Raynaud Phenomenon and Vasomotor Syndromes

Epidemiology

Estimates of the prevalence of RP range from 5% to 20% in women and 4% to 14% in men. The large variation between studies reflects, in part, the ethnic balance of the populations studied, as well as the climate of the region where the study patients live. A study of children aged 12 to 15 in Manchester, United Kingdom, reported an overall prevalence of 18% in girls and 12% in boys with values increasing with age in this population. In general, RP is more common among women, younger age groups, and family members of patients with RP. ^{, ,} For obvious reasons, patients living in colder climates are more likely to present for evaluation and at younger ages. Although the large majority of patients with RP do not have, nor will they develop, an associated rheumatologic or vascular disorder, it is important to recognize that RP may herald significant rheumatic disease. RP occurs at high frequency (80% to 90%) in children with SSc or mixed connective tissue disease (MCTD) and is often the initial symptom of these disorders, preceding other manifestations of disease in some instances by years. New-onset RP should, therefore, prompt consideration and examination for signs and symptoms of systemic disease and, potentially, further rheumatologic evaluation.

Etiology/Pathogenesis

In his thesis published in 1862, Maurice Raynaud ascribed the features he saw to “increased irritability of the central parts of the cord presiding over the vascular innervations.” ^, Observing that local sympathectomy did not cure RP, Sir Thomas Lewis proposed in 1929 that RP was the result of a “local fault,” rather than a defect in the central nervous system. Current data support this view, suggesting that RP primarily represents excessive activation of normal local physiological vasomotor responses to cold temperature (i.e., lowering of blood flow to the skin, thereby reducing the loss of body heat and preserving core body temperature) and/or emotional stress. In broad terms, blood flow volume is regulated by an interactive system involving neural signals, cellular mediators, circulating hormones, and soluble vasoactive compounds. ^{, ,} The inherent tone, or contractile activity, of vascular smooth muscle varies substantially between different arterial structures, ranging from relatively high basal tone in the coronary circulation to low or absent in the pulmonary circulation, and can increase or decrease dramatically. Numerous mechanisms participate in the regulation of vascular tone, including both intrinsic functions of vascular smooth muscle and endothelial cells and extrinsic effects of nerves, adjacent tissues, circulating cells, and soluble factors ( Box 30.2 ). ^{, ,}

The pathophysiologic mechanisms influencing RP can be segregated into three broad headings: vascular, neural, and intravascular abnormalities. ^, Vascular dysfunction in primary RP is, by definition, fully reversible, whereas secondary RP may combine defective function and structural abnormalities. Endothelial cells play an active role in regulating vascular tone. Depending on their state of activation, endothelial cells can produce both potent vasodilating agents (e.g., prostacyclin and nitric oxide) and potent vasoconstricting agents (e.g., endothelins and angiotensin). Endothelial nitric oxide (NO) production, for example, has a large effect on vascular tone, regulating vascular smooth muscle contraction, proliferation, and migration. NO also inhibits platelet aggregation, stimulates platelet disaggregation, and inhibits the adhesion of platelets, lymphocytes, and neutrophils to the endothelial surface, all of which can have secondary effects on vascular function. SSc-associated RP fundamentally differs from primary RP because of its associated vasculopathy, involving fibrous intimal proliferation with associated intravascular thrombi. Endothelin-1 and angiotensin are potent vasoconstrictors with profibrotic activities that have been shown to be overexpressed in the skin of patients with SSc and other forms of secondary RP. These are but a few examples from a long list of agents and functions that have been proposed to contribute to the pathogenesis of vascular abnormalities in SSc.

Neurotransmitters from both autonomic and sensory afferent nerves also alter digital vascular tone. Blood vessels can receive innervation from three main classes of neurons: sympathetic vasoconstrictor neurons, sympathetic or parasympathetic vasodilator neurons, and sensory neurons that can also mediate vasodilation. Whereas the sympathetic nervous system, via release of norepinephrine, is considered a major mediator of vasoconstriction in the skin, local nerve endings also sense the microenvironment and release both vasodilating (substance P, vasoactive intestinal peptide, calcitonin gene-related peptide, neurokinin A) and vasoconstricting (somatostatin, neuropeptide Y) neuropeptides that contribute to the balance of vascular function. Although central mechanisms alone cannot account for the characteristic features of RP, many patients report stress-induced vasospasm, suggesting influence of the central nervous system (CNS) on local vasospasm. Studies investigating the differential effects of mental stress on vascular tone and finger perfusion in patients with RP have produced mixed results, and have failed to clarify the role of the sympathetic nervous system in the pathogenesis of this disorder. In addition to these factors, vascular reactivity is also affected by shear stress, vasoactive substances released by platelets (thromboxane, serotonin), changes in blood viscosity, and changes in the rheological properties of blood (e.g., altered red blood cell deformability), highlighting the complexity of regulatory mechanisms involved. ^,

The marked sensitivity to cold in both primary and secondary RP appears to be mediated, at least in part, by an abnormal or enhanced response to stimulation of alpha adrenergic receptors in the digital and cutaneous vessels. Alpha adrenergic receptors are increased in small vessels relative to larger vessels in normal subjects and are particularly high in cutaneous arteries and veins relative to other tissue beds. In humans, the administration of “selective” alpha-1 and alpha-2 adrenergic agonists causes a reduction in skin or finger blood flow. Cold exposure has been shown to selectively amplify the vascular smooth muscle constriction in response to norepinephrine mediated through alpha adrenergic receptors. ^, Interestingly, estrogen has been shown to increase expression of alpha-2 adrenergic receptors in vascular smooth muscle and thereby increase cold sensitivity—a finding that may explain the greater prevalence of RP among postpubertal women. ^, Within the alpha-2 adrenergic receptor family, individual subtypes (e.g., alpha-2a, -2b, and -2c) have been shown to display differing sensitivity to cold both in humans and in mice. ^{, , ,} Under normal conditions (37° C) alpha-2c adrenoreceptors in cutaneous arteries are stored within the Golgi apparatus. Cooling induces activation of a Rho/Rho kinase signaling pathway, prompting translocation of alpha-2c adrenoreceptor from the Golgi complex to the plasma membrane and augmenting sensitivity of contractile proteins to calcium ions. One trigger for Rho/Rho kinase signaling may be a rapid increase of reactive oxygen species (ROS) seen in smooth muscle cells after cold exposure (28° C). ^, Ischemia and reperfusion associated with RP may, in turn, induce production of additional ROS by mitochondria, leading to further activation of the Rho/Rho kinase pathway and thus provoking repeated or persistent cycles of vasospasm. Interestingly, selective inhibition of the alpha-2 adrenergic receptor abolishes cold-induced vasoconstriction of isolated blood vessels in vitro, and inhibition of the rho kinase signaling pathway prevents translocation of the alpha-2 adrenoreceptor from the Golgi to the cell surface on cooling.

It is of interest that increased contractile protein response to alpha-2 adrenergic agonists and cooling, and the associated increased Rho/Rho kinase and protein tyrosine kinase activity are observed in both primary and secondary RP subjects compared with healthy controls. These findings provide a possible unifying explanation for cold-induced vascular reactivity in primary and secondary RP, as well as a target of mutations that may contribute to familial and ethnic clustering and highlight opportunities for the development of new therapeutics. ^{, ,}

A large number of diseases, disorders, drugs, and environmental exposures have been associated with secondary RP, presumably reflecting a common endpoint of vascular injury and the complex nature of the mechanisms responsible for control of vessel reactivity ( Box 30.3 ). ^{, ,} As noted above, unique changes in the microvascular system develop in association with intimal fibrosis and endothelial dysfunction in SSc. Changes in endothelial cell function appear to occur at an early stage of disease and are associated with increased platelet adhesion, decreased storage of von Willebrand factor, and decreased adenosine uptake. Ischemic reperfusion injury results in increased production of ROS, which, in turn, alters smooth muscle adrenoreceptor expression and vascular function. However, not all increased vascular reactivity in patients with SSc can be attributed to endothelial injury or fibrosis. These mechanisms may occur in concert with, or even induce, increases in alpha-2 adrenergic receptor reactivity. Other observations in SSc include enhanced endothelial cell proliferation, reduced activity of NO, increased circulating levels of endothelin-1, and increased expression of endothelin receptors. Intravascular or circulating factors have also been implicated in either the pathogenesis or the exacerbation of RP, especially when associated with SSc. Platelet activation, defective fibrinolysis, and oxidant stress have all been reported. Although their actions are not fully understood, these intravascular factors may exacerbate the effect of digital vasospasm by reducing basal blood flow in the microvasculature.

It is beyond the scope of this chapter to consider the range of potential mechanisms of injury that may affect the vasculature of patients with SSc, and the reader is directed to detailed discussions of this disease in Chapter 27 .

History

The complaint of cold hands or feet is very common and must be distinguished from RP, which involves both cool skin and cutaneous color changes. Normal individuals may have cool skin and show skin mottling on cold exposure. However, unlike RP, the recovery phase of vascular flow is not delayed and there is no prolonged or sharp demarcation of color changes in the skin. A diagnosis of RP may be made if the patient provides a history of the sudden onset of symptoms characteristic of a Raynaud episode, and history alone is accepted as diagnostic in general practice because no simple clinical test consistently triggers an attack. If necessary, digital arteriolar blood flow can be documented by Doppler flow studies. ^, Characteristic changes have also been reported by plethysmography and arteriography, although the latter is not usually necessary or indicated in patients with severe RP and is associated with some danger of precipitating acute catastrophic arteriolar spasm. In practice, digital artery ultrasound is readily available and depicts the same anatomical structures as angiography, and it is cheaper, faster, and noninvasive. Whereas measurement of digital blood pressure, digital blood flow, or skin temperature responses to cooling may be predictive in a research setting, attempts to induce attacks and measure these features in an office setting are not consistent, even in those with definite RP. ^, A simple approach employing the use of standard questionnaires and color photos of actual attacks has proven useful in clinical trials and epidemiological studies. ^,

A detailed patient history should be collected including affected sites, frequency and severity of attacks, duration of attacks, color pattern, triggers, seasonality, and associated symptoms (i.e., numbness, paresthesia, or pain). Patients should also be questioned for any history suggestive of autoimmune disease such as unexplained fever, fatigue, rash, morning stiffness, arthralgia, myalgia, dysphagia, peripheral edema, lymphadenopathy, or oral ulcers, as well as about changes in digits such as pits, ulcers, poor healing, and the incidence of infection. They should also be asked about possible associated or precipitating factors including frostbite, drug or toxin exposure, infection, or vibration injury, as well as personal and family history of RP or autoimmune diseases, migraine, weight loss or eating disorders, and cardiovascular diseases.

Clinical Criteria

Specific criteria for the diagnosis of RP were first proposed in 1932. Several modifications designed to improve the differentiation of primary and secondary RP have been proposed and validated (see Box 30.1 ). ^, The diagnosis of RP is based fundamentally on a history of episodic vasospastic attacks precipitated by cold or stress. Characteristic features include sharply demarcated lesions, bilateral symptoms, and white, blue, and/or red color changes, although the spectrum of symptoms observed is broad. ^, Among adults who were cold sensitive, Maricq et al. reported that only 1% had tri-phasic color changes and 37% had white or blue color only. In a retrospective review of 123 pediatric patients, Nigrovic et al. reported that 24% of children with primary RP and 19% of children with secondary RP reported tri-phasic color changes, whereas 40% to 50% had only monophasic color changes. An interesting cross-sectional study of patients in the Netherlands indicated that reactive hyperemia at the end of an attack and discoloration of the earlobes and nose were more likely to be associated with primary RP than with secondary RP.

Significant factors differentiating primary from secondary RP are the absence of evidence for vascular disease by clinical examination (including blood pressure, pulses, and nailfold capillaroscopy) in primary RP and the presence of abnormal nailfold capillaries and/or laboratory studies suggesting systemic disease in secondary RP. Primary RP attacks typically involve all fingers in a symmetrical pattern and are not commonly associated with significant pain. Asymmetrical finger involvement and severe pain, in contrast, are suggestive of an underlying pathology and should prompt a more vigorous evaluation. Although patients with primary RP are, by definition, generally healthy, comorbid conditions including hypertension, atherosclerosis, cardiovascular disease, and diabetes mellitus can increase the frequency or severity of symptoms (see Box 30.3 ). Anatomical variants of normal, such as incomplete palmar arterial arch (positive clinical Allen test) can augment vasospasm, leading to earlier and more severe presentations. An issue important in the evaluation of children with RP is the use of stimulants for attention deficit disorder, which may exacerbate vascular dysfunction. ^,

As highlighted in Box 30.2 , the regulation of regional blood flow is complex and susceptible to a variety of stimuli. Correspondingly, the number of disorders associated with RP is extensive (see Box 30.3 ). ^, As research progresses, the border between idiopathic and disease-associated symptoms becomes blurred. Ultimately, primary RP is a diagnosis of exclusion supported by the lack of progression to development of an associated disorder over time. Whereas extensive special testing is not always necessary, every patient with a diagnosis of RP should be carefully evaluated for features that suggest a concurrent or incipient disease. Among these, the rheumatologic diagnoses most often associated with secondary RP are SSc, MCTD, and other autoimmune diseases (e.g., systemic lupus erythematosus [SLE], overlap syndromes, polymyositis, dermatomyositis, Sjögren syndrome, and vasculitis). Other disorders that must be considered include occlusive vascular disease, drug effects, hematological abnormalities, and other vasospastic syndromes. ^{, ,} Standard clinical tests, such as chest radiography, pulmonary function tests, electrocardiogram (ECG), echocardiography, high-resolution lung computed tomography (CT) scanning, or gastrointestinal (GI) evaluation, may be needed to evaluate a patient for associated rheumatic and nonrheumatic disorders.

Nailfold Capillary Microscopy

Nailfold capillary microscopy is a simple yet powerful diagnostic tool that has been shown to significantly improve the predictive power of clinical evaluation. ^{, , ,} The examination can be performed at the bedside using a handheld magnifier or with a low power microscope ( Fig. 30.3 ). Enlarged or distorted capillary loops, telangiectasias, and a relative paucity or loss of capillary loops strongly suggests a concurrent or incipient connective tissue disease and their presence in a patient with RP should prompt an immediate and vigorous search for related findings.

Laboratory Testing

If the history and physical examination, including nailfold capillary microscopy, are not suggestive of a cause for secondary RP, a diagnosis of primary RP may be made and there is no need for further specialized testing. In particular, blood tests such as the erythrocyte sedimentation rate (ESR) and antinuclear antibody (ANA) are not necessary and may be misleading. If, however, there is a clinical suspicion of a secondary cause of RP, then special testing is appropriate as indicated by the clinical assessment. Recommended laboratory testing for possible connective tissue disorders includes a complete blood count, a general blood chemical analysis with tests of renal and liver function, urinalysis, complement (C3 and C4), and ANA. If the ANA is positive, tests for specific autoantibodies may assist with formulating a diagnosis (e.g., anti–double-stranded DNA, anti-SSA [Ro], anti-SSB [La], anti-RNP, anti–Scl-70, and antiphospholipid antibodies). Anticentromere pattern ANA and antitopoisomerase (anti–Scl-70) antibodies have the highest sensitivity for predicting evolution to SSc and the risk for development of digital ischemia, including ulcers and digit loss ^, (see also Chapter 27 ). It is important to recognize that whereas most pediatric patients with secondary RP will have a positive ANA (85% to 100%), a significant number of pediatric patients with primary RP also have a positive ANA without evidence for an associated rheumatic disorder. ^{, ,} Conversely, in a cohort of 1039 adult patients monitored prospectively, only 6.3% patients with negative autoantibody studies developed an autoimmune disease over more than 10 years of follow-up, whereas nearly 60% of patients with RP and reactive ANA pattern were ultimately diagnosed with a connective tissue disease (CTD). A study of patients with incipient RP without a known CTD identified abnormal nailfold capillaries, ANA, and a low hemoglobin as features most strongly associated with future mortality. About 30% of pediatric patients with primary or secondary RP were also found to have antiphospholipid antibodies, although none of the patients had features of antiphospholipid syndrome.

Although anticentromere or antitopoisomerase antibodies are associated with development of SSc, the combination of autoantibodies and nailfold capillary microscopy may be more informative than either test alone. In a 20-year prospective study of 586 patients with RP who had no known autoimmune disease at enrollment, the overall incidence of limited (CREST variant) or diffuse SSc was 13%. In those with one or more related autoantibodies or abnormal nailfold capillary microscopy the incidence of SSc was 47%, whereas in those with both an autoantibody and abnormal nailfold capillary microscopy the incidence of SSc was nearly 80%.