated in high-quality studies. A single study found improved tolerance to cold exposure and delayed onset of vasospasm in five of 11 patients with primary Raynaud phenomenon; the dosage used was 12 fish-oil capsules daily.[46] Antioxidant supplementation has not been shown to produce clinical improvement.[35]

Medication Summary

Drugs in a variety of classes have been studied for use in Raynaud syndrome. None is currently approved for this indication by the US Food and Drug Administration (FDA).

Drugs with clear evidence of benefit shown through randomized controlled trials include calcium channel blockers and the vasodilator iloprost. Other agents used in treatment of Raynaud phenomenon include the following:

Nifedipine (Adalat, Procardia, Nifediac CC, Nifedical XL)

Clinical Context:  Nifedipine inhibits transmembrane influx of extracellular calcium ions across myocardial and vascular smooth muscle cell membranes without changing serum calcium concentrations; this results in inhibition of cardiac and vascular smooth muscle contraction, with consequent dilation of main coronary and systemic arteries. Vasodilation with decreased peripheral resistance and increased heart rate result.

For Raynaud phenomenon, the extended-release form of nifedipine is most often selected. Treatment should be initiated at the lowest dose available and titrated upward as tolerated, with the goal of diminishing the frequency and/or severity of attacks.

Nicardipine (Cardene, Cardene SR)

Clinical Context:  Nicardipine is used for vasodilatation and possible antiplatelet effects. Start with lowest dose available. Extended-release preparations are preferred.

Class Summary

These agents are used for vasodilation and possible antiplatelet effects. Calcium channel blockers of the dihydropyridine class contain potent vasodilators and are the first line of treatment after nondrug therapy. Of the dihydropyridines, nifedipine has been extensively studied; however, in the same category, felodipine, amlodipine, and isradipine seem to be equally effective.

Iloprost (Ventavis)

Clinical Context:  Iloprost is a synthetic analogue of prostacyclin (prostaglandin I2 [PGI2]) that dilates systemic and pulmonary arterial vascular beds. It is approved for use in pulmonary arterial hypertension, but has been found effective for secondary Raynaud syndrome, administered either orally or intravenously.

Epoprostenol (Flolan, Veletri)

Clinical Context:  Epoprostenol is an analogue of PGI2 that has potent vasodilatory properties, immediate onset of action, and a half-life of approximately 5 minutes. In addition to producing vasodilation, it also contributes to inhibition of platelet aggregation and plays a role in inhibition of smooth muscle proliferation.

Alprostadil (Prostin VR)

Clinical Context:  Alprostadil (Prostaglandin E1) is used primarily to keep patency of ductus arteriosus but also has a mild pulmonary vasodilatory effect. It is reported to inhibit macrophage activation, neutrophil chemotaxis, and release of oxygen radicals and lysosomal enzymes. It affects coagulation by inhibiting platelet aggregation and possibly by inhibiting activation of factor X. It may promote fibrinolysis by stimulating production of tissue plasminogen activator. Has been found to be effective for secondary Raynaud syndrome.

Class Summary

Agents in this class have potent vasodilatory effects.

Bosentan (Tracleer)

Clinical Context:  Topical nitroglycerin is used in Raynaud phenomenon for its local vasodilatory effects.

Class Summary

Topical nitroglycerin is used in Raynaud phenomenon for its local vasodilatory effects.

Sildenafil (Revatio)

Clinical Context:  Studies of sildenafil in Raynaud phenomenon have used in doses ranging from 25 mg three times daily to 50 mg twice daily.

Tadalafil (Adcirca)

Clinical Context:  Studies of tadalafil in Raynaud phenomenon have used in doses ranging from 20 mg dailiy to 20 mg three times a week. Doses may need to be adjusted for renal or hepatic impairment.

Vardenafil (Levitra, Staxyn ODT)

Clinical Context:  Vardenafil has been used in dosages of 10 mg twice daily for Raynaud phenomenon

Class Summary

Phosphodiesterases are a complex group of enzymes that help to tightly regulate the degradation of intracellular cyclic nucleotides. Intracellular responses to both NO and prostacyclin are mediated by the cyclic nucleotides cGMP and cyclic adenosine monophosphate (cAMP), respectively. So, by bolstering the vasodilatory effect of both NO and prostacyclin, these agents may be useful in the treatment of Raynaud phenomenon.

Fluoxetine (Prozac)

Clinical Context:  Fluoxetine selectively inhibits presynaptic serotonin reuptake with minimal or no effect in the reuptake of norepinephrine or dopamine. Doses of 20 mg daily have been used in treatment of Raynaud phenomenon, with better results reported in primary Raynaud phenomenon.

Sertraline (Zoloft)

Clinical Context:  Sertraline selectively inhibits presynaptic serotonin reuptake, with minimal or no effect on reuptake of norepinephrine or dopamine.

Citalopram (Celexa)

Clinical Context:  Citalopram enhances serotonin activity through selective reuptake inhibition at the neuronal membrane. No head-to-head comparisons of SSRIs have been done; however, on the basis of metabolism and adverse effects, citalopram is considered the SSRI of choice for patients with head injury.

Escitalopram (Lexapro)

Clinical Context:  Escitalopram is an SSRI and an S-enantiomer of citalopram. It is used for the treatment of depression. Its mechanism of action is thought to be potentiation of serotonergic activity in the CNS, resulting from inhibition of CNS neuronal reuptake of serotonin. The onset of depression relief may be obtained after 1-2 weeks—sooner than is possible with other antidepressants.

Class Summary

Serotonin is a potent vasoconstrictor that is released from nerve endings and during platelet activation. SSRIs do not have consistent evidence showing sustained benefit in Raynaud phenomenon, but they may be chosen if hemodynamic side effects develop with calcium channel blockers or prostacyclin analogues. However, some case reports describe exacerbation of Raynaud syndrome following the initiation of SSRI treatment.

Bosentan (Tracleer)

Clinical Context:  Bosentan is approved for use in the treatment of pulmonary arterial hypertension, but has been used off-label in patients with severe Raynaud phenomenon unresponsive to other therapies. Bosentan is approved in the United Kingdom for the prevention of new digital ulcers in patients with systemic sclerosis.[27]

Class Summary

These agents inhibit 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.

Losartan (Cozaar)

Clinical Context:  Losartan is a nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Short-term treatment at 50 mg/day has proved useful, with better results in patients with systemic sclerosis than in those with primary Raynaud phenomenon.

Candesartan (Atacand)

Clinical Context:  Candesartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. In addition, candesartan does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.

Eprosartan (Teveten)

Clinical Context:  Eprosartan is a nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. In addition, eprosartan does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.

Irbesartan (Avapro)

Clinical Context:  Irbesartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II at the tissue receptor site In addition, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.

Losartan (Cozaar)

Clinical Context:  Losartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. In addition, Losartan does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.

Olmesartan (Benicar)

Clinical Context:  Olmesartan blocks the vasoconstrictive effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptors in vascular smooth muscle. Its action is independent of the pathways for angiotensin II synthesis.

Valsartan (Diovan)

Clinical Context:  Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from AT1 receptors and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

In addition, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.

Class Summary

These agents are used for vasodilation and for their possible antifibrotic and anti-inflammatory effects.

Lidocaine (Xylocaine)

Clinical Context:  Lidocaine is an amide local anesthetic; it inhibits depolarization of type C sensory neurons by blocking sodium channels.

Bupivacaine (Marcaine)

Clinical Context:  Bupivacaine decreases permeability to sodium ions in neuronal membranes. This results in the inhibition of depolarization, blocking the transmission of nerve impulses.

Class Summary

Local anesthetics are used for local pain relief. Local infiltration of lidocaine or bupivacaine at the base of the involved digits decreases sympathomimetic input, reduces ischemic pain, and improves blood flow.

Acetylcysteine (Acetadote)

Clinical Context:  Acetylcysteine may prevent worsening of baseline renal insufficiency. It may scavenge oxygen-derived free radicals and improve endothelium-dependent vasodilation.

Class Summary

Agents in this class may be used in patients with systemic sclerosis and digital ulcers.

Botulinum toxin type A (BOTOX)

Clinical Context:  This agent binds to receptor sites on motor nerve terminals and inhibits the release of acetylcholine, which in turn inhibits the transmission of impulses in neuromuscular tissue.

Anticoagulants, Hematologic

Clinical Context:  In patients with rapidly advancing ischemia, anticoagulant therapy may be necessary. Anticoagulants prevent recurrent or ongoing thromboembolic occlusion of the vertebrobasilar circulation.

Heparin

Clinical Context:  Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse thrombi but is able to inhibit further thrombogenesis. Heparin prevents recurrence of a clot after spontaneous fibrinolysis.

Class Summary

These agents produce symptomatic improvement in strength, autonomic symptoms, or both in some patients.

What is Raynaud phenomenon?What is the difference between primary and secondary Raynaud phenomenon?What are the diagnostic criteria for primary Raynaud phenomenon?Which groups are at risk of developing an autoimmune disease due to Raynaud phenomenon?What is the first line of therapy for primary and secondary Raynaud phenomenon?What is the pathophysiology of Raynaud phenomenon?What are the mechanisms for the pathogenesis of primary and secondary Raynaud phenomenon?What is the role of vascular abnormalities in the pathogenesis of Raynaud phenomenon?What is the role of neural abnormalities in the pathogenesis of Raynaud phenomenon?Which intravascular abnormalities are associated with the pathogenesis of Raynaud phenomenon?What causes primary Raynaud phenomenon?What are the causes of secondary Raynaud phenomenon?What is the prevalence of primary and secondary Raynaud phenomenon in the US?What are the racial predilections of Raynaud phenomenon?How does the prevalence of Raynaud phenomenon vary by sex?How does the prevalence of Raynaud phenomenon vary by age?What is the prognosis of primary Raynaud phenomenon?What is the prognosis of secondary Raynaud phenomenon?What information about Raynaud phenomenon should patients receive?What are the signs and symptoms of Raynaud phenomenon?What should be noted when considering occupational history of patients with Raynaud phenomenon?Which autoimmune disorders are associated with secondary Raynaud phenomenon?Which infectious syndromes are associated with secondary Raynaud phenomenon?Which neoplastic syndromes are associated with secondary Raynaud phenomenon?What are the environmental risks for Raynaud phenomenon?Which metabolic syndromes are associated with secondary Raynaud phenomenon?Which hematologic syndromes are associated with secondary Raynaud phenomenon?Which medications increase the risk for Raynaud phenomenon?Which findings from exam of the digits suggest primary or secondary Raynaud phenomenon is suspected?What is the role of nailfold capillary microscopy in the evaluation of secondary Raynaud phenomenon?How is a cold challenge test used to evaluate Raynaud phenomenon?Which physical finding is required for a diagnosis of Raynaud phenomenon?What are the signs and symptoms of other syndromes associated with secondary Raynaud phenomenon?Which anatomic syndromes should be considered in the differential diagnosis of Raynaud phenomenon?Which circulatory syndromes should be considered in the differential diagnosis of Raynaud phenomenon?Which vasospastic syndromes should be considered in the differential diagnosis of Raynaud phenomenon?Which disorders should be considered in the differential diagnosis of Raynaud phenomenon?Which drugs should be considered in the differential diagnosis of Raynaud phenomenon?What are the differential diagnoses for Raynaud Phenomenon?How is Raynaud phenomenon diagnosed?What is the role of lab studies in the diagnosis of Raynaud phenomenon?Which lab tests may be useful in the workup of Raynaud phenomenon?What is the role of MRI in the diagnosis of Raynaud phenomenon?What are the treatment options for Raynaud phenomenon?What is the first-line therapy for primary Raynaud phenomenon?What are the treatment options for secondary Raynaud phenomenon?What drugs are used in the treatment of secondary Raynaud phenomenon?Which nondrug therapies may be used in the treatment of primary Raynaud phenomenon?What is the role of laser therapy in the treatment of Raynaud phenomenon?What is the role of acupuncture and biofeedback in the treatment of Raynaud phenomenon?What is the role of calcium channel blockers in the treatment of Raynaud phenomenon?Why is it important that blood pressure be monitored regularly in patients with Raynaud phenomenon?What other medications are used to treat Raynaud phenomenon?What is the role of topical nitroglycerin in the treatment of Raynaud phenomenon?What is the role of SSRIs in the treatment of Raynaud phenomenon?What is the role of antiplatelet agents in the treatment of Raynaud phenomenon?How is critical digital ischemia treated in patients with secondary Raynaud phenomenon?Which specialist consultations are required for the treatment of Raynaud phenomenon?What dietary modifications may be beneficial in Raynaud phenomenon?Which medications are used to treat Raynaud phenomenon?Which medications in the drug class Neuromuscular Blocker Agents, Botulinum Toxins are used in the treatment of Raynaud Phenomenon?Which medications in the drug class Metabolic & Endocrine, Other are used in the treatment of Raynaud Phenomenon?Which medications in the drug class Local Anesthetics, Amides are used in the treatment of Raynaud Phenomenon?Which medications in the drug class ARBs are used in the treatment of Raynaud Phenomenon?Which medications in the drug class Endothelin Antagonists are used in the treatment of Raynaud Phenomenon?Which medications in the drug class Antidepressants, SSRIs are used in the treatment of Raynaud Phenomenon?Which medications in the drug class Phosphodiesterase-5 Enzyme Inhibitors are used in the treatment of Raynaud Phenomenon?Which medications in the drug class Nitrates, Angina are used in the treatment of Raynaud Phenomenon?Which medications in the drug class Prostaglandins are used in the treatment of Raynaud Phenomenon?Which medications in the drug class Calcium channel blockers are used in the treatment of Raynaud Phenomenon?

Author

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

Disclosure: Nothing to disclose.

Coauthor(s)

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

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Specialty Editors

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

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

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Disclosure: Nothing to disclose.

Additional Contributors

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

Disclosure: Received consulting fee from Genentech for consulting; Received consulting fee from Centacor for consulting; Received consulting fee from Novartis for review panel membership.

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

Disclosure: Nothing to disclose.

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

Raynaud phenomenon showing demarcation of color difference.

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

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.

Raynaud phenomenon showing demarcation of color difference.