Raynaud's Disease
Diseases

A Bit More...

...abuot Epidemiology

Another risk factor whcich could conduce to RP is the type of occupation.
In particular:
-jobs involving vibration, particularly drilling, suffer from vibration white finger
-exposure to vinyl chloride, mercury
-exposure to the cold (e.g. by working as a frozen food packer)

...about Pathogenesis

NO and ADMA

Nitric oxide (NO) is an important physiological signalling molecule, a free radical, potent vasodilator, and mediator of oxidative stress. Although NO is a gas, it is a highly reactive, short-lived, molecule able to rapidly diffuse across cell membranes. Nitric oxide exerts its biological effects by the reaction of NO with a diverse range of targets such as haem groups, iron and zinc clusters, and cysteine residues. Nitric oxide is synthesised from L-arginine by NO synthase (NOS), and three main isoforms of NOS have been identified. In patients with RP it was observed a particular situation in which NO production by eNOS in endothelial cells is decreased.Therefore, reduced eNOS expression and microcirculatory dysfunction are in part contributory to the associated Raynaud's Phenomenon. ENOS levels are controlled by the NOS inhibitor asymmetric dimethylarginine (ADMA). Indeed, there is further evidence to indicate increased circulatory levels of ADMA in the serum of RP patients, suggesting an NOS reduction later on in the disease. In turn, this come from S-nitrosylation of the ADMA regulating enzyme dimethylarginine dimethylaminohydrolase (DDAH) which diminishes DDAH activity, leading to an accumulation of ADMA.
Thus has been suggested that NO deficiency contributes to the pathogenesis of Raynaud's phenomenon, and this has therapeutic relevance because topical application/delivery of NO is known to increase blood flow.

(Modulation of Fibrosis in Systemic Sclerosis by Nitric Oxide and Antioxidants.2011)

Endothelin Receptors

The endothelium produces also vasoconstrictors and the one which has attracted most recent interest in Raynaud's phenomenon is endothelin-1 (ET-1), especially now that it is possible to block its action therapeutically with receptor antagonists. Endothelin-1 is an extremely potent vasoconstrictor. It seems likely that endothelin is implicated. ET-1 is a 21-amino acid polypeptide expressed primarily by endothelial cells. It acts locally, binding to the surface of smooth muscle cells and acts on the vascular endothelium itself in an autocrine manner. ET-1 signaling is mediated by two transmembrane G-protein-coupled receptors (ETA and ETB) with different binding affinity and physiologic effects. ETA receptors are expressed on vascular smooth muscle cells and primarily mediate vasoconstriction whereas ETB receptors are expressed on both endothelial cells, mediating vasodilatation, and on smooth muscle cells, mediating vasoconstriction. In addition, bosentan (an endothelin-1 receptor antagonist) has been shown to confer benefit in studies of digital ulceration. Moreover studies reported that endothelin-1 levels, as well as being elevated at baseline, rose more in patients with RP than in controls in response to a cold challenge.

(Endothelin receptors and calcium signaling.1995)

Tyrosine Kinase Signal

Moreover new insights are provided by a recent series of studies which investigated the role of the protein tyrosine kinase signal transduction pathway in RP by examining responses in dermal arterioles. Responses to three vasoconstrictors—an α2-adrenergic agonist, serotonin and angiotensin II—were increased in RP patients, and were reversed by protein tyrosine kinase inhibitors. Therefore it seems that there is an hyperactivity of tyrosine kinases and ,in this way, tyrosine phosphorylation increases in RP patients on cooling.

(Cooling-induced contraction and protein tyrosine kinase activity of isolated arterioles in secondary Raynaud's phenomenon.2005)

... about Central mechanism

That is correlate with Raynaud's stress-induced vasospasm, and it therefore seems intuitive that even if neural abnormalities are primarily local to the digits, there must also be a central nervous component. However, this is a difficult area of research, and there is little direct evidence in support of central mechanisms. Studies showed that patients with RP do not habituate in the same way as healthy controls to the components of the ‘alerting response’ evoked by acute emotional stress. This alerting response includes vasodilation in forearm muscle and vasoconstriction in the cutaneous circulation of the digits. The authors suggested that in this patients central nervous mechanisms prolonged vasoconstriction on cooling, but there is a superimposed effect of locally released vasoconstrictors, especially endothelin-1.

(Idiopathic and secondary Raynaud's phenomenon. A comparative psychosomatic approach.1990)

...about Intravascilar Abnormalities

Hyperhomocysteinemia

Data demonstrate that patients with RP have higher plasma levels of homocysteine. In addittion the role of homocysteine as a risk factor for cardiovascular disease is suggested to be mediated by homocysteine down-regulating production of DDAH in the body. This suggests that homocysteine may play a role in RP and may provide new clues in understanding of the vasomotor dysregulation.

(Homocysteine and Raynaud's phenomenon: a review.2009)

White blood cell activation

White blood cell activation has been reported in patients PRP and may contribute to oxidative stress, described below.
In some cases neutrophil and platelet activation, through the release of inflammatory agents such as endothelin-1 and TNF-alpha, contribute to the endothelial damage seen with more severe RP.

(The role of endothelin-1 and selected cytokines in the pathogenesis of Raynaud's phenomenon associated with systemic connective tissue diseases.2006)

... about Other Factors

Hormonal factors

Raynaud's phenomenon is much more common in women than in men and it is likely that hormonal factors are important, especially as variations in blood flow with the menstrual cycle have been described: during the immediate preovulatory period, healthy controls demonstrated digital vascular reactivity similar to that of patients with Raynaud's phenomenon. In addition, during menopause, changes in reproductive hormone levels substantially alter thermoregulatory control of skin blood flow. This altered control might contribute to the occurrence of hot flashes. However at present we do not fully understand the hormonal contribution to vascular tone.

Genetic Factors

RP, especially primary, appears to have a strong familial component suggesting a genetic link, though this link is yet to be clarified. For example MTHFR mutation can be associated with hyperhomocysteinemia and high homocysteine levels are shown to be associated with decreased vasodilation. However it seems that there is not a single gene which cause the disease but the predisposition is multifactorial.
Another example is about occupational vinyl chloride monomer (VCM) exposure. It can induce Raynaud's phenomenon (RP). However, not all VCM workers developed RP, which suggests an underlying genetic susceptibility. Genetic polymorphisms of glutathione S-transferases (GSTs), involved in VCM metabolism, have been shown to influence certain VCM-related health effects. Partciculary GST M1 and GST T1 gene polymorphisms were studied , either separately or in combination, and the presence of RP. None of the GST M1 and GST T1 genotypes seem to contribute to the presence of RP when taken alone. However, the combination of both positive GST M1 and GST T1 genotypes appears to contribute to susceptibility to RP in VCM-exposed subjects.

(Heredity and genetic aspects of Raynaud's disease.2006)
(Glutathione S-transferase M1 and GST T1 genetic polymorphisms and Raynaud's phenomenon in French vinyl chloride monomer-exposed workers.2006)

...about Treatment

Treatment options are dependent on the type of Raynaud's present. Raynaud's syndrome is treated primarily by addressing the underlying cause while treatment of primary Raynaud's focuses on avoiding triggers:
-Environmental triggers should be avoided, e.g. cold, vibration, etc.
-Emotional stress is another recognized trigger.
-Extremities should be kept warm
-Consumption of caffeine, smoking and other stimulants and vasoconstrictors must be prevented.
-Dangerous drugs should be discontinued.

Pharmacotherapy is usually unnecessary in patients with primary Raynaud’s phenomenon. In the most severe case, if these measures are inadequate, then drugs are used:

- Calcium-channel blockers are the most widely used (nifedipine).

- As already mentioned above, several studies have evaluated the efficacy of targeting the vasoconstrictor endothelin-1 (ET-1) using endothelin receptor antagonists (ETRA) for the treatment of RP. Endothelin receptor antagonists are a class of PAH-specific drugs that block the interaction of ET-1 with its receptors. ETRAs can selectively act on ETA receptors to varying degrees, thus interfering with the vasoconstrictive effects of ET-1, but there are nonselective ETRA too (targeting both ETA/ETB ).

(Endothelin Receptor Antagonists for the Treatment of Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis.2011)

- In addition we can observe the important role of Phosphodiesterases (PDEs). They are isoenzymes, found on a variety of tissues, that control the level of intracellular cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) by hydrolyzing them. PDE isoenzyme 5 (PDE-5) selectively breaks down the cGMP, a critical smooth muscle tone regulator. Nitric oxide (NO), produced by nitric oxide synthase, signals the conversion of GMP into cGMP which accumulates inside the cell. Inhibition of the PDE-5 enzyme increases the available intracellular cGMP which leads to vasodilatation through activation of PKG and the subsequent pattern. PDE-5Is are available in oral formulation, are rapidly absorbed from the gastrointestinal tract, and are metabolized by hepatic enzymes via cytochrome P450 s.

(PDE-5 Inhibitors in Scleroderma Raynaud Phenomenon and Digital Ulcers: Current Status of Clinical Trials.2011)

- In alternative some authors propose a microsurgical technique, sympathectomy or microvascular surgey to treat upper limb chronic digital ischemia that is resistant to medical therapy.

(Microsurgical distal sympathectomy in chronic vasospastic syndromes of the hand.2005)

- In the end more research are required in the field of antithrobotics (prostanoids and others drugs with antiplatelet effect) and antioxidant (for endothelium protection), which both could improve symptoms of Raynaud's Phenomenon.

RAYNAUD’S PHENOMENON

Raynaud’s phenomenon is a vasospastic disorder causing discoloration of the fingers, toes and occasionally other areas (nose, ears and tongue) and it can also lead nails to become brittle with longitudinal ridges. Named for French physician Maurice Raynaud (1834–1881), the cause of the phenomenon is believed to be the result of vasospasms that decrease blood supply to the respective regions; Maurice Raynaud described the phenomenon which so famously bears his name in 1862. Summarizing his observations, he stated that ‘local asphyxia of the extremities’ was a result of ‘increased irritability of the central parts of the cord presiding over vascular innervation’. Approximately 70 yearsr later, Lewis suggested that the cause of the phenomenon was not central but peripheral, due to ‘spasm of the digital arteries’ and that ‘the abnormal element in the reaction to cold is a direct reaction and due to a peculiar condition of the vessel wall locally: it is not the result of a reflex through the vasomotor nerves’.

It comprises:

Raynaud’s disease (“Primary Raynaud’s phenomenon” PRP) where the phenomenon is idiopatic: emotional stress and cold are classic triggers of the phenomenon.

Raynaud’s syndrome (“Secondary Raynaud’s phenomenon”) ; occurs secondary to a wide variety of other conditions as connective tissue disorders (Systemic Sclerosis [SSc], systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome), eating disorders (anorexia nervosa), obstructive disorders (atherosclerosis, Takayasu’s arteritis, thoracic outlet syndrome) and drugs (beta-blockers, ciclosporin, sulfasalazine).

In Raynaud’s phenomenon there are three classic color changes of the fingers or toes: first, vasoconstriction results in a white blanching of the fingertips; second, vasodilatation with sludging of vascular flow results in blue, cyanotic digits; finally with recovery there is increased blood flow with resulting red color due to reactive hyperaemia.
With observation of two of the three color changes, Raynaud’ phenomenon is considered present.
One or more digits may be involved, and this involvement may be unilateral.

SYMPTOMS

Signs and symptoms of Raynaud’s depend on the frequency, duration and severity of the blood vessel spasms that underlie the disorder; these symptoms include:
• Cold fingers and toes.
• Sequence of color changes in the skin (white-blue-red as previously said).
• Numb and prickly feeling of stinging pain.
Occasionally, an attack affects just one or two fingers or toes; attacks don’t necessarily always affect the same digits. An attack may last less than a minute to several hours.

EPIDEMIOLOGY
The prevalence of primary Raynaud phenomenon varies among different populations, from 4.9%-20.1% in women to 3.8%-13.5% in men, with women three times more likely to be diagnosed than men; people in their thirties are most likely to develop Raynaud’s.
Primary Raynaud phenomenon does not usually cause death or serious morbidity. However, in very rare cases, ischemia of the affected body part can result in necrosis.
Secondary Raynaud phenomenon is important as a possible marker for other diseases that may lead to morbidity and mortality.

PATHOGENESIS

The last 20 years have witnessed enormous increases in understanding of different mechanisms which may contribute to the phenomenon.
Vascular abnormalities include both structure and function.
Neural abnormalities include deficiency of the vasodilator calcitonin gene-related peptide (released from sensory afferents), α2C-adrenoreceptor’s up-regulation (it is normally “silent”) and a central nervous system component.
Intravascular abnormalities include platelet activation, impaired fibrinolysis, increased viscosity and oxidant stress.
It has been suggested that the pathogenesis of Raynaud's phenomenon, especially when secondary to SSc (Systemic Sclerosis), can be explained on the basis of dysregulated neuroendothelial control mechanisms; The key issue is the imbalance between vasoconstriction and vasodilation (in favour of vasoconstriction).

Vascular Abnormalities

• STRUCTURAL: although microvascular abnormalities may occur in PRP (Raynaud’s disease), it is generally accepted that in PRP the vascular defect is primarily functional. In contrast, structural vascular abnormalities of both the microvasculature and digital artery are well recognized in SSc. The pathogenesis of the structural vascular abnormalities in SSc includes endothelial cell apoptosis, up-regulation of adhesion molecules, and the interaction of a large number of cytokines and growth factors.

• FUNCTIONAL: in patients with SSc, the balance between vasodilation and vasoconstriction may be disturbed in favour of vasoconstriction (in addition to the endothelium becoming procoagulant and proinflammatory). While it is possible that endothelial activation occurs also in PRP (some investigators have reported raised levels of von Willebrand factor), endothelial abnormalities are less likely to be major players in the pathogenesis of PRP. This may result from a defect in the endothelium, or reduced concentrations of endogenous vasodilators acting on the endothelium.
- It has been suggested that NO deficiency contributes to the pathogenesis of Raynaud's phenomenon. A recent study of 20 patients with PRP and 20 with secondary Raynaud's (seven had SSc) reported higher circulating levels of asymmetrical dimethylarginine (an endogenous inhibitor of endothelial NO synthase) and of endothelin-1 in the secondary Raynaud's group.
- Prostacyclin production is reduced on cold exposure ; patients with SSc might be resistant to prostacyclin, although this resistance could be overcome by pharmacological doses.
- Endothelin-1 is overexpressed in sclerodermatous skin and endothelin-binding density is increased in skin biopsies from patients with SSc .
- A recent study reported increased circulating levels of angiotensin II in patients with diffuse cutaneous SSc (although not in limited cutaneous SSc). It is now recognized that ACE inhibitors have effects on endothelial function.

Neural Abnormalities

• PERIPHEAL MECHANISMS: autonomic and peripheral neuropathy are being increasingly recognized in SSc. The situation is complex and a variety of neurotransmitters and their receptors seem to be involved; paraesthesia is common.

• IMPAIRED VASODILATOR: nerves supplying blood vessels produce a number of vasodilatory substances. Calcitonin gene-related peptide (CGRP), released from sensory afferents, has been most studied: others include substance P, neurokinin A and vasointestinal peptide. Immunohistochemical studies have shown a reduction in the number of CGRP-immunoreactive nerve fibres in biopsies of finger skin from patients with SSc and with PRP.

• INCREASED VASOCONSTRICTION: vasoconstriction to noradrenaline is mediated by α1 and α2-adrenoreceptors, but the α2-adrenoreceptors are thought to be more important in the regulation of digital vascular tone . In a cell model, in response to cooling, the normally “silent” α2C-adrenoreceptors relocate from the Golgi compartments to the cell surface. Therefore, the α2C-adrenoreceptors may be responsible for cold-induced augmentation of α2-adrenoreceptor activity.

• CENTRAL MECHANISMS: central mechanisms may contribute to vasospasm but in most situations peripheral neural mechanisms are the more important.

Intravascular Abnormalities

• PLATELET ACTIVATION: platelet activation is well recognized in SSc and PRP; it can be demonstrated by increased circulating levels of thromboxane and of β-thromboglobulin, released from platelet α-granules. Synthesis of thromboxane, a potent vasoconstrictor as well as a platelet aggregator, is increased in patients with SSc, especially on cooling, and so may contribute to vasospasm in SSc, and expression of the gene encoding thromboxane synthase was recently found to be increased in leucocytes from patients with SSc. Serotonin, another vasoconstrictor produced from platelets, has also been implicated in the pathophysiology of Raynaud's .

• FIBRINOLYSIS: defective fibrinolysis has been reported in SSc. At least a proportion of patients with SSc have impaired fibrinolysis, which will predispose towards fibrin deposition and vascular obstruction.

• REDUCED RED BLOOD CELL DEFORMABILITY: has been reported in SSc, but not in PRP and may reflect damage to the erythrocyte membrane by free radicals.

• INCREASED VISCOSITY: viscosity is increased in patients with PRP at low temperatures and it is associated with low flow rates.

• OXIDATIVE STRESS: free radicals may be produced by a variety of mechanisms, including the hypoxanthine–xanthine oxidase system and activation of polymorphonuclear leucocytes. In SSc, it seems likely that oxidative stress contributes to endothelial injury through peroxidation of cell membrane lipids.

Other Factors

- SMOKING: in patients with SSc, there is an association between cigarette smoking and the severity of digital ischaemia, and although the mechanisms behind this association are not clear, they are likely to include endothelial damage caused by smoking, increased viscosity and impaired fibrinolysis.

- HORMONAL FACTORS: Raynaud's phenomenon is much more common in women than in men and it is likely that hormonal factors are important, especially as variations in blood flow with the menstrual cycle.

DIAGNOSTIC TESTS
- Blood tests to check for antinuclear antibodies, rhemautoid factor, cryoglobulins.
- Serum proteins’ electrophoreses.
- Cervical spine X-rays.
- Angiography for delineation of type and location of arterial disease.

TREATMENT

Inhibiting Vasoconstriction. There is currently increased interest in ACE inhibitors, especially now that their effects on endothelial function and vascular remodelling are recognized, and also in angiotensin II receptor antagonists. The action of serotonin can be blocked by serotonin reuptake inhibitors and results from an open study suggest that fluoxetine, a selective serotonin reuptake inhibitor, may be beneficial in both primary and secondary Raynaud's.

Increasing Vasodilation. Intravenous prostanoid therapy is well established in severe digital ischaemia. Supplementation of the L-arginine/NO pathway is being explored in several ways, including with transdermal NO, oral administration of L-arginine, and via phosphodiesterase inhibition (which enhances the effect of NO by inhibiting the degradation of cyclic guanosine monophosphate).

Endothelium Protection. Antioxidant therapies and smoking cessation are actively promoted.