Materiały źródłowe

• #1 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Raynaud phenomenon manifests as recurrent vasospasm of the fingers and toes that usually occurs in response to cold exposure or stress. […] The pathogenesis involves disruption of the balance between vasoconstriction and vasodilation, with complex interactions between the vascular wall, nerves, hormones, and humoral factors. […] A deficiency of vasodilatory mediators, including nitric oxide, has been implicated in the pathogenesis of Raynaud phenomenon. […] In addition, endothelin-1, a potent vasoconstrictor found in the endothelium, has been found to be circulating in high levels in patients with secondary Raynaud phenomenon. […] Angiotensin has vasoconstrictive and profibrotic effects. […] In patients with systemic sclerosis, structural abnormalities related to fibrotic proliferation of the vasculature leading to reduced blood flow to the digits have been found. This differs from primary Raynaud disease.

• #2 Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

  https://www.vsijournal.org/journal/view.html?uid=1349&vmd=Full

  Raynauds phenomenon (RP) is a condition characterized by episodic, excessive vasoconstriction in the fingers and toes, triggered by cold or stress. […] The pathogenesis of RP involves a complex interaction between the vascular wall, nerves, hormones, and humoral factors, disrupting the balance between vasoconstriction and vasodilation. […] The complex pathogenesis of RP remains incompletely understood. […] Primary and secondary RP likely follow distinct pathogenetic pathways. […] In primary RP, vascular abnormalities are primarily functional, while secondary RP exhibits both structural and functional impairments. […] Primary RP originates from a functional abnormality of thermoregulatory AVAs. […] In contrast, secondary RP is characterized by structural abnormalities in the nutritional capillaries, leading to frequent tissue ischemia and thermoregulatory dysfunction.

• #3 Mechanisms of Raynaud’s disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/16444858/

  Raynaud’s phenomenon is due to transient cessation of blood flow to the digits of the hands or feet. An attack of Raynaud’s phenomenon is classically manifested as triphasic color changes. The white phase is due to excessive vasoconstriction and cessation of regional blood flow. This phase is followed by a cyanotic phase, as the residual blood in the finger desaturates. The red phase is due to hyperemia as the attack subsides and blood flow is restored. An attack is frequently associated with pain and/or paresthesia due to sensory nerve ischemia. […] The mechanisms of Raynaud’s disease include increased activation of the sympathetic nerves, in response to cold or emotion; an impaired habituation of the cardiovascular response to stress may contribute. In addition, there appears to be a local fault, which is likely multifactorial. This local fault is due to an alteration in vascular function rather than vascular structure. The alteration in vascular function may be related to increased sensitivity to cold of the adrenergic receptors on the digital artery vascular smooth muscle. In some cases, locally released or systemically circulating vasoconstrictors may participate, including endothelin, 5-hydroxytryptamine and thromboxane. A deficiency or increased degradation of nitric oxide, possibly due to increased oxidative stress, may be involved in some cases. These recent pathophysiological insights may lead to new therapeutic options.

• #4 Treating Raynaud phenomenon: Beyond staying warm | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/84/10/797

  Raynaud phenomenon is an overactive vascular response to cold and emotional stress that results in cutaneous color changes and sensory symptoms in the digits. […] It is thought to be triggered by a heightened sympathetic vasoconstrictive response of small arteriovenous anastomoses in the fingers, toes, ears, and tip of the nose. […] Secondary Raynaud phenomenon can be seen with a wide array of systemic conditions as well as environmental and drug exposures. […] A variety of disorders that cause vasospasm or vascular occlusion of the peripheral circulation can mimic typical Raynaud phenomenon, including peripheral nerve injury, complex regional pain syndrome, occlusive vascular disease, vasculitis, acrocyanosis, and thoracic outlet syndrome. […] The skin color changes are due to rapid alterations in blood flow in digital skin. The pale white is due to markedly reduced or absent flow secondary to intense vasoconstriction, the blue-black is due to hypoxemic venous stasis, and the red blush is due to hyperemic reperfusion.

• #5 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In Raynaud phenomenon, blood-flow restriction occurs during cold temperatures and emotional stress. Specifically, in Raynaud phenomenon, there is vasoconstriction of the digital arteries and cutaneous arterioles. Overall, Raynaud phenomenon is a transient and peripheral vasoconstrictive response to cold temperatures or emotional stress. […] Three mechanisms contribute to Raynaud phenomena. These are decreased blood flow, blood vessels constriction, neurogenic responses, and inflammatory and immune responses. […] The somatosensory system helps with temperature perception based on environmental stimuli. Afferent nerve fibers stimulated by cold temperatures activate A-delta and unmyelinated C-fibers. This eventually leads to activation of cold receptor TRPM8 (transient receptor potential ion channel) which monitors variations in cold temperatures. Activation of TRPM8 results in cutaneous vasoconstriction, thermogenesis, and avoidance of cold.

• #6 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  With cold temperatures, the sympathetic nervous system causes the release of vasoconstricting neuropeptides and norepinephrine leading to vasoconstriction of arteriole smooth muscle and decreased blood flood to the skin. Of note, in secondary Raynaud phenomena, endothelin-1 is released by endothelial cells which causes vasoconstriction. […] In primary Raynaud phenomenon, an increase in alpha-2 adrenergic sensitivity in the digital and cutaneous vessels results in the vasoconstrictive response to cold temperatures and emotional stress. Alpha-2 adrenergic receptors are present on the distal arterial smooth muscles of the digits and affected by the sympathetic nervous system. Studies demonstrated that the use of alpha-2 adrenergic receptor inhibitors in patients with cold-induced attacks decreased the severity of the attack.

• #7 Raynaud Phenomenon: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/331197-overview

  Edwards et al proposed that primary Raynaud’s disease involves abnormal function of brain stem areas that integrate the cardiovascular components of the response to acute stress. […] Impaired vasodilation may be involved in Raynaud phenomenon. An important neuropeptide, calcitonin gene-related peptide, is a potent vasodilator secreted by nerves that supply blood vessels. […] Enhanced vasoconstriction in Raynaud phenomenon may involve overactivity of 2C adrenoreceptors; these adrenoreceptors have been found to enable cold-induced vasoconstriction of the blood vessels. […] Raynaud phenomenon has been associated with the following intravascular abnormalities: increased platelet activation and aggregation, increased production of platelet thromboxane A2, impaired fibrolytic system, and oxidative stress by reactive oxygen species has also been implicated in the pathogenesis of Raynaud phenomenon.

• #8 ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon | Nature Communications

  https://www.nature.com/articles/s41467-023-41876-5

  Raynauds phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. […] We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p9.61027) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.121.22, p4.81013) as candidate causal genes through integration of gene expression in disease relevant tissues. […] Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of 2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms. […] We highlight two independent disease mechanisms supported by those loci that challenge and advance our current understanding of primary RP, with ADRA2A highlighting the role of 2A-adrenoreceptors and IRX1 as a putative regulator of vasodilation by altering prostaglandin and/or bradykinin responsiveness.

• #9 Raynaud’s Phenomenon | IntechOpen

  https://www.intechopen.com/chapters/62852

  In SSc, endothelial injury represents a key pathogenic step that mediates the processes of inflammation, thrombus formation, and fibrosis. […] The role of endothelin-1 in pathogenesis of primary RP has also been implicated in some studies, but the evidence is weaker in comparison with SSc. […] Calcitonin gene-related peptide (CGRP) is a neuropeptide and a potent vasodilator produced by peripheral sensory nerves. In RP (primary and secondary RP in SSc), especially the secondary forms in SSc, a reduction in the number of CGRP immunoreactive neurons in the skin was found.

• #10

  https://link.springer.com/article/10.1007/BF00053426

  The pathogenetic theories and treatment of Raynaud’s phenomenon are reviewed. In primary Raynaud’s disease, most evidence supports a local defect at the digital artery level, with vasoconstriction or vasospasm of the digital arteries inducing the color changes. […] Normal sympathetic activity, low transmural arterial distending forces, and serotonin may be associated factors in the production of vasospastic attacks. […] In Raynaud’s phenomenon, persistent vasoconstriction, thickened vessel walls, increased blood viscosity, and low digital artery blood pressure distal to obstructions may lead to vasospastic attacks with normal sympathetic nerve stimuli. […] Since the underlying cause of primary Raynaud’s disease is unknown, treatment involves the use of agents to reduce sympathetic nerve activity or to prevent vascular smooth muscle contraction. […] Ketanserin, a serotonergic S2-receptor antagonist, which has been shown to decrease the frequency of vasospastic attacks, and parenteral prostacyclin are among the new promising therapies.

• #11 Raynaud Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499833/

  In secondary Raynaud phenomenon, the underlying disease is the factor that disrupts normal vessel reactivity to cold temperatures. Usually, the endothelial function of the digital and cutaneous vessels is compromised leading to eventual vasoconstriction with resulting tissue ischemia. For instance, fibrosis of the vascular system in systemic scleroderma leads to endothelial dysfunction followed by tissue ischemia.

• #12 SciELO Brazil – Fenômeno de Raynaud Fenômeno de Raynaud

  https://www.scielo.br/j/rbr/a/CvrqjZCBhHnyJSNyVb5cX3s/?lang=en

  While primary RP is related to functional alterations alone, in RP secondary to SSc, structural alterations of the vascular wall are also found. […] Hyperactivity of the 2-adrenoceptor and alteration in the production of neuropeptides (e.g. calcitonin gene-related peptide), are some of the mechanisms involved in the vasospasm episodes induced by cold in primary and secondary RP. […] In RP, especially when secondary to SSc, endothelial lesion and activation cause an imbalance between the production of vasoconstrictors and vasodilatory mediators, with an increase in the production of endothelin-1 (powerful vasoconstrictor) and a decrease in the production of NO and prostacyclin (vasodilating agents). […] Besides the functional and contractile alterations, structural alterations are found in secondary RP, mainly in SSc. Proliferation and intimal fibrosis of the small arteries and arterioles result in decrease of vessel lumen; these alterations cause decrease of blood flow and lead to a state of chronic ischemia of the involved organs.

• #13 Raynaud’s Phenomenon: A Current Update on Pathogenesis, Diagnostic Workup, and Treatment

  https://www.vsijournal.org/journal/view.html?uid=1349&vmd=Full

  Endothelial dysfunction, a key factor in secondary RP, particularly SSc, disrupts the endotheliums normal function. […] The neural pathogenic mechanism may originate from cold-induced increased sympathetic tone or, in some cases, peripheral nerve compression. […] Regarding intravascular factors, both primary and secondary RP involve platelet activation and the subsequent release of vasoactive substances like thromboxane and serotonin, which further promote platelet aggregation. […] Impaired erythrocyte flexibility and increased blood viscosity in RP contribute to the rationale for using rheologic drugs like pentoxifylline to improve blood flow. […] A summary of the factors involved in RP pathogenesis is presented in Fig. 1.

• #14 Raynaud’s Phenomenon | IntechOpen

  https://www.intechopen.com/chapters/62852

  The vasospasm in primary RP is reversible, while the secondary Raynauds phenomenon in systemic sclerosis is associated with endothelial injury and subsequent structural abnormalities that lead to tissue damage. […] Adrenergic alpha-2 receptors that are more important than alpha-1 receptors in the control of vasoconstriction of digital arteries are suggested to be abnormal in RP. The receptor subtype alpha-2c is found to predominate in the vascular smooth muscle cells of distal cutaneous vessels. […] The endothelium controls blood vessel tone via production of vasodilators (nitric oxide (NO), prostacyclin) and vasoconstrictors (endothelin-1, angiotensin). Endothelial damage in secondary RP in SSc leads to disbalance between vasodilators and vasoconstrictors. […] In SSc-related RP, increased level of asymmetric dimethylarginine (an endogenous NO synthesis inhibitor produced by endothelial cells) was observed. Elevated plasma level of endothelin-1 was found in SSc as compared with primary RP.

• #15 Raynaud, Digital Ulcers and Calcinosis in Scleroderma | Reumatología Clínica

  https://www.reumatologiaclinica.org/en-raynaud-digital-ulcers-calcinosis-in-articulo-S2173574312001323

  Nitric oxide, prostacyclin and endothelin regulate the vascular tone our body. Both nitric oxide and prostacyclin are potent endogenous vasodilators that also have antiproliferative action. In contrast, the endothelin system acts as a counterweight for vascular tone, being a potent vasoconstrictor. […] Endothelial cells are involved in vascular homeostasis by regulating both muscle tone and cell proliferation. Vasoconstriction is caused by an imbalance of the mediators listed above. Cellular inflammation and perivascular infiltrates with complement deposition and release of proinflammatory mediators complete the picture. […] From the viewpoint of pathogenesis, ET1’s role explains the different events in the endothelial phase. […] The ET1 prehormone is activated by the endothelin converting enzyme, and its biosynthesis stimulated by mechanisms such as hypoxia, metabolic disorders and various procoagulants disorders.

• #16 Raynaud, Digital Ulcers and Calcinosis in Scleroderma | Reumatología Clínica

  https://www.reumatologiaclinica.org/en-raynaud-digital-ulcers-calcinosis-in-articulo-S2173574312001323

  In addition to its potent vasoconstrictor, ET1 has proinflammatory action, promoting cell proliferation and fibrosis. […] The action of endothelin is genetically encoded by the transforming growth factor beta (TGF-beta), which, by binding to its tissue receptor overexpresses proteins called Smad, which are the genes encoding collagen. […] Once the endothelial phase of the disease is installed, baseline hypoxia activates the overproduction of endothelin. This excess disturbs the balance of endothelin with nitric oxide and prostacyclins, generating a potent vasoconstrictor action that is not countered, establishing a vicious circle in which the unresolved tissue ischemia leads to increased vasoconstriction, release of proinflammatory cytokines and platelet aggregation as well as stimulation of fibroblast activity.

• #17 SciELO Brazil – Fenômeno de Raynaud Fenômeno de Raynaud

  https://www.scielo.br/j/rbr/a/CvrqjZCBhHnyJSNyVb5cX3s/?lang=en

  In this context, the vasospasm of RP secondary to SSc is usually more serious, leading to reperfusion-ischemia episodes. It is suggested that in SSc, it’s suggested that the repeated episodes of reperfusion-ischemia cause an increase in free radicals activity (oxidative stress) and a persistent activation of the endothelial system. […] Finally, several intravascular abnormalities, such as platelet activation, increase of the fibrinolysis, leukocyte activation, and reduction of the deformation capacity of the red blood cells have been implicated as coadjuvant factors in the RP pathogenesis.

• #18 Raynaud Syndrome – Cardiovascular Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/cardiovascular-disorders/peripheral-arterial-disorders/raynaud-syndrome

  Raynaud syndrome is probably due to an exaggerated alpha-2 adrenergic response that triggers vasospasm; the mechanism is not defined. […] Raynaud syndrome may accompany migraine headaches, variant angina, and pulmonary hypertension, suggesting that these disorders share a common vasospastic mechanism. […] Treatment of primary Raynaud syndrome involves avoidance of cold, smoking cessation, and, if stress is a triggering factor, relaxation techniques (eg, biofeedback) or counseling. […] Calcium channel blockers or prazosin is also indicated, given as above for primary Raynaud syndrome. […] Cervical or local sympathectomy is controversial; it is reserved for patients with progressive disability unresponsive to all other measures, including treatment of underlying disorders.

• #19 Calcitonin gene-related peptide-targeting drugs and Raynaud’s phenomenon: a real-world potential safety signal from the WHO pharmacovigilance database | The Journal of Headache and Pain | Full Text

  https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-022-01424-w

  Migraine is responsible for significant disability and societal burden. […] The deficiency of CGRP is involved in Raynauds phenomenon, which consists of abnormal vasoconstriction of the digits. […] CGRP is the main neuropeptide released by the trigeminal nerve, whose signaling may be a key mechanism underlying the pathogenesis of migraine attacks, as CGRP is a potent vasodilator. […] The deficiency of CGRP is believed to play a role in Raynauds phenomenon. […] The involvement of the deficiency of CGRP in the pathogenesis of Raynauds phenomenon has been described as far back as the 1990s. […] This mechanism likely underpins the involvement of CGRP-targeting drugs in Raynauds phenomenon. […] CGRP blockade might be the last straw that disrupts the physiological balance of vascular response in patients at-risk of Raynauds phenomenon.

• #20 ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon | Nature Communications

  https://www.nature.com/articles/s41467-023-41876-5

  Our finding may imply that overstimulation or increased expression of 2A-adrenergic receptors contributes to the vasospastic effects characteristic of RP and its symptoms, also in line with RP being an adverse effect of 2-adrenergic agonists such as clonidine. […] The RP risk-increasing G-allele was also associated with an increased risk for coronary artery disease (beta=0.06; p1.8108) in data from BioBank Japan. […] We lastly observed no strong evidence for a shared genetic architecture with suspected cardiovascular comorbidities for primary RP but did observe a novel detrimental effect of low fasting plasma glucose that might help to guide primary RP management. […] We identified overexpression of IRX1, the second strongest signal for RP, in muscle cells and possibly the tibial artery as a putative RP risk-increasing mechanism.

• #21 Raynaud phenomenon

  https://dermnetnz.org/topics/raynaud-phenomenon

  First line medications for primary Raynaud phenomenon include calcium channel blockers, such as nifedipine or diltiazem. Verapamil appears ineffective. The calcium channel blockers act by dilating the small blood vessels, thereby increasing the blood flow to the peripheries. […] There are promising reports that botulinum toxin injections into the neurovascular bundles at the palmar arch at the base of the digits result in rapid reduction in pain and can heal digital ulcers. […] A very small minority of patients with severe and intractable Raynaud phenomenon may require a sympathectomy. This involves cutting the nerves that constrict the peripheral blood vessels.

• #22 Treating Raynaud phenomenon: Beyond staying warm | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/84/10/797

  Calcium channel blockers are first-line agents for both primary and secondary Raynaud phenomenon that does not adequately respond to nonpharmacologic interventions. […] These medications should be started at the lowest dose and titrated up over several weeks as tolerated to achieve their maximal effect. […] A short-acting calcium channel blocker or combination therapy with a calcium channel blocker and a PDE5 inhibitor or topical nitrate should be started. […] The endothelin receptor inhibitor bosentan has been shown to decrease recurrent digital ulcers in patients with scleroderma, and while bosentan does not decrease the frequency of Raynaud attacks, it can be used in this select group to prevent new digital ulcers.

• #23 The mechanism of botulinum A on Raynaud syndrome | DDDT

  https://www.dovepress.com/the-mechanism-of-botulinum-a-on-raynaud-syndrome-peer-reviewed-fulltext-article-DDDT

  Botulinum neurotoxin type A (BoNT/A) is emerging as a treatment modality for Raynaud’s phenomenon (RP). However, the mechanism of the role of BoNT/A in antagonizing the constriction of arteriola in RP remains unclear. […] Currently, accumulating evidence suggested that upregulated vascular smooth muscle 2C adrenergic receptor may play an important role in RP through inducing hyperfunction of the sympathetic nervous system and causing vasoconstriction. […] The mechanism was similar to the cholinergic one, in which the vesicle release of sympathetic neurons could be inhibited by cleavage of SNAP-25. The end result was blocked vesicle fusion with the presynaptic membrane after BoNT/A treatment, inhibiting the release of the NE. […] Our study showed that BoNT/A could significantly inhibit electrical stimulation-induced arteriole vasoconstriction through the sympathetic pathway.

• #24 The mechanism of botulinum A on Raynaud syndrome | DDDT

  https://www.dovepress.com/the-mechanism-of-botulinum-a-on-raynaud-syndrome-peer-reviewed-fulltext-article-DDDT

  The BoNT/A inhibition effect may be mechanistically related to the cleavage of SNAP-25 which is also observed on cholinergic nerves. […] Our results showed that the sympathetic adrenoceptors 1 and 2A were coexpressed on rat cremaster arteriole. However, 2B and 2C adrenoceptors were not detected by immunofluorescence. […] Our findings suggested that BoNT/A might inhibit sympathetic nerves to mediate vasodilation. […] The inhibitory effect of BoNT/A on NE release in sympathetic neurons might be related to SNAP-25 as well.

• #25 The pathogenesis, diagnosis and treatment of – ProQuest

  https://www.proquest.com/scholarly-journals/pathogenesis-diagnosis-treatment-raynaud/docview/1790102396/se-2

  Abstract | The past 10 years have seen the publication of results from several multicentre clinical trials in primary and systemic sclerosis (SSc)-related Raynaud phenomenon. The publication of these studies has occurred as a result of new insights into the pathogenesis of Raynaud phenomenon, which are directing new treatment approaches, and increased international collaboration between clinicians and scientists. […] Although the pathogenesis of Raynaud phenomenon is complex, abnormalities of the blood vessel wall, of neural control mechanisms and of intravascular (circulating) factors are known to interact and contribute. Key players relevant in drug development include nitric oxide, endothelin-1, alpha adrenergic receptor activation, abnormal signal transduction in vascular smooth muscle, oxidative stress and platelet activation. […] The ultimate aim is to translate the advances made in the pathophysiology and early diagnosis into development of treatments to prevent and reverse digital vascular dysfunction and injury.

• #26 The pathogenesis, diagnosis and treatment of Raynaud phenomenon | Nature Reviews Rheumatology

  https://www.nature.com/articles/nrrheum.2012.96

  The past 10 years have seen the publication of results from several multicentre clinical trials in primary and systemic sclerosis (SSc)-related Raynaud phenomenon. […] Although the pathogenesis of Raynaud phenomenon is complex, abnormalities of the blood vessel wall, of neural control mechanisms and of intravascular (circulating) factors are known to interact and contribute. […] Key players relevant in drug development include nitric oxide, endothelin-1, alpha adrenergic receptor activation, abnormal signal transduction in vascular smooth muscle, oxidative stress and platelet activation. […] Although the pathogenesis of Raynaud phenomenon is complex and incompletely understood, progress is being made and new insights are directing novel approaches to treatment. […] Abnormalities of the blood vessel wall, of neural control mechanisms, and of intravascular (circulating) factors can all contribute to the pathogenesis of Raynaud phenomenon. […] In patients with Raynaud phenomenon, presence of SSc-specific autoantibodies and abnormal nailfold capillary pattern are independent predictors of an underlying SSc-spectrum disorder.

• #27 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-is-Raynauds-Syndrome.aspx

  Raynaud’s syndrome, also called Raynaud’s phenomenon, is an exaggerated response to cold or stress induced vasospasm of cutaneous blood vessels. […] The vasospasm or constriction of blood vessels protects the body from excessive heat loss, and hence can be observed as a compensating mechanism. This protective mechanism is mediated by the release of norepinephrine from the sympathetic nervous system. […] Research focusing on elucidating the exact mechanisms regulating the various vasoconstriction and vasodilation pathways is vital. This can ultimately deliver promising agents for the treatment of Raynauds syndrome, especially the secondary form of the disease.

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