INTRODUCTION — One of the normal physiologic responses to cold temperature is the lowering of blood flow to the skin, thereby reducing the loss of body heat and preserving normal core temperature [1]. Blood flow to the skin is regulated by a complex interactive system involving neural signals, circulating hormones, and mediators released from both circulating cells and blood vessels.

Raynaud phenomenon (RP) is an exaggerated vascular response to cold temperature or emotional stress. The phenomenon is manifested clinically by sharply demarcated color changes of the skin of the digits. Abnormal vasoconstriction of digital arteries and cutaneous arterioles due to a local defect in normal vascular responses is thought to underlie the primary form of this disorder [2-5].

RP is considered primary if these symptoms occur alone without evidence of any associated disorder. By comparison, secondary disease refers to the presence of RP in association with a related illness, such as systemic lupus erythematosus and systemic sclerosis (SSc).

The pathogenesis of RP will be reviewed here. The definition, clinical manifestations, diagnosis, and treatment of the disorder are presented separately. (See "Clinical manifestations and diagnosis of Raynaud phenomenon" and "Treatment of Raynaud phenomenon: Initial management" and "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".)

OVERVIEW — Maurice Raynaud in 1862 stated that "local asphyxia of the extremities" was a result of "increased irritability of the central parts of the cord presiding over the vascular innervation" [6]. He wrote, "…I hope to prove that this kind of gangrene has its cause in a vice of innervation of the capillary vessels." In 1930, after observing that even when reflex vasodilation is produced by warming the body, vasospasm could still be induced by putting the hands in cold water, and conversely, that vasospasm could not be produced by body cooling if the hands were kept warm, Sir Thomas Lewis concluded that Raynaud phenomenon (RP) was due to a "local fault" rather than a defect in the central nervous system [7]. A local defect(s) is hypothesized to be responsible for RP. However, the exact abnormality may vary depending upon the underlying cause [8].

●In primary RP, evidence suggests the defect is in part due to an increase in alpha-2 adrenergic responses in the digital and cutaneous vessels [2,5].

●In secondary RP, the defect may vary depending upon the underlying insult to the normal physiology of the digital and cutaneous arteries. Many diseases, disorders, drugs, and environmental exposures have been associated with secondary RP (table 1).

NORMAL THERMOREGULATION — In a thermoneutral environment, the level of the body's heat production equals heat loss, and the body core temperature remains constant. Minor changes in the environmental temperature are handled by changes in skin blood flow [9]. In warm or hot temperatures, vasodilation of cutaneous vessels increases blood flow to the skin, resulting in loss of heat by convection. Sweating also reduces body temperature [9]. In a cold environment, a decrease in heat loss occurs via vasoconstriction of cutaneous vessels [10]. During severe cold exposure, heat is generated by thermogenesis via shivering and by subcutaneous brown adipose tissue [11]. Local skin cooling triggers both immediate vasoconstriction and subsequent neural signals to the central nervous system. The preoptical/anterior hypothalamus in the brain is known to act as a "thermostat," receiving information from peripheral signals and coordinating efferent responses [10,12]. The core body temperature and skin surface temperature are thus integrated by the peripherally located thermosensitive neurons sending signals to the central nervous system, which then regulates systemic responses.

NORMAL SENSORY SYSTEM — Blood vessels in the skin are dually innervated by sympathetic noradrenergic nerves that mediate vasoconstriction and sympathetic cholinergic nerves that mediate vasodilation [1]. Temperature perception is a critical function of the somatosensory system that protects us from extreme thermal conditions [13]. Afferent nerve fibers of the somatosensory system detect environmental stimuli and in cold temperatures activate both A-delta- and unmyelinated C-fibers. Temperature-sensitive ion channels on specialized dorsal root ganglion neurons allow cutaneous nerves to respond to both heat and cold. A cold receptor, Transient Receptor Potential ion channel (TRPM8), is responsible for detection of various degrees of cold temperature [14]. These primary afferent neurons convert thermal stimuli into action potentials that relay sensory information to the spinal cord and brain [15]. Activation of the cold receptor TRPM8 in animal models leads to cold avoidance behavior, skin vasoconstriction, and brown fat thermogenesis, all occurring to maintain normal core temperature [16].

While TRPM8 neurons are a molecularly diverse population, a direct association with a defect or unique subtype in these receptors causing Raynaud phenomenon (RP) has not been shown. Whole-body cold exposure and chilling elicits cutaneous vasoconstriction. Sympathetic mediated vasoconstrictor and vasodilator nerves innervate arterioles and regulate regional blood flow in the skin. An increase in blood flow allows heat to dissipate, while a decrease in cutaneous blood flow preserves body heat. Noradrenaline is the primary neurotransmitter mediating vasoconstriction via alpha-adrenergic receptors on cutaneous thermoregulatory blood vessels. Local cooling of the skin leads to a rapid vasoconstriction followed by transient vasodilation and then prolonged vasoconstriction [10]. While the vasodilation is poorly understood, it is thought to counteract the potential tissue damaging effect of prolonged vasoconstriction. Recent studies suggest the cold-induced vasodilation triggers endothelium-derived hyperpolarization and activation of endothelial calcium-activated potassium (KCa) channels causing vascular smooth muscle relaxation [17]. There is speculation that RP can be caused by a defect in the vasodilation response leading to unopposed vasoconstriction [17].

Role of neuropeptides — While the sympathetic nervous system is the major mediator of vasoconstriction in the skin via release of norepinephrine during cold exposure and vasodilation via release of acetylcholine during hot temperature exposure [18], nonadrenergic mechanisms also contribute to reflex vasoconstriction. Nerve endings sense the microenvironment and release factors that contribute to the balance between vasodilation and vasoconstriction [19]. The peripheral nervous system releases vasodilating (substance P, vasoactive intestinal peptide, calcitonin gene-related peptide, neurokinin A) and vasoconstricting (somatostatin, neuropeptide Y) neuropeptides. In addition, angiotensin II can mediate vasoconstriction of cutaneous vessels by activation of angiotensin II type1 receptors [20]. A reduction in the number of calcitonin gene-related peptide (CGRP) immunoreactive neurons in the skin of patients with RP is reported, suggesting a defect in vasodilation is implicated in RP [21]. Supporting this concept are case series reporting that treatment of migraine headaches with monoclonal antibodies that are CGRP antagonists is associated with the onset or aggravation of RP [22].

NORMAL VESSEL REACTIVITY — Whole-body cold exposure or local cooling of the skin cause vasoconstriction by several pathways, including adrenergic receptors, regulation of nitric oxide release from the endothelium, and both sensory nerves and non-neuronal pathways [1]. Blood vessels in the skin have the dual purpose of providing nutrition to the tissue and a unique mechanism of shifting cutaneous blood flow to maintain a core body temperature within a narrow range. There is a subpapillary superficial plexus and a deeper vascular plexus in the lower dermis that are interconnected but have distinct functions. The superficial plexus is the source of cutaneous capillaries that provide nutritional blood flow. Thermoregulation is mainly accomplished by numerous arteriovenous anastomoses (AVAs), low-resistance conduits that allow shunting of blood from arterioles to venules at high flow rates. The AVAs are mainly concentrated in non-hairy glabrous skin of the palmar surface of the hands and feet; they do not contribute to nutritional blood flow that occurs in the cutaneous capillaries. The AVAs are solely innervated by sympathetic vasoconstrictor nerves [10]. Vasodilation of the AVAs increases digital skin blood flow rapidly and dramatically allowing heat loss. Heat preservation occurs through cold- or emotional stress-induced vasoconstriction in the peripheral circulation of the digits of the hands and feet where the AVAs are preferentially located. Cold activates vasoconstriction by selectively amplifying vascular smooth muscle constriction to the sympathetic neurotransmitter, norepinephrine [18]. The vasoconstriction depends on local activation of adrenergic nerves and the number and affinity of the postsynaptic alpha-2 receptors on cutaneous vessels [23]. AVAs have a particularly dense sympathetic innervation and are thus activated to constrict and reduce skin blood flow following sympathetic output of norepinephrine from either central or peripheral stimuli. The distribution of the AVAs to the extremities focuses the decrease in blood flow in response to cold to the fingers more than other body areas such as the forearm or trunk. In a normal individual, the thermal reactivity of the AVAs occurs without compromising nutritional blood flow. On cold exposure, patients with RP have a more dramatic drop in digital blood flow compared with individuals without RP due to abnormal reactivity of the AVAs and associated terminal arteries. The more proximal artery vasoconstriction can further compromise capillary nutritional blood flow. In addition, the exaggerated vasoconstriction may be coupled with a defect in the normal compensatory vasodilation [17]. Thus, the process of skin thermoregulation can be disrupted or perturbed at several potential sites, with the final clinical manifestation being RP.

Role of endothelial cells — Although vascular smooth muscle can respond directly to circulating hormones or environmental stimuli, important physiologic control of smooth muscle activity is indirectly mediated by endothelial cells (see "Coronary artery endothelial dysfunction: Basic concepts"). Endothelium-derived nitric oxide (NO) contributes to this protective action by inhibiting vascular smooth muscle contraction, proliferation, and migration [24,25]. NO also inhibits platelet aggregation, stimulates platelet disaggregation, and inhibits the adhesion of platelets, lymphocytes, and neutrophils to the endothelial surface [26].

Endothelial cells also release prostaglandins that are vasodilatory (prostacyclin) and endothelin-1 that is a potent vasoconstrictor. Both prostacyclin and endothelin are thought to affect vascular remodeling [27]. It is notable that endothelin-1 is not released during normal vascular response but is released when there is vascular disease such as occurs in secondary forms of RP [28].

Role of intravascular factors — Vascular reactivity is also affected by shear stress, vasoactive substances released during platelet activation (thromboxane, serotonin), changes in blood viscosity, and potentially changes in rheological properties of blood such as altered red blood cell deformability. Function of the fibrinolytic system appears to be normal in primary RP [29]. The thermoregulatory actions of sex hormones take place at the thermosensitive neurons in the central nervous system and in the peripheral vasculature, making the net influences of sex hormones on body temperature complex [30]. Population surveys find that RP is more common in age-matched females than males, suggesting that estrogen may have a role as a mediator of changes in peripheral vascular tone [31]. Epidemiologic studies also find a positive association between RP and unopposed estrogen use in postmenopausal women [32]. There is evidence to suggest that noradrenaline-mediated vasoconstriction is higher in premenopausal females at their mid-menstrual cycle, a stage of a high estrogen level [33]. Yet estrogen has a vasodilatory effect and increases sweating, mediating a decrease in body temperature [30]. Studies addressing endothelial function and vasomotor changes in scleroderma patients with RP showed that acute and chronic estrogen administration has some positive effect on flow-mediated dilation of the brachial artery [34,35]. Interestingly, in vitro studies demonstrate the alpha-2C receptors on cutaneous vessels are upregulated when vessels are exposed to estrogen [36]. Estrogen-induced activity of alpha-2C adrenoreceptor was followed by a potentiated cold-induced vasoconstrictive response in mouse tail arteries, providing evidence that estrogen plays a role in the vasospasm of RP [36]. Subsequent studies show that estrogen acts through the Epac/JNK/AP-1 signaling pathway to induce alpha-2c adrenoreceptor expression [37].

PRIMARY RP — In primary Raynaud phenomenon (RP), there is compelling evidence that the increased sensitivity to cold temperatures is mediated in part by abnormal alpha-adrenergic responses, particularly mediated by alpha-2 adrenoreceptors. In normal subjects, alpha-1 and alpha-2 adrenoceptors are present on the vascular smooth muscle of arteries of human extremities, but alpha-2 adrenoceptors are more prominent on distal arteries. This points to an increased contribution of alpha-2 adrenoceptors to thermoregulation in the distal arteries [38]. The arteriovenous anastomoses (AVAs) are mainly responsible for cold induced sympathetic adrenergic vasoconstriction that occurs in the digits. The role of the adrenergic receptors in thermoregulation is demonstrated following the administration of "selective" alpha-1 and alpha-2 adrenergic agonists to human volunteers, which causes a marked reduction in skin or finger blood flow [39,40].

In patients with primary RP, the pathogenic importance of alpha-2 receptors is suggested by experiments with selective receptor antagonists [41-43]. In one report of 23 patients, for example, the number of fingers with cold-induced vasospastic attacks was markedly reduced with yohimbine (an alpha-2 receptor blocker) compared with prazosin (an alpha-1 receptor blocker)—0.3 versus 2.3 fingers [42].

The analysis of responses to exogenous administration of agonists has not provided a clear answer to the underlying reason for the increased cold sensitivity of alpha-2 receptors in primary RP. In different studies, the responses to "selective" alpha-2 adrenergic agonists were either increased or unchanged in patients with RP when compared with controls, and responses to "selective" alpha-1 adrenergic agonists were either not changed, increased, or decreased in affected patients [42-44].

Different subtypes of alpha-2 receptors (alpha 2A, 2B, and 2C) display differing sensitivity to cold. Experiments using isolated murine tail artery revealed that the alpha 2C subtype is responsible for the thermoregulatory function of the alpha-2 receptors [45]. This suggests that an altered pattern of expression of these alpha-2 subtypes could modify alpha-2 receptor sensitivity during cold exposure, but not at normal temperatures.

It is notable that local cooling of the skin causes more dramatic reduction of digital blood flow and AVAs blood in patients with RP than in individuals without RP [46]. Local cooling enhances alpha-2 receptor mediated vasoconstriction, particularly by through the alpha-2C subtype [47]. Alpha 2C-adrenoreceptors play a prominent role in vasoconstriction of cutaneous arteries after moderate cooling [48]. Under normal conditions (37ºC), alpha 2C-adrenoreceptors are "silently" stored within the Golgi apparatus. They translocate to the cell surface after cold exposure and contribute to the adrenergic constrictive response. Cooling induces activation of Rho/Rho kinase signaling pathway and this prompts translocation of alpha 2C-adrenoreceptors from the Golgi complex to the plasma membrane together with augmented sensitivity to Ca++ of contractile proteins [49].

The initial trigger for Rho/Rho kinase signaling may be provided by a rapid increase of reactive oxygen species (ROS) in smooth muscle cells following cold exposure (28ºC) [50]. This is a relevant observation, since Raynaud vasospastic attacks may initiate a cycle of ischemia and reperfusion with further production of ROS, subsequent activation of Rho/Rho kinase pathway thus provoking repeated episodes of vasospasm.

Increased contractile responses to alpha 2-adrenergic agonists and cooling observed in patients with RP compared with healthy controls is associated with increased protein tyrosine kinase (PTK) activity and tyrosine phosphorylation [51,52]. These abnormalities are described in arteries from both primary and secondary RP subjects, providing a theoretical unifying explanation for the cold-induced vascular reactivity.

Other possibilities for the increased cold sensitivity of alpha-2 receptors in primary RP may be unrelated to a direct alteration in alpha receptor expression. These include increased production of endothelin-1 [53], decreased sensory nerve innervation (calcitonin gene-related peptide [CGRP]-containing nerve fibers) [21], and impaired dilator function of the endothelium [54]. However, subsequent studies have failed to demonstrate altered activity of endothelin-1 [54,55], endothelial dilator activity in primary RP [56], or increased activity of 5-hydroxytryptamine [41]. Cold-induced cutaneous vasoconstriction is also restrained by simultaneous cold-induced vasodilation; thus, a defect in the regulation of sympathetic-induced vasodilation could lead to excessive vasoconstriction. Vascular disease is generally associated with a decreased protective role of the endothelium and diminished activity of nitric oxide (NO) [24]. The decreased activity of NO may then contribute to worsening vasoconstriction. Among the complex mechanisms that regulate vascular tone, there may more than one responsible for the excessive vasoconstriction seen clinically as an attack of RP. In primary RP, the endothelial vasodilatory function is preserved [57]; thus, nutritional blood flow to the skin is only mildly affected.

Based upon the studies demonstrating increased sensitivity of alpha-2 receptors, it is unlikely that nonadrenergic mechanisms alone contribute to cold-induced vasospasm in primary RP. However, nonadrenergic mechanisms could act indirectly to selectively modulate the alpha-2 adrenergic response.

It is of interest that primary RP usually has an age of onset between 15 and 30 years, is more common in females, and may occur in multiple related family members. This suggests an influence of several factors including the influence of sex hormones, changes in body fat composition with age that alters thermogenesis, a shift away from adrenergic responses in cutaneous vessels with aging, a blunting of thermal sensitivity with age, metabolic acclimation as we age, and genetic factors [58].

Genetic — Additional insight into the underlying mechanism of primary RP may be derived via the study of patients who belong to families in which the disease is clustered [59-62]. Up to 50 percent of patients with primary RP have a first-degree relative who also has RP and cold sensitivity, and RP is more common among monozygotic twins than dizygotic twins [63,64]. A genome-wide screen among families tentatively identified five genetic loci (on the X chromosome and chromosomes 6, 7, 9, and 17) that may be linked with the disease [65]. Another study aimed to assess the association between RP and single-nucleotide polymorphisms (SNPs) in genes TRPA1, TRPM8, CALCA, CALCB, and NOS1. The authors identified one polymorphic variant within the NOS1 gene as significantly associated with RP in the general population [66].

SECONDARY RP — In secondary forms of Raynaud phenomenon (RP), it is thought that the underlying vascular disease disrupts the normal mechanisms responsible for control of vessel reactivity. When a compromise to endothelial function occurs, it leads to a defect in vascular function that causes a significant compromise to nutritional flow and a risk of critical tissue ischemia. In systemic sclerosis (scleroderma), for example, unique changes in the microvascular system develop in association with intimal fibrosis and endothelial dysfunction [67]. The endothelial cell damage or dysfunction appears to occur at an early stage, and is associated with increased platelet adhesion, decreased storage of von Willebrand factor, and decreased adenosine uptake [29,68-72]. Increased activity of reactive oxygen species (ROS) that follows ischemic reperfusion injury may then alter smooth muscle receptor expression and vascular function [73]. (See "Coronary endothelial dysfunction: Clinical aspects".)

However, not all increased vascular reactivity can be attributed to problems with endothelial function or fibrosis in patients with systemic sclerosis. As an example, a selective increase in alpha-2 adrenergic receptor reactivity may occur in the arterioles of sclerodermatous skin in the absence of demonstrable endothelial cell dysfunction [74]. Other changes have been demonstrated, including enhanced endothelial cell thymidine labeling, suggesting the presence of endothelial injury and repair [75], increased circulating levels of endothelin-1 and reduced activity of nitric oxide (NO) [76-78], and increased expression of endothelin receptors in microvessels [54,77]. (See "Pathogenesis of systemic sclerosis (scleroderma)".)

While mechanistic studies are lacking in other rheumatic diseases, it is likely that any perturbation of the endothelium will alter vascular reactivity and cause RP. For example, microvascular changes defined by abnormal nailfold changes seen in systemic lupus erythematosus are associated with severe RP [79]. A similar association of nailfold capillary changes and RP is reported in inflammatory muscle disease and other connective tissue diseases [80].

There are several other diseases associated with abnormal vascular reactivity that either cause RP or are associated with RP (table 1). For example, vibration exposure is a common cause of RP (vibration Raynaud syndrome, vibration white finger syndrome, hand-arm vibration syndrome). Direct damage to vessels and neural dysfunction have been implicated in vibration-induced RP. There are reports that RP is common among patients with fibromyalgia and that the mechanism causing RP differs from patients with primary RP alone [58]. This is based on reported differences in symptoms, baseline temperature of the digits, and observations of differences in color patterns of the digits following cold challenge [58]. Insights into the mechanism behind these differences are not defined due to the lack of robust studies.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Raynaud phenomenon (Beyond the Basics)")

SUMMARY

●Temperature perception is a critical function of the somatosensory system that protects us from extreme thermal conditions. Afferent nerve fibers of the somatosensory system detect environmental stimuli and, in cold temperatures, activate both A-delta- and unmyelinated C-fibers. Temperature-sensitive ion channels on specialized dorsal root ganglion neurons allow cutaneous nerves to respond to both heat and cold. Like the endothelium, nerve endings sense the microenvironment and release factors that contribute to the balance between vasodilation and vasoconstriction. (See 'Normal sensory system' above and 'Role of neuropeptides' above.)

●Control of blood vessel reactivity is a complex interactive system involving neural signals, circulating hormones, and mediators released from cells and the blood vessel. This process can be disrupted or perturbed at several potential sites, but the clinical manifestations of Raynaud phenomenon (RP) may be the final expression of abnormal reactivity of the terminal arteries. (See 'Normal vessel reactivity' above.)

●Although vascular smooth muscle can respond directly to circulating hormones or to environmental stimuli, important physiologic control of smooth muscle activity is indirectly mediated by endothelial cells. Vascular reactivity is also affected by shear stress, vasoactive substances released during platelet activation (thromboxane, serotonin), changes in blood viscosity, and, potentially, changes in rheological properties of blood such as altered red blood cell deformability. (See 'Role of endothelial cells' above and 'Role of intravascular factors' above.)

●RP is an exaggerated vascular response to cold temperature or emotional stress. Abnormal vasoconstriction of digital arteries and cutaneous arterioles due to a local defect in normal vascular responses is thought to underlie the primary form of this disorder. In primary RP, evidence suggests the defect is an increase in alpha-2 adrenergic responses in the digital and cutaneous vessels. (See 'Overview' above and 'Primary RP' above.)

●In secondary RP, the defect may vary depending upon the underlying insult to the normal physiology of the digital and cutaneous arteries. Many diseases, disorders, drugs, and environmental exposures have been associated with secondary RP (table 1). In secondary forms of RP, it is thought that the underlying vascular disease disrupts the normal mechanisms responsible for control of vessel reactivity. (See 'Overview' above and 'Secondary RP' above.)