Pathogenesis and pathophysiology of Raynaud phenomenon

INTRODUCTION — 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 [1-4].

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 (SLE) 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".)

BACKGROUND — Maurice Raynaud stated in 1862 that "local asphyxia of the extremities" was a result of "increased irritability of the central parts of the cord presiding over the vascular innervation" [5]. 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 [6]. A local defect(s) is hypothesized to be responsible for RP. However, the exact abnormality may vary depending upon the underlying cause [7].

THERMOREGULATION — In a thermoneutral environment, the level of the body's heat production equals heat loss, and the body's core temperature remains constant. Minor changes in the environmental temperature are handled by changes in skin blood flow [8]. 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 [8]. One physiologic response to cold temperature is the lowering of blood flow to the skin, thereby reducing the loss of body heat and preserving normal core temperature [9]. 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. Heat loss is reduced via vasoconstriction of the cutaneous arterioles and arteriovenous anastomoses (AVAs) that shunt blood from superficial to deep [10]. During severe cold exposure, heat is also generated by thermogenesis via shivering and by subcutaneous brown adipose tissue [11].

Cutaneous arteriovenous shunts — The function of the microcirculation (defined as blood vessels with a diameter <220 to 150 micrometers; composed of arterioles, venules, and capillaries) is to provide nutrition to tissue, remove waste products, and regulate regional blood flow. Arterioles have vasomotor capacity to alter regional blood flow to tissues. The organization of the microcirculation and the control of tissue blood flow varies among different tissues [12]. The cutaneous microcirculation has arterioles and venules that form two plexuses in the dermis, a superficial one in the upper papillary dermis and a lower deep plexus that is located in the dermal-subcutaneous junction [13]. While the plexuses interconnect, they have distinct physiologic functions. The superficial plexus, from which cutaneous capillary loops emerge, runs horizontally, providing nutritional blood flow to the tissue. Numerous AVAs, which are low-resistance conduits that connect the superficial to the deep plexus (figure 1), are present and concentrated in nonhairy glabrous skin of the fingers and toes, palmar surface of the hands and feet, ears, nose and also in some nonglabrous skin sites.

These AVAs bypass the nutritional capillaries and do not directly contribute to the nutritional blood flow that occurs in the cutaneous capillaries. These AVA structures act as the major thermoregulatory vessels in the skin. The AVAs are richly innervated by the sympathetic adrenergic system, and when stimulated, the AVAs vasoconstrict and shunt blood to the deep plexus leading to heat conservation. Upon whole-body cold exposure, the shunting of blood from the superficial arterioles to the venules in the deep plexus occurs at high flow rates. This vasoconstrictor reflex has a greater impact on blood flow through the AVA than nutritional blood flow [14]. While nonglabrous skin contains only a few AVAs, vasodilation and constriction in the superficial arterioles still occurs, providing an additional role in regulating body temperature. The larger digital arteries (fingers, toes) will also react to increased sympathetic tone.

Cutaneous vasoconstriction decreases skin blood flow during cold conditions but maintains nutritional flow via compensatory vasodilation and continued flow in digital arteries, arterioles, and capillaries that maintain tissue perfusion through the non-AVA flow. Even with moderate cold exposure, nutritional blood flow is preserved despite a total reduction in finger flow [14]. Thus, tissue injury does not occur. However, in response to extreme cold exposure, prolonged periods of vasoconstriction in both AVAs and the nutritional capillary can occur [15]. This may lead to tissue injury due to tissue ischemia-reperfusion injury (eg, frostbite). Tissue ischemia with reperfusion injury can also occur if there is microvascular or macrovascular dysfunction or a disease state leading to structural damage of vessels (eg, vasculitis or systemic sclerosis [SSc]). (See 'Secondary Raynaud phenomenon' below.)

Afferent and efferent pathways — Temperature perception is a critical function of the somatosensory system that protects us from extreme thermal conditions [16]. The preoptical/anterior hypothalamus in the brain is known to act as a "thermostat," receiving information from peripheral signals and coordinating efferent responses [10,17]. The core body temperature and skin surface temperature are thus integrated by peripherally located thermosensitive neurons sending signals to the central nervous system, which then regulates systemic responses.

Cutaneous nerves respond to changes in temperature (cold, heat). Afferent pathways are triggered by topical cooling of the skin or general environmental cold temperatures. Local skin cooling triggers both immediate vasoconstriction and subsequent neural signals to the central nervous system. Afferent nerve fibers of the somatosensory system detect environmental stimuli via receptors located on these nerves and on other tissues including blood vessels. The primary afferent neurons convert thermal stimuli into action potentials that relay sensory information to the spinal cord and brain. Cold temperatures activate both A-delta and unmyelinated C fibers [18]. The transient receptor potential ion channel (TRPM8) is the receptor (figure 2) responsible for detection of various degrees of cold temperature [19]. 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 [20]. 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. (See 'Primary Raynaud phenomenon' below.)

The efferent sympathetic mediators regulated by the central nervous system are released from vasoconstrictor and vasodilator nerves that regulate regional blood flow in the skin via the AVAs and small cutaneous arterioles. Blood vessels in the skin are dually innervated by sympathetic noradrenergic nerves that mediate vasoconstriction and sympathetic cholinergic nerves that mediate vasodilation [9]. An increase in blood flow dissipates heat, while a decrease in cutaneous blood flow preserves body heat. Norepinephrine (ie, noradrenaline) is the primary neurotransmitter mediating vasoconstriction via alpha-adrenergic receptors on cutaneous thermoregulatory blood vessels. Under normal conditions, 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.

Alpha-2-adrenergic receptors — Cold activates vasoconstriction by selectively amplifying vascular smooth muscle contraction to the efferent sympathetic neurotransmitter, norepinephrine (ie, noradrenaline) [21]. 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 vasoconstriction depends on local activation of adrenergic nerves and the number and affinity of the postsynaptic alpha-2 receptors on cutaneous vessels [22]. 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. The role of the adrenergic receptors in thermoregulation was demonstrated following the administration of "selective" alpha-1- and alpha-2-adrenergic agonists to human volunteers, which caused a marked reduction in skin or finger blood flow [23,24]. Using an antagonist during local digital cooling alpha-2 blockade was more effective than alpha-1 blockade, suggesting that alpha-2 adrenoreceptors are the dominant receptor involved in thermoregulation [24].

Local cooling enhances alpha-2 receptor-mediated vasoconstriction, particularly through the alpha-2C subtype [25]. Different subtypes of alpha-2 receptors (alpha 2A, 2B, and 2C) display differing sensitivity to cold using in vitro studies of vessels from both a mouse model and cutaneous human vessels [26,27]. Experiments using an isolated murine tail artery revealed that the alpha 2C subtype is responsible for the thermoregulatory function of the alpha-2 receptors [26]. 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 [28]. Alpha 2C adrenoreceptors play a prominent role in vasoconstriction of cutaneous arteries after moderate cooling [27]. In a 37°C (98.6°F) in vitro assay using a mouse tail artery, alpha 2C adrenoreceptors are noted to be "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 the 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 [29]. In vitro studies in a murine model provide evidence that the initial trigger for Rho/Rho kinase signaling is proceeded by a rapid increase of reactive oxygen species (ROS) in smooth muscle cells following cold exposure (28°C) [30]. This is a relevant observation since Raynaud vasospastic attacks may initiate a cycle of ischemia and reperfusion with further production of ROS and subsequent activation of the Rho/Rho kinase pathway thus provoking repeated episodes of vasospasm. (See 'Primary Raynaud phenomenon' below.)

Endothelial mediators — 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. This is important in the regulation of vascular reactivity of both microvascular and larger vessels like digital arteries. Endothelium-derived nitric oxide (NO) contributes to this protective action by inhibiting vascular smooth muscle contraction, proliferation, and migration [31,32]. NO also inhibits platelet aggregation, stimulates platelet disaggregation, and inhibits the adhesion of platelets, lymphocytes, and neutrophils to the endothelial surface [33]. Endothelial cells also release prostaglandins, which are vasodilatory (prostacyclin), and endothelin-1, which is a potent vasoconstrictor. Both prostacyclin and endothelin are thought to regulate regional blood flow and maintain normal vascular integrity [34]. 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 [35]. Vascular reactivity is also affected by shear stress, vasoactive substances released during platelet activation (thromboxane, serotonin), changes in blood viscosity, and potentially changes in rheologic properties of blood such as altered red blood cell deformability. Function of the fibrinolytic system appears to be normal in primary RP [36]. (See 'Primary Raynaud phenomenon' below.)

Other thermoregulatory responses

●Nonadrenergic – While the sympathetic nervous system is the major mediator of vasoconstriction in the skin via release of norepinephrine (ie, noradrenaline) during cold exposure and vasodilation via release of acetylcholine during hot temperature exposure [21], nonadrenergic mechanisms also contribute to reflex vasoconstriction. Nerve endings sense the microenvironment and release factors that contribute to the balance between vasodilation and vasoconstriction [37]. The peripheral nervous system releases vasodilating (eg, substance P, vasoactive intestinal peptide, calcitonin gene-related peptide, neurokinin A) and vasoconstricting (eg, somatostatin, neuropeptide Y) neuropeptides. In addition, angiotensin II, a systemic peptide hormone, can mediate vasoconstriction of cutaneous vessels by activation of angiotensin II type 1 receptors [38]. Other studies suggest the cold-induced vasodilation triggers endothelium-derived hyperpolarization and activation of endothelial calcium-activated potassium channels causing vascular smooth muscle relaxation [39]. There is speculation that RP can be caused by a defect in the vasodilation response leading to unopposed vasoconstriction [39].

●Hormonal – The thermoregulatory actions of sex hormones take place at the thermosensitive neurons and peripheral vasculature. Estrogen receptors have been localized in several of the hypothalamic structures involved in temperature regulation. Thus, estrogen can influence both the central nervous system and the peripheral vasculature, making the net influences of sex hormones on body temperature complex [40]. There is evidence to suggest that norepinephrine (ie, noradrenaline)-mediated vasoconstriction is higher in premenopausal females at their midmenstrual cycle, a stage of a high estrogen level [41]. Yet estrogen has a vasodilatory effect and increases sweating, mediating a decrease in body temperature [40]. Interestingly, in vitro studies demonstrate the alpha-2C receptors on cutaneous vessels are upregulated when vessels are exposed to estrogen [42]. Subsequent studies show that estrogen acts through the Epac/JNK/AP-1 signaling pathway to induce alpha-2C adrenoreceptor expression [43].

●Emotional – The specific responses of the distal circulation to emotional stress are not well documented. Early studies demonstrated that emotional stress increases responses to cold to the fingers. Neurons in the dorsomedial hypothalamus (DMH) play a key role in physiologic responses to exteroceptive ("emotional") stress in rats, including tachycardia [44]. Tachycardia evoked from the DMH or seen in experimental stress in rats is blocked by microinjection of muscimol, a gamma-aminobutyric acid type A (GABAA) receptor agonist, into the rostral raphe pallidus (rRP), an important thermoregulatory site in the brain stem, where disinhibition elicits sympathetically mediated activation of brown adipose tissue and cutaneous vasoconstriction in the tail.

PRIMARY RAYNAUD PHENOMENON — Studies of whole-body cold exposure or local cooling of the skin have defined several potential thermoregulatory pathways (see 'Thermoregulation' above) that can lead to the exaggerated vasoconstriction seen in Raynaud phenomenon (RP). The cause of primary RP is thought to be a "local defect" of thermoregulation in the involved peripheral circulation. Abnormal expression of vascular adrenergic receptors, dysregulation of endothelium, and defects in both sensory nerves and non-neuronal pathways have all been suggested as causes of primary RP [9].

Unlike individuals with secondary RP, patients with primary RP may exhibit reduced total digital blood flow via arteriovenous anastomoses (AVAs), but flow is typically preserved in the nutritional capillaries. Thus, patients with primary RP do not develop critical ischemia.

Altered cutaneous shunts — The distribution of the AVAs to the extremities focuses the decrease in blood flow in response to cold to the fingers and toes more than other body areas such as the forearm or trunk. (See 'Cutaneous arteriovenous shunts' above.)

This unique distribution has implicated a defect or abnormal response in the cutaneous AVA system in patients with RP. Studies show that even in a thermoneutral environment, finger blood flow is lower in patients with RP (primary or secondary) compared with control subjects [45]. Following localized cooling of the fingers, individuals with primary RP demonstrate increased sensitivity to cold and prolonged recovery of finger blood flow on rewarming. An increase in sympathetic tone causes vasospasm in digital arteries as well as in the cutaneous microcirculation. However, studies using general body cooling found that digital blood flow does not fall to zero in patients with primary RP [46]. In control subjects, total and AVA blood flow is reduced following cool exposure, but nutritional capillary flow is maintained [45]. Nutritional blood flow can be reduced in primary RP under some circumstances, but the reduction is less compared with subjects with secondary RP. In the absence of severe cold conditions, critical ischemic events are not seen in patients with primary RP [45]. (See 'Secondary Raynaud phenomenon' below.)

Altered alpha-adrenergic response — In primary 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. This points to an increased contribution of alpha-2 adrenoceptors to thermoregulation in the AVAs and cutaneous arteries. (See 'Alpha-2-adrenergic receptors' above.)

The abnormal response via alpha-2 receptors may mediate the exaggerated vasoconstriction as seen in RP [47]. In patients with primary RP, the pathogenic importance of alpha-2 receptors is suggested by experiments with selective receptor antagonists [48-50]. As an example, in 1 report of 23 patients, the mean 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]) [49]. It is notable that local cooling of the skin by immersing the finger in ice water was reported to cause more dramatic reduction of digital blood flow and AVA blood in patients with RP than in individuals without RP [28]. However, 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 [49-51].

Altered nonadrenergic responses — Other than increased sensitivity of alpha-2 receptors as discussed above, there may be other nonadrenergic mechanisms responsible for the excessive vasoconstriction seen clinically as an attack of RP. However, it is unlikely that nonadrenergic mechanisms alone contribute to cold-induced vasospasm in primary RP. Among the complex mechanisms that regulate vascular tone, impaired dilator function of the endothelium [52], increased production of endothelin-1 from the endothelium [53], or decreased sensory nerve innervation (calcitonin gene-related peptide [CGRP]-containing nerve fibers) [54] may also be involved.

●Endothelial defects – Cold-induced cutaneous vasoconstriction is normally constrained by simultaneous cold-induced vasodilation (see 'Afferent and efferent pathways' above); thus, in theory, a defect in the regulation of sympathetic-induced vasodilation could lead to excessive vasoconstriction.

•A defect in vasodilation is implicated in RP by a study reporting a reduction in the number of CGRP immunoreactive neurons in the skin of patients with RP [54]. 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 [55].

•Vascular disease is generally associated with a decreased protective role of the endothelium and diminished activity of nitric oxide (NO) [31]. In theory, a decreased activity of NO may then contribute to worsening vasoconstriction. However, studies in primary RP suggest that the endothelial vasodilatory function is preserved [56]. Studies have failed to demonstrate altered activity of endothelin-1 [52,57], reduced response to vasodilators in primary RP [58], or increased activity of 5-hydroxytryptamine [48].

●Modulation of alpha-adrenergic agonists – Nonadrenergic mechanisms could act indirectly to selectively modulate the alpha-2-adrenergic response. 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 [44,45,59]. These abnormalities are described in arteries from patients with primary and secondary RP, providing a theoretical unifying explanation for the cold-induced vascular reactivity. Tyrosine kinase signaling is known to play a key role in vascular biology. In vitro studies using arterioles from humans showed increased contractile responses to alpha-2-adrenergic agonists and cooling in patients with RP compared with healthy controls [60,61]. The agonists elicited large increases in tyrosine phosphorylation only in arterial segments from patients with RP at 31°C. Cooling from 37°C to 31°C elicited a large increase in tyrosine phosphorylation in arterioles from RP patients but not those from control subjects. The increases in tyrosine phosphorylation could be prevented by the PTK inhibitor genistein [61]. Although these studies are dated and used nonspecific inhibitors, they provide another possible interesting explanation for abnormal cold-induced vascular reactivity.

Age-related and hormonal influences — Primary RP usually has an age of onset between 15 and 30 years, is more common in females compared with males, and may occur in multiple related family members. This suggests an influence of several factors including 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 [62]. Population surveys report 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 [63]. Epidemiologic studies also find a positive association between RP and unopposed estrogen use in postmenopausal women [64]. In vitro studies demonstrate that estrogen upregulates the alpha-2C receptors on cutaneous vessels [42]. In experimental studies, 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 [42].

Genetic factors — Additional insight into the underlying mechanism of primary RP may be derived by studying patients who belong to families in which the disease is clustered [65-68]. 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 [69,70].

●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 [71].

●A study assessed the association between RP and single-nucleotide polymorphisms (SNPs) in genes TRPA1, TRPM8, CALCA, CALCB, and NOS1 [72]. TRPA1 and TRPM8 act as neuronal and vascular cold sensor s. CGRP is a vasodilator neuropeptide that exists in two isoforms in humans, alpha-CGRP and beta-CGRP, encoded by the genes CALCA and CALCB, respectively. The authors also identified one polymorphic variant within the NOS1 gene as significantly associated with RP in the general population. The involvement of neuronal nitric oxide synthase (nNOS)-derived NO in mediating the restorative vasodilator responses after cold exposure provided rationale for investigating the gene NOS1 encoding nNOS.

●Another genome-wide association study identified 5147 cases of RP in the United Kingdom Biobank cohort (based on billing codes in medical records) and compared them with 439,294 controls [73]. Two candidate causal genes were associated with an increased risk for RP including ADRA2A (rs7090046, odds ratio [OR] per allele 1.26; 95% CI 1.20 to 1.31) and IRX1 (rs12653958, OR 1.17; 95% CI 1.12 to 1.22). The association remained for primary RP when excluding cases with secondary diseases. The authors postulated that ADRA2A may increase expression of alpha 2A adrenoreceptors in arterial tissue, while IRX1 may alter genes involved in prostaglandin and/or bradykinin sensing and production. However, the potential role of these genes in the pathogenesis of RP requires further study. (See 'Altered alpha-adrenergic response' above and 'Altered nonadrenergic responses' above.)

SECONDARY RAYNAUD PHENOMENON — Several diseases (table 1) are associated with abnormal vascular reactivity that either cause vasospasm or are associated with Raynaud phenomenon (RP). It is important to note that the term "secondary RP" includes various diseases that cause vascular compromise with vasospasm that are not classic RP. As an example, vasculitis can damage isolated vessels, leading to critical ischemic events with vasospasm that is isolated to the involved vessels without typical RP events. Unlike individuals without RP or patients with primary RP, during laboratory-based cold exposure, patients with secondary RP exhibit not only reduced total digital blood flow via arteriovenous anastomoses (AVAs) but also reduced flow in the nutritional capillaries; thus, they are more likely to develop critical ischemic events.

In secondary forms of RP, it is thought that the underlying vascular disease directly disrupts the normal mechanisms responsible for control of vessel reactivity (table 1). Examples of conditions or exposures resulting in secondary forms of RP and their potential mechanisms are described below:

●Systemic sclerosis – Systemic sclerosis (SSc) is an example of the complexity of mechanisms that can cause secondary RP. In SSc, unique changes in the microvascular system develop in association with intimal fibrosis and endothelial dysfunction [74,75]. 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 [36,76-80]. In SSc, endothelial dysfunction has been suggested with decreased nitric oxide (NO) and prostacyclin but enhanced endothelin-1 production. Changes have been demonstrated, including enhanced endothelial cell thymidine labeling, suggesting the presence of endothelial injury and repair [81]. Increased circulating levels of endothelin-1 and reduced activity of NO [82-85] and increased expression of endothelin receptors in microvessels are thought to lead to vasospasm, tissue hypoxia, and injury [52,84]. Increased activity of reactive oxygen species (ROS) that follows ischemic reperfusion injury may occur due to acute and chronic ischemia-reperfusion injury. (See "Pathogenesis of systemic sclerosis (scleroderma)".)

Not all increased vascular reactivity can be attributed to problems with endothelial function or fibro-occlusive vascular disorder seen in patients with SSc.

•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 [86].

•Studies addressing endothelial function and vasomotor changes in patients with SSc and RP showed that acute and chronic estrogen administration has some positive effect on flow-mediated dilation of the brachial artery [87,88].

●Systemic lupus erythematosus – 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 (SLE) are associated with severe RP [89]. A similar association of nailfold capillary changes and RP is reported in inflammatory muscle disease and other connective tissue diseases [90]. These findings demonstrate that direct injury to the nutritional capillaries can complicate RP in these patients.

●Vibration exposure and other conditions – Another example of secondary RP is vibration exposure (vibration Raynaud syndrome, vibration white finger syndrome, hand-arm vibration syndrome). Direct damage to vessels and neural dysfunction is implicated in vibration-induced RP.

For other conditions associated with secondary RP (table 1), the pathophysiologies responsible for microvascular dysfunction leading to RP are poorly characterized, but related mechanisms (eg, inflammation, endothelial dysfunction) may be responsible (eg, thromboangiitis obliterans) [91].

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SUMMARY

●Raynaud phenomenon – Raynaud phenomenon (RP) is an exaggerated vascular response to cold temperature or emotional stress. However, the exact pathogenetic mechanisms of RP are incompletely understood but appear to involve several aspects of thermoregulation. (See 'Introduction' above and 'Background' above.)

●Thermoregulation – Temperature perception is a critical function of the somatosensory system that protects us from extreme thermal conditions. 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. (See 'Thermoregulation' above.)

●Pathogenesis – The clinical manifestations of RP may be the final expression of altered thermoregulation.

•Primary Raynaud phenomenon – 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 'Primary Raynaud phenomenon' above.)

•Secondary Raynaud phenomenon – 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 'Secondary Raynaud phenomenon' above.)