US Pharm. 2008;33(4):36-48.

Raynaud's phenomenon was named for French physician Maurice Raynaud (1834-1881) and was first described in 1862. This disorder is referred to as Raynaud's disease when the cause is unknown and Raynaud's phenomenon when it is secondary to another condition.1 It is characterized by attacks of vasospasm of digital arteries and arterioles that leads to intermittent pallor or cyanosis of the skin. It primarily affects the fingers, usually distal to the knuckles, and less commonly the toes. More rarely, Raynaudsymptoms may affect the nose, tongue, and ear lobes. Several case reports have described Raynaud's as affecting the nipples of breastfeeding women and suggest that this may be a treatable cause of painful breastfeeding, especially if no other signs of infection or trauma are present.2-4 These attacks may last from minutes to hours and are relatively benign in most patients.

Raynaud's phenomenon may be secondary to many more serious conditions and may foretell the development of these diseases by months or years. Therefore, any patient who presents with complaints of Raynaud's symptoms should be carefully evaluated for any underlying cause, undergo a thorough drug history, and be educated as to the importance of lifestyle changes that might control disease symptoms.

Epidemiology and Pathophysiology
Due to diagnostic uncertainties, the precise incidence of Raynaud's symptoms in the general population is unclear. Although some sources cite an incidence as high as 20%, 1,5 more recent reviews place the prevalence at 3% to 5%.6 It most commonly occurs in women of childbearing age.5 Raynaud's disease, also known as primary Raynaud's, is caused by reversible spasm of the smallest arteries and arterioles; no abnormalities of the endothelium are observed. In these cases, the erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), and nailfold capillaries are usually normal. 7 The arterial vasospasm that characterizes Raynaud's is thought to be secondary to exaggerated reflex sympathetic vasoconstriction. The threshold for vasospastic response is lowered by anything that activates sympathetic outflow or leads to the release of catecholamines, such as cold temperatures or emotional upset.8 A clinical association with migraine headaches, variant (Prinzmetal's) angina, and pulmonary hypertension suggests a common mechanism for vasospasm in multiple arterial beds.9 There definitely appears to be a familial component to primary Raynaud's; smoking worsens the frequency and intensity of attacks, and there seems to be a hormonal component to the condition.6,10,11

Primary Raynaud's usually results in a milder form of the disease than do most cases of Raynaud's phenomenon, and many cases do not require pharmacologic treatment. The condition may progress in approximately 30% of patients, although long-term complications are rarely severe enough to cause gross tissue loss. The skin of the digits may become smooth, shiny, and tight with the loss of subcutaneous tissue (sclerodactyly), small painful ulcers may appear on the tips of the fingers, and, in very advanced cases, the arterial intima may thicken and thromboses may form in small arteries.

Raynaud's phenomenon, also known as secondary Raynaud's, usually begins later in life and includes a variety of pathophysiologic features including vasospasm, endothelial cell changes, vessel obstruction, and hemorheologic deformations.5,7 Because secondary Raynaud's is associated not only with vasospasm but also with fixed blood vessel defects, the ischemia is often much more severe and more difficult to treat.12,13 The differences between primary and secondary Raynaud's are detailed in TABLE 1.

Many serious, potentially life-threatening conditions may be associated with secondary Raynaud's. Secondary Raynaud's is most commonly associated with scleroderma (system sclerosis) or limited scleroderma (CREST syndrome), occurring in 90% to 95% of all cases.7 More important, secondary Raynaud's may be the initial manifestation of disease in 70% of patients with scleroderma, and it may present several years before more obvious signs of connective tissue disease (CTD) are evident.5 Because the Raynaud's that develops in conjunction with scleroderma is often very severe and may progress to gangrene and/or autoamputation, it is important for prognostic and therapeutic reasons to determine if these symptoms are associated with an underlying condition that may benefit from earlier and more aggressive treatment.

In a study from 2003, 113 women and 29 men were divided into either "primary" or "possible secondary" Raynaud's groups. Overall, 20 (14.1%) of these patients progressed to a definite CTD diagnosis over a median follow-up period of 12.4 years. Factors associated with transition to a CTD included initial presence of ANA, thickening of fingers, a higher age at onset of Raynaud's symptoms, and female sex.14 An earlier meta-analysis involving 639 patients with presumed primary Raynaud's documented the development of a secondary disorder in 81 (12.6%) of these patients, at a mean time of 10.4 years from the onset of Raynaud's symptoms.15

Secondary Raynaud's may also be associated with several other rheumatologic or dermatologic conditions including rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, and polymyositis. In a review of 105 cases (69 polymyositis, 36 dermatomyositis), it was noted that Raynaud's symptoms were an early presenting sign in 51% of the cases.16

Atherosclerosis may be associated with symptoms of secondary Raynaud's, especially in older male patients. One study assessed 103 patients suffering from Raynaud's phenomenon without any obvious underlying disease. Forty-four (43%) of these patients were determined to have atherosclerotic vascular disease, almost one half of whom had a dyslipidemia, most commonly of familial origin.17 In younger men who smoke, thromboangiitis obliterans (Buerger's disease) may be associated with secondary Raynaud's.

Other causes include disorders that increase blood viscosity (e.g., cryoglobulinemia, myeloproliferative disorders), cancer, hypothyroidism, anorexia nervosa, neurologic disorders (e.g., stroke, poliomyelitis, carpal tunnel syndrome), traumatic injuries (e.g., vibration injury, electric shock injury, cold injury/frostbite), exposure to vinyl chloride, continued exposure to cold (e.g., frozen food packing), typing, or piano playing. Secondary Raynaud's is quite common in people whose jobs involve the use of vibrating equipment (e.g., drills, jackhammers, and drums).

Secondary Raynaud's may also be associated with several drug therapies including beta-blockers, ergot alkaloids, sympathomimetics, clonidine, narcotics, cocaine, methysergide, some chemotherapeutic agents (e.g., bleomycin, vinblastine, cisplatin), estrogen, and cyclosporine. Some patients may benefit from a change to a low-estrogen or progesterone-only oral contraceptive.

Clinical Presentation and Diagnosis
Raynaud's is characterized by intermittent attacks of blanching or cyanosis of the digits, which is usually precipitated by exposure to cold temperatures and/or emotional upset.6 The affected digits often feel cold and numb, and there is a typical triphasic series of skin color changes, which proceeds from pallor (white) to cyanosis (blue) to reactive hyperemia (red). A painful throbbing may occur during the hyperemic phase, and paresthesias are frequent. Raynaud's is diagnosed primarily by a history of these classic symptoms, which are relatable to common precipitating factors, or the finding of a history of exposure to environmental or occupational factors that are associated with secondary Raynaud's. No single office or laboratory test confirms the diagnosis.

In secondary Raynaud's, the signs and symptoms of the underlying disorder may or may not be present, since Raynaud's may be an early sign of such disorders. The presence of Raynaud's symptoms indicates the need to rule out an autoimmune process, which requires the examination of specific laboratory parameters such as the complete blood count (CBC), ESR, ANA, rheumatoid factor, and disease-specific autoantibodies. The finding of distorted capillaries in the nailfolds using an ophthalmoscope may be the best predictor of associated CTD.6,18 Patients with a history of single-digit or asymmetric attacks should undergo testing for presence of large-artery disease, such as vasculitis, atherosclerosis, or other embolic conditions. Thyroid function tests may be indicated to rule out hypothyroidism. In older patients who present with new-onset Raynaud's symptoms, a malignancy should be strongly considered during diagnostic workup, especially in patients who also present with symptoms consistent with bone pain. Patients diagnosed with primary Raynaud's should be followed closely for clinical or laboratory signs that suggest development of a secondary disorder. If such signs do not develop within a two-year period, some clinicians suggest that a secondary disease is unlikely.6

Nonpharmacologic Treatment
Most patients with primary Raynaud's experience only mild and infrequent episodes. Therefore, patient education, reassurance, and nondrug interventions may often be adequate.8 Patients should be instructed to avoid inciting environmental factors such as direct contact with frozen foods or cold drinks. These patients may need to wear insulation against cold weather or use electric or chemical warming devices.12 Gloves may need to be worn in temperatures that would be considered mild by normal individuals. It is important to remove any predisposing drugs (as previously described) from the patient's medication regimen. These patients should be strongly encouraged to stop smoking, which aggravates optimal oxygen delivery to the tissues.12 Biofeedback and relaxation techniques may help some patients, especially those who demonstrate Raynaud's symptoms secondary to emotional upset. If ulcerations develop, patients should be encouraged to keep them sterile and to see a doctor if an infection is present. If such ulcers progress or are severe, a wound care specialist may need to be consulted.

The first-line therapy for secondary Raynaud's is to treat the underlying disorder, if possible. These patients may develop increasingly severe Raynaud's symptoms if the underlying disorder continues untreated. In addition, as the underlying disease worsens, the treatment of complications from Raynaud's becomes increasingly difficult.

Pharmacologic Treatment

Several drugs may be used to treat the symptoms of Raynaud's if nonpharmacologic treatments are inadequate. A summary of recommended agents is listed in TABLE 2.

Calcium Channel Blockers: The most commonly used drugs for the treatment of Raynaud's symptoms are the dihydropyridine calcium channel blockers (CCBs), of which nifedipine is the most studied agent. These agents act primarily by increasing vasodilation and decreasing vasospasm in the affected arteries; however, they may also inhibit the growth and proliferation of vascular smooth muscle cells, depress T-cell function, and possess limited antiplatelet activity.19,20 Most of the early studies demonstrating the efficacy of these agents were done with immediate-release nifedipine, which led to a significant number of adverse effects, including headache, hypotension, flushing (~10%), tachycardia, and peripheral ankle or pedal edema (~30%).12,19

Two recent studies have shed further light on the efficacy and tolerability of these agents. The Raynaud's Treatment Study Investigators compared sustained-release (SR) nifedipine with temperature biofeedback in the treatment of 313 patients with primary Raynaud's in a randomized trial with one-year follow-up. These patients were diagnosed by medical history and normal nailfold capillaries and had a history of two or more attacks per day during the previous cold season. Patients treated with nifedipine demonstrated a 66% decrease in verified attacks versus placebo (P <.001); however, adverse effects associated with nifedipine resulted in therapy discontinuation in 15% of the patients. Temperature biofeedback training did not decrease attacks significantly versus control biofeedback. The authors concluded that SR nifedipine is a safe and effective treatment for primary Raynaud's and is more effective than temperature biofeedback.1

A meta-analysis investigated the efficacy of CCBs for the treatment of Raynaud's secondary to scleroderma. This study analyzed eight randomized trials, which included a total of 109 patients. These patients demonstrated a mean reduction of 8.3 attacks every two weeks, and the attacks were judged to be about 35% less severe. The authors concluded that CCBs appear to lead to significant clinical improvement in both the frequency and severity of ischemic attacks, although the effect was judged to be "moderate." They also suggested that low dosing may have contributed to the modest effects.13 However, patients with secondary disease, in whom structural damage to the vessel wall is pronounced and fixed, would not be expected to respond as well to CCBs as patients suffering primarily from vasospasm (primary Raynaud's).

Several other CCBs have also demonstrated efficacy in the treatment of Raynaud's symptoms, including amlodipine, felodipine, nisoldipine, and isradipine.21-24 Nicardipine has been investigated in several studies with mixed results. 20,25-27 Although not a dihydropyridine agent, diltiazem has also been investigated for the treatment of Raynaud's symptoms.28 It is probably less effective than the dihydropyridine class, and its effectiveness has been demonstrated for primary Raynaud's only; however, it may be a reasonable alternative for patients who cannot tolerate the dihydropyridine agents. The CCBs should be used for up to six weeks before a therapeutic assessment is made.19

ACE Inhibitors and ARBs: An excellent review of the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in the treatment of Raynaud's was recently published.29 These authors reviewed several small, short-term studies (12 weeks or less) that had evaluated captopril, enalapril, and losartan. They concluded that these agents may provide minor benefits, although no definitive evidence exists to suggest that they are superior to dihydropyridine CCBs.

However, two of the studies did find a significantly decreased number of attacks with the use of losartan, one in patients with primary Raynaud's and one that included patients with secondary Raynaud's.30,31 The second study directly compared losartan with nifedi!= pine in a randomized, parallel group, controlled trial that included 25 patients with primary Raynaud's and 27 patients with Raynaud's secondary to scleroderma. A reduction in the severity of the episodes followed both treatments, but the effect was greater in the losartan arm (P <.05). Episode frequency was decreased only in the losartan group (P <.01); however, as might be expected, clinical benefit was greatest in the primary Raynaud's group. The authors suggested that losartan may have additional disease-modifying potential if used for secondary Raynaud's associated with scleroderma.31

In conclusion, there is not convincing evidence to favor these renin-angiotensin mediators over CCBs for first-line therapy, but they might be recommended as an alternative if CCBs are ineffective or not tolerated. Losartan may be preferred over the ACE inhibitors, especially in patients with secondary Raynaud's.

PDE-5 Inhibitors: The phosphodiesterase type 5 (PDE-5) inhibitors have demonstrated efficacy in the treatment of Raynaud's symptoms in several case reports and clinical trials. A comprehensive summary of this topic was recently published.32 These agents (i.e., sildenafil, tadalafil, and vardenafil) decreased the metabolism of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells, which results in enhanced cGMP-dependent microvascular and macrovascular dilation. It was originally reported that the treatment of pulmonary hypertension with sildenafil in a patient with scleroderma was associated with significant improvement of coexisting secondary Raynaud's. 33 In several subsequent case reports, these agents have been shown to provide symptomatic improvement, ulcer healing, and objective improvements in blood flow in patients with both primary and secondary Raynaud's.32

Vardenafil was investigated in an open-label pilot study of 40 patients, 33 of whom had secondary Raynaud's. Overall, digital blood flow improved in 70% of these patients, and in the patients who responded, it improved by 35% during a cold-exposure test after two weeks of therapy (P <.01). Clinical symptoms improved in 68% of the patients, and the Raynaud condition score (RCS) improved significantly (P <.001). The response rates of patients with primary or secondary Raynaud's were similar, as was the response rates of smokers versus nonsmokers.34

Tadalafil was compared to pentoxifylline in a small study of patients with severe Raynaud's secondary to autoimmune disease. The tadalafil-treated patients showed significant improvement in the RCS and significant decreases in both attack frequency and duration. These patients also demonstrated continued improvement over the four-week treatment period.35

Sildenafil was investigated in a double-blind, placebo-controlled, fixed-dose, crossover study in 16 patients with symptomatic secondary Raynaud's resistant to vasodilator therapy. While taking sildenafil, the mean frequency of Raynaud attacks was lower (P = .0064), the cumulative attack duration was shorter (P = .0038), and the mean RCS was lower (P= .0386). More impressively, the mean capillary blood flow velocity for all patients more than quadrupled after treatment with sildenafil (P = .0004). Only two patients discontinued sildenafil due to side effects, and 16 patients subsequently requested off-label continuation of therapy.36 Overall, the PDE-5 inhibitors appear to be a promising class of agents, especially for the treatment of patients with severe secondary Raynaud's who have not found relief with first-line vasodilators.

Fluoxetine: Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was compared with nifedipine for the treatment of Raynaud's symptoms in a study published in 2003. Serotonin is a selective vasoconstrictor, and infusion into the brachial artery has resulted in the characteristic sequential color changes associated with Raynaud's. In addition, anecdotal reports had suggested that fluoxetine may be beneficial in Raynaud's.37,38 Twenty-six patients with primary and 27 patients with secondary Raynaud's were randomly assigned to receive six weeks of treatment with fluoxetine or nifedipine. After a two-week washout period, each group was crossed over to the other treatment arm. Results demonstrated a reduction in attack frequency and severity in patients treated with either agent; however, the effect was statistically significant only in the fluoxetine-treated group. Subgroup analysis showed that the greatest response was seen in females and in patients with primary Raynaud's. No significant adverse effects occurred in the fluoxetine-treated group.39

Bosentan and Iloprost: For severe cases of secondary Raynaud's, usually associated with scleroderma, several studies and case reports have supported the use of either the oral endothelin receptor antagonist bosentan or the IV administration of the synthetic prostacyclin (PGI2) analogue iloprost. The efficacy of bosentan was suggested through its use for pulmonary arterial hypertension in scleroderma patients who experienced coincident prevention or healing of skin ulcers associated with severe Raynaud's.40,41 The efficacy of this agent has been reported primarily via case reports; however, the reported clinical benefits have been quite impressive in patients with severe tissue injury.42-45 A placebo-controlled, double-blind, prospective study of patients with pulmonary hypertension receiving bosentan demonstrated a 48% reduction in the mean number of new ulcers during the 16-week treatment period. In addition, a statistically significant improvement in hand function was observed. There was no difference between treatment groups in healing of existing ulcers.46

A study reported in 1989 compared the long-term effects of short-term iloprost infusion with those of nifedi!= pine in patients with Raynaud's secondary to scleroderma. Patients received iloprost at 2 ng/kg/minute for eight hours on three consecutive days with a further single infusion at week 8. The nifedipine dose was increased to 60 mg/day during the study. Both regimens produced a decrease in the number, duration, and severity of attacks; the mean number of digital lesions was also decreased with both treatments. However, more adverse effects were associated with nifedipine therapy. This study concluded that both iloprost and nifedipine are beneficial in the treatment of secondary Raynaud's.47

A more recent trial evaluated the effects of long-term cyclic therapy with iloprost compared with nifedipine on skin score and RCS in patients with Raynaud's secondary to scleroderma. Iloprost significantly reduced the skin score compared to nifedipine; however, there was no significant difference in RCS scores.48 IV iloprost is not available in the U.S.; however, a related agent, epoprostenol, might be considered for patients with critical ischemia.6

Other Agents: Both oral and topical nitroglycerin products have been used to treat the symptoms associated with Raynaud's; however, little controlled data exist to support the use of these agents, and systemic products are associated with bothersome side effects such as flushing, headache, and hypotension.6,12 The alpha1-receptor blocker prazosin has been found in two randomized controlled trials to be more effective than placebo in the treatment of Raynaud's secondary to scleroderma. However, the positive response is modest, and side effects such as dizziness, hypotension, and palpitations, may be limiting.49 Pentoxifylline, with or without aspirin, has been commonly used, but there is very little clinical trial information supporting its use. These therapies may be best reserved for more severely affected patients who have evidence of endothelial damage. These two agents, in combination with nifedi!= pine, may be effective in patients suffering from hand-arm vibration syndrome.50 The selective PDE-3 inhibitor cilostazol, which inhibits platelet aggregation and acts as a vasodilator, was studied in 40 subjects with Raynaud's. This agent increased brachial artery diameter but did not demonstrate positive benefits regarding microvascular flow or disease symptoms.51

Raynaud's is a disorder classically associated with transient digital ischemia in response to cold or emotional stress. It is classified into two distinct entities, which suggests important differences in diagnostic strategies, prognoses, and therapeutic choices. Primary Raynaud's (Raynaud's disease) is idiopathic, symmetric, associated with normal nailfold capillaries, generally presents an uncomplicated, self-limited course, and often responds adequately to nonpharmacologic measures. Secondary Raynaud's (Raynaud's phenomenon) is usually associated with an older age at onset, abnormal vessel pathology, the presence of a secondary cause on the basis of history and/or physical examination, a more severe clinical course (e.g., tissue necrosis, ulcerations, gangrene), and the need for definitive pharmacologic therapy

Important nonpharmacologic treatments include cold avoidance, stress management, and smoking cessation. When pharmacologic therapy is indicated, a dihydro!= pyr!= i!= dine CCB is usually preferred as first-line therapy. Rational alternatives include diltiazem, losartan, fluoxetine, or possibly an ACE inhibitor. For more severe cases, or those not responsive to these therapies, a PDE-5 inhibitor, bosentan, or, in very severe cases, epoprostenol may be considered. For patients with fixed arterial pathology, pentoxifylline and/or low-dose aspirin may be beneficial. In addition, in secondary Raynaud's, it is critical to treat the underlying cause as effectively as possible.

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