Raynaud Phenomenon - Clinical Tree

Raynaud phenomenon (RP) was first described by Maurice Raynaud (1834–1881) in 1862 when he reported 25 patients with intermittent digital ischemia and recognized the relationship of local cold and emotional stress in the causation of the episodes. RP is an exaggeration of the normal physiologic response and is defined as episodic pallor or cyanosis of the fingers caused by vasoconstriction of small digital arteries or arterioles occurring in response to cold or emotional stress. Although this term typically applies to the fingers, the toes can also be affected. The hallmark of RP is the change in skin temperature and color brought on by exposure to cold. A typical vasospastic attack is characterized by the sudden onset of pallor of part or all of one or more digits. Cyanosis follows as static blood in the capillaries becomes desaturated. The attack subsides with the return of arterial inflow, and postischemic vasodilatation results in hyperemia and rubor of the skin ( Figs. 142.1 and 142.2 ).

Raynaud’s through the years has been described as both a disease and phenomenon. Early literature referred to Raynaud’s as “Raynaud’s disease” almost exclusively until the 1940s. The nomenclature “Raynaud phenomenon” started appearing in the literature soon thereafter. People have differentiated Raynaud disease, which is primary Raynaud’s, versus Raynaud phenomenon, which is secondary or associated with other diseases. This nomenclature can be confusing, as many patients who start out with primary Raynaud’s will develop associated connective tissue disorders over time. We have preferred to refer to all people with this condition as having Raynaud syndrome (RS).

RP consists of two sub-types: primary and secondary RP. Primary RP is the most common and is the idiopathic form. Secondary RP is associated with an underlying disease process, such as systemic sclerosis, rheumatoid arthritis, or other connective tissue disease (CTD). Primary RP is considered to be a benign process and is not associated with structural vascular change. In contrast, patients with secondary RP have some degree of fixed vascular obstruction to blood flow, which decreases the threshold for cold-induced vasospasm. This can progress to digital ulceration, scarring, or gangrene.

Epidemiology and Natural History

The prevalence of RP in the general population varies greatly with climate and ethnic origin. Several epidemiologic studies investigating disease prevalence have been performed, primarily in populations in colder climates. Overall estimates of disease prevalence in the general population range from 3.3% to 22%. Women are also more commonly affected than men, with a prevalence of 0.5% to 8.3% in men and 2.5% to 21% in women. Two longitudinal population-based studies have been performed to determine the incidence of primary RP. In a 14-year study in a community in southern France, the annual incidence of primary RP was 0.25%. In addition, similar findings were noted in the epidemiologic analysis of the Framingham off spring study cohort. Over a 7-year period, the incidence of RP was 2.2% in women and 1.5% in men. Patients with primary RP typically follow a benign clinical course, with up to 33% experiencing a resolution of symptoms over time. In contrast, secondary RP is more frequently associated with digital ulcers and amputations. Furthermore, secondary RP is a marker for early mortality compared to age and sex-matched controls, particularly in the presence of abnormal nail-fold capillaroscopy or decreased hemoglobin levels.

Normal Arterial Flow to the Hand

Circulation in the hand is complex with frequent anatomic variants. The deep and superficial arches supply the metacarpal arteries and in turn the proper digital arteries ( Fig. 142.3 ). In most patients, branches of both the deep and superficial arches provide blood flow to all five fingers, and the two palmar arches provide important collateral flow between the radial and ulnar systems. The superficial arch is incomplete in 21.5% of people. ^, Severe digital ischemia can occur with occlusion of the radial or ulnar artery and an incomplete superficial arch.

Figure 142.3, Normal hand arterial anatomy. 1 , radial artery; 2 , ulnar artery; 3 , deep palmer arch; 4 , common digital (metacarpal) artery; 5 , proper digital artery.

The metacarpal arteries in the palm originate from the superficial arch and provide blood flow to the digits. At the web space, the common digital (metacarpal) arteries branch to supply the proper digital arteries that run the length of each finger. In at least 86% of extremities, all five digits are supplied by arteries from both the deep and superficial arches. Each finger has two digital arteries, which is important in preventing critical ischemia if one digital artery becomes occluded. The end of the finger is highly vascular with a dense network of blood vessels in the pulp of the fingers.

Regulation of Blood Flow in the Digits

Blood flow in the digits is highly variable and can range from less than 1 mL/min per 100 mL of tissue to 180 mL/min. Blood flow to the skin of the digits has two functions, nutritional and thermoregulatory. Approximately 80% to 90% of blood flow through the digits is controlled by thermoregulatory mechanisms and serves an important role in controlling body temperature. Blood vessels that are superficially located in the skin dilate to radiate excess heat to the environment, and this reduces body core temperature. In response to cold, these arteries constrict to decrease blood flow and conserve body heat.

Maximum vasoconstriction in response to cold occurs at 10°C to 20°C. At lower temperatures, cold-induced vasodilatation results in slight reopening of arteries to allow a trickle of blood into the digits. With cold exposure, there is a regular rhythmic fluctuation in finger flow caused by periods of vasoconstriction and vasodilatation in the fingers every 30 seconds to 2 minutes. Other investigators have found similar rhythmic fluctuations in finger flow with a frequency of 5 to 10 per minute. These alternating periods of vasoconstriction and dilatation have been called the hunting response. This cold-induced vasodilatation, which protects the fingers from freezing in a cold environment, is impaired in those with secondary RP because of the presence of occlusive arterial disease.

Pathogenesis

The exact pathogenesis of RP is unknown. Originally, Raynaud proposed that hyperactivity of the sympathetic nervous system was the cause. Lewis in 1929, disproved this theory by demonstrating that blockade of digital nerve conduction did not prevent vasospasm. Lewis, in turn, theorized that “local vascular fault” in the digital arteries causing increased sensitivity of the blood vessel to cold led to RP. It is most likely a multifactorial problem involving a combination of vascular, neural, and humoral factors ( Fig. 142.4 ).

Figure 142.4, There are many potential causes of vasospastic attacks in primary Raynaud phenomenon. Norepinephrine (NE) released from the sympathetic nerve ending acts on the post junctional α-2 receptor located on vascular smooth muscle. Local cooling enhances the response of the α-2 receptor, thereby causing increased arterial contraction. Endothelial dysfunction may lead to insufficient nitric oxide or increased endothelin-1, which changes the balance toward arterial constriction. Activated platelets release thromboxane A2 (TXA2) and serotonin (5-hydroxytryptamine [5-HT] ), which may aggravate arterial vasospasm. A decrease in intraluminal distending pressure may decrease the “critical dosing pressure” threshold and result in a vasospastic attack.

Vascular

Impaired Vasodilatation

Vascular endothelial cells synthesize several vasodilating and vasoconstricting substances. Endothelial-derived relaxing factors include nitric oxide (NO), prostacyclin, adenosine triphosphate (ATP), and bradykinin. NO is a potent vasodilator synthesized from amino acid l -arginine by the activity of the enzyme NO synthase. NO diffuses from the endothelium into smooth muscle, where it activates guanylate cyclase to increase intracellular guanosine monophosphate (cGMP), which leads to vascular relaxation. Decreased NO formation can be found in patients with both systemic sclerosis and RP. S-nitrosothiols are bioactive forms of NO that are involved in cell signaling and have been shown to be decreased in patients with systemic sclerosis and RP. Additionally, decreased levels of asymmetric dimethyl-arginine, an inhibitor of endothelial NO synthase, have also been demonstrated in patients with secondary RP. A deficiency of one or more of these factors could potentially increase responsiveness of digital arteries to vasoconstrictive influences and increase the likelihood of vasospasm.

Endothelial dysfunction has been shown to be an important cause of RP in numerous studies. In one study, patients underwent a series of sequential infusions with acetylcholine, prostacyclin, glyceryl trinitrate, and l -arginine. Patients with a history of RP had a greater digital artery vasodilator response to intra-arterial glyceryl trinitrate (an endothelium-independent vasodilator), whereas in control patients, the difference in response was less pronounced.

Increased Vasoconstriction

The endothelial cell also produces factors that cause vessel contraction, such as endothelin-1 (ET-1), which is a potent vasoconstrictor, as well as a promoter of fibroblast and smooth muscle proliferation. Plasma ET-1 levels become elevated in response to cold, which may suggest an association between the rise in ET-1 levels and cold-induced vasoconstriction. A threefold rise in ET-1 concentration has been reported in subjects with primary RP. However, more recent literature has challenged the relationship of ET-1 and RP. Smyth and colleagues found that increases in ET-1 levels in patient with both primary RP and scleroderma were similar to control subjects with cooling-induced vasospasm.

Angiotensin is another endogenous peptide with vasoconstrictive effects that has been implicated in the mechanism of vasospasm. The exact mechanism of involvement of angiotensin in RP remains unclear. Increased levels of angiotensin II have been shown in patients with scleroderma. However, activation of the renin–angiotensin system has not been demonstrated in primary RP.

Neural Factors

The current focus of RP pathophysiology has been on alterations in peripheral adrenoceptor activity. Early laboratory studies showed a marked reduction in cold-induced digital arterial vasospasm after the intra-arterial administration of reserpine. This suggested that patients with RP may possess abnormal adrenergic receptors that become increasingly sensitive to stimulation after exposure to cold.

Characterization of α1 and α2 adrenoceptors has led to an improved understanding of the mechanisms of RP. Sympathetic nerves can respond to cold and emotional stress by releasing neurotransmitters such as norepinephrine, which act on the postsynaptic α2 receptor and cause vascular smooth muscle contraction. Cold also causes increased affinity of the α2 receptor for norepinephrine, which results in enhanced smooth muscle contraction in the cold. The initiation of the α2 adrenoceptor to cold is due to the activation of Rho-protein kinase signaling.

Freedman and colleagues studied the effects of brachial artery infusions of an alpha-1, an alpha-2 antagonist, or both while vasospastic attacks were induced by cooling in 23 patients with idiopathic RP. They found that in patients who were infused with yohimbine (α2 antagonist), there were significantly fewer attacks compared to the non-infused hand and compared to the group receiving prazosin (α1 antagonist) alone, demonstrating the importance of α2 adrenoceptors. However, in another randomized, controlled trial to evaluate the efficacy of a high potency α2c adrenoceptor antagonist (ORM-12741) in patients with systemic sclerosis, subjects randomized to ORM-12741 had a longer time to temperature recovery time. These mixed results show continued investigations regarding the effect of α adrenoceptors in the pathophysiology of RP and the therapeutic potential of adrenoceptor antagonists are needed.

Humoral Factors

Many circulating humoral factors have been implicated in the pathogenesis of RP. These include hormonal, genetic, platelet activation, and fibrinolysis. RP is more frequent in women than men and tends to be more frequent and severe between menarche and menopause. Investigators have demonstrated elevated sympathetic tone and decreased basal cutaneous circulation in women in comparison to men. The role of estrogen is less clear. In human cell culture and in mouse models, estrogen has been demonstrated to increase expression of α2 adrenoceptors. Approximately one-quarter of patients with primary RP have a family history of RP in a first-degree relative. However, it has been difficult to differentiate genetic factors from shared environmental causes. Although a number of chromosomal regions have been evaluated in genomic studies, no significant differences in allelic frequency have been directed between patients with RP and normal controls.

Activation of platelets and increased levels of serotonin in the plasma have been detected in patients with RP. Elevated circulating levels of activated platelet products, such as thromboxane and B-thromboglobulin, have been induced by cooling of subjects with RP. The relationship between serotonin elevations in the pathogenesis of RP is less clear and remains to be defined.

Abnormalities of fibrinolysis have been primarily implicated in patients with secondary RP, and elevated levels of tissue plasminogen activator inhibitor have been shown in patients with scleroderma. Impairment in thrombolysis is also thought to predispose to fibrin deposition and vascular obstruction.

Risk Factors

Many factors have been found to be associated with RP. These include genetic factors, such as gender; occupational; and drug exposure. RP predominantly affects young women, and has a male:female ratio close to 1:1.6. The usual age of onset ranges from 11 to 45, while older patients with RP are more likely to have a contributing underlying arterial disease. The relationship between smoking and RP is less clear. In a study of the Framingham heart study offspring cohort, no association was found between smoking and RP in women; however, there was a significant association in men, particularly in those with other cardiovascular risk factors, with an odds ratio of 2.6. Similar to smoking, the relationship between alcohol and RP remains to be clarified. A recent systematic review and meta-analysis of observational studies reported smoking as a major risk factor with an odds ratio of 1.27, while alcohol had an odds ratio of 0.33. An association between cannabis use and RP has also been reported.

Vibration-induced RP was first recognized in 1918 by Hamilton, and it has been estimated that as many as 1.5 million American workers involved in a variety of occupations using vibrating tools are now at risk. Chronic vibration appears to cause structural damage to the arterial wall with hypertrophy of the intima and media. Vibration is believed to cause sympathetic overactivity, endothelial damage, and smooth muscle hypertrophy, leading to vibration-induced vasospasm. The prognosis may be poor because of the development of digital artery obstruction after prolonged exposure to vibration.

Several drugs have been implicated in the development of RP. For example, the incidence of RP in hypertensive patients taking beta blockers was 40% in a Scandinavian study in which patients responded to a questionnaire. Vasospasm occurs with both selective and nonselective beta-blockers. Despite this, many patients with RP tolerate beta blockers, and many studies show no adverse effects on digital blood flow. Therefore, beta-blockers are not contraindicated in patients with RP. Other drugs associated with RP include chemotherapeutic agents such as cisplatin, vinblastine and bleomycin, bromocriptine, amphetamine, cocaine, and ergot preparations used for migraine headaches, which are a well-known cause of severe extremity vasospasm and ischemia. More recently the tyrosine kinase inhibitors (e.g., imatinib, nilotinib, erlotinib) have been associated with the development of RP although the mechanism is unknown.

Associated Diseases

Secondary causes of RP are typically associated with some degree of fixed digital arterial obstruction. When the artery is narrowed because of preexisting large- or small-vessel disease, there is a lower “critical closing pressure,” and a relatively normal vasoconstrictor response to cold or other stimuli will result in temporary closure of the vessel. RP is common in CTDs such as scleroderma, where intimal hyperplasia, thrombosis, and fibrosis result in luminal narrowing of the digital arteries, but this process may also involve the more proximal arteries of the hand and forearm.

The list of secondary causes of RP is extensive ( Box 142.1 ). In a large series of 1039 patients with RP referred to the Oregon Health and Science University from 1970 to 1995, more than half had primary vasospasm with no identifiable disease. In those with associated abnormalities, the most common underlying disorder was CTD, which accounted for 27% of cases of RP. Scleroderma was the most likely CTD, followed by undifferentiated and mixed CTD. Atherosclerosis was less common, followed by “hypersensitivity angiitis,” Buerger disease, cancer, and vibration-induced white finger. A wide range of cancers have been associated with secondary RP. The most common associated malignancies are adenocarcinomas and hematologic malignancies, and possible mechanisms of arterial disease caused by malignancy include coagulopathy, cryoglobulinemia, or small-vessel vasculitis ( Fig. 142.5 ).

BOX 142.1

Conditions Associated with Secondary Raynaud Phenomenon

Connective Tissue Diseases

Progressive systemic sclerosis (scleroderma)
Systemic lupus erythematosus
Rheumatoid arthritis
Sjögren syndrome
Mixed connective tissue disease
Overlap connective tissue disease
Dermatomyositis and polymyositis
Vasculitis (small, medium-sized vessels)

Occlusive Arterial Disease

Atherosclerosis
Thromboangiitis obliterans (Buerger disease)
Giant cell arteritis
Arterial emboli (cardiac and peripheral)
Thoracic outlet syndrome

Occupational Arterial Disease

Hypothenar hammer syndrome
Vibration induced

Drug-Induced Vasospasm

β-Adrenergic blocking drugs
Vasopressors
Ergot
Cocaine
Amphetamines
Vinblastine/bleomycin

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