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Cardiovascular Research 1997 33(1):25-30; doi:10.1016/S0008-6363(96)00183-6
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Raynaud's phenomenon

Jill Belch

Department of Medicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK

Received 2 January 1996; accepted 14 July 1996

KEYWORDS Raynaud's phenomenon; Vasospasm; Infection; Inflammation; Sympathetic nervous system


   1. Introduction and spectrum of Raynaud's phenomenon
Top
 1. Introduction and spectrum...
2. Characteristics of vasospasm
 3. Pathophysiology of vascular...
 4. Management of Raynaud's...
 5. Conclusion
 References
 
Raynaud's phenomenon (RP) may affect as many 20–30% of young women [1] and have an overall prevalence in the population of approximately 10% [2]. In the UK RP is the blanket term used to describe any form of cold related vasospasm and can be further subdivided into Raynaud's syndrome (RS) where there is an associated disorder and primary Raynaud's disease (RD) where there is not. In the USA the terminology most used is primary RP and secondary RP. Australasia uses RP and RS interchangeably and thus care must be taken with literature comparisons to ensure the different terminologies are used in a standard fashion. Most workers define their population in terms of CTD association, otherwise at the start of each paper and until a standard nomenclature is accepted, this practice should continue. By far the largest group of patients presenting to their primary care physician are those with the primary disorder. However, recent studies have shown that the phenomenon may pre-date systemic illness by up to two decades. Since the development of sensitive laboratory procedures, we now know that more than half of the patients referred to hospital because of RP will have an associated systemic disease [1, 3, 4]. There is a wide spectrum of disease associated with RS including those reported in the mystery cases (i.e., drug-induced RS), that associated with thromboangiitis obliterans and with occupational vibration exposure. The best recognised of the associated disorders are the connective tissue disorders (CTDs) and RS of occupational origin (Table 1).


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  		Table 1 Conditions associated with Raynaud's phenomenon

 
RS accompanies systemic sclerosis (SSC) in 95% of cases and also in the majority of patients with mixed connective tissue disease (MCTD) (85%). Between 10–45% of patients with systemic lupus erythematosus also suffer vasospastic attacks as do 33% of Sjögren's syndrome patients and 20% of those with dermatomyositis/polymyositis [5]. RS is classically reported in occurring in rheumatoid arthritis, but the frequency with which it does so is similar to the frequency seen in the general population (10%); however, the symptomatology tends to be more severe.

The most common form of occupational RS is hand arm vibration syndrome (HAVS) [6]. As its name suggests, HAVS occurs in workers exposed to vibrating machines such as pneumatic drills, grinders, buffs and chainsaws. It is estimated that about half of all workers using vibrating equipment can develop RS although some resolution of symptoms may occur in 25% of cases, if a job change is effected early (i.e., before grade 2 on the Taylor Pelmear scale) [7]. Workers exposed to polyvinyl chloride can also develop RP of occupational origin and vasospasm can occur in ammunition workers outside their place of work when the vasodilatory effects of the nitrate are removed[8].

As delineated in one of the Mystery Cases, drug- or chemical-induced vasospasm is not a new phenomenon and was reported frequently in association with ergot poisoning. Ergot compounds are still used today in the treatment of persistent migraine and are usually contraindicated in patients with RP. It is interesting to speculate whether the newer migraine treatments such as the serotonin agonists will also RP precipitate in susceptible individuals. A more common form of drug-induced RP is that seen with beta-blockers. Even the more modern ‘selective’ drugs can produce clinical vasospasm in some cases. Vasoconstriction is also a well-recognised side-effect of some cytotoxic agents and when infused in error during intravenous infusion into the tissues, can be responsible for significant tissue destruction, in part related to the severity of the induced local vasoconstriction.

Obstructive vascular disease is the commonest cause of RP in the older age group, 60% of RP occurring above the age of 60 years is atherosclerotic in origin [9]. Repeated microemboli from the heart or from some stenotic upper limb artery can also produce Raynaud-like symptoms. Obstructive vascular disease can also cause problems in the younger age group particularly in heavy cigarette smokers when the appearance of ischaemic symptoms in the lower limbs associated with superficial thrombophlebitis and Raynaud's phenomenon in the digits should alert the clinician of the possible diagnosis of thromboangiitis obliterans (Buerger's disease). Previously thought to be limited to male smokers, with the increased female smoking habit, it is now know to affect both sexes. Smoking cessation invariably stops the progression of the disease. Obstruction caused by pressure from outside the vessels such as occurs in thoracic outlet syndrome can also cause RP. Cervical rib is a common cause of thoracic outlet syndrome and can be clinically suspected in a patient with unilateral RP or RP affecting the upper limb only. Furthermore, signs of brachial plexus compression may also be present.

Many other conditions are associated with RS (Table 1). The challenge in this condition is in differentiating primary RD from secondary RS and, most importantly, detecting early those who may progress to CTD so that the correct management can be employed [10, 11].


   2. Characteristics of vasospasm
Top
 1. Introduction and spectrum...
 2. Characteristics of vasospasm
3. Pathophysiology of vascular...
 4. Management of Raynaud's...
 5. Conclusion
 References
 
In 1862, Maurice Raynaud first described the syndrome which bears his name as episodic digital ischaemia provoked by cold and emotion. It is classically manifested by blanching of the affected part (pallor) reflecting vasospasm, followed by cyanosis and rubor. Venostasis is the cause of cyanosis, and rubor is caused by a reactive hyperaemia following the return of blood flow. There is a familial predisposition to RP which occurs in association with the primary form and is more marked if the age of RP onset is less than 30 years [5].

Some of the original aspects of Maurice Raynaud's definition now appear to require some modification in the light of recent work. For example, it is now recognised that a biphasic colour change can still reflect significant vasospasm, although blanching must be present in order to diagnose RP. Furthermore, stimuli other than cold and emotion can provoke an attack such as those chemicals previously discussed, and additionally tobacco smoke [12], hormones [13] and trauma.

Furthermore, in the majority of cases, vasospasm is not limited to the digits but may be visually observed in the earlobes and the tip of the nose. Recently the concept of ‘systemic vasospasm’ has been mooted with vasospasm being reported in the lung vasculature [14], coronary arteries[15] and oesophageal vessels [16] after cold challenge in RP sufferers. The link with RP and migraine has been known for many years. With this evidence of vasospasm in many vascular beds, it is interesting to speculate that abnormalities of the vasculature may exist throughout the patient and contribute to the wide spectrum of symptoms seen in RP, such as pregnancy-associated hypertension, essential hypertension and impotence.


   3. Pathophysiology of vascular spasm
Top
 1. Introduction and spectrum...
 2. Characteristics of vasospasm
 3. Pathophysiology of vascular...
4. Management of Raynaud's...
 5. Conclusion
 References
 
There are three factors which should be considered as having aetiological importance in RP: (1) neurogenic mechanisms, (2) blood and blood vessel wall interactions and (3) abnormalities of the inflammatory and immune response. Whilst the first of these is likely to be most important in primary RD, the latter two have important roles in secondary RS.

3.1. Neurogenic mechanisms
Maurice Raynaud believed in the hyperactivity of the sympathetic nervous system, whereas Lewis [17] hypothesized a ‘local fault’. Abnormalities described include increased {alpha}-adrenergic receptor sensitivity and/or density[18] but also an increase in the responsiveness of β presynaptic-receptors in the RS peripheral vessels [19]. A role for the central sympathetic system is suggested as local vibration of one hand induces vasoconstriction of the other [20].

An interesting finding is one that relates to a potential dysfunction of the calcitonin gene-receptor peptide-dependent neurovascular axis. Calcitonin-gene-related peptide (CGRP), a potent vasodilator, has been evaluated in the digital skin of RP and results suggest that the quantity of CGRP-containing nerves may be decreased [21].

3.2. Blood and blood vessel interaction
Alteration in blood vessel tone cannot explain all the features of RP. Blood flow in the microcirculation is critically dependent on the various properties of the liquid and cellular elements of blood and on the integrity of the endothelium.

The endothelium is a functioning organ releasing important chemicals such as prostacyclin (PGI2) a potent antiplatelet agent and vasodilator, nitric oxide formerly ‘endothelium derived relaxing factor’, and endothelin, a potent vasoconstrictor. Whilst PGI2 may be elevated in the early stages of vascular disease [22], PGI2 stimulating factor may be decreased in the later stages [23] facilitating platelet aggregation and vasoconstriction. Similarly, NO production is reported to be decreased in RP whilst endothelin production is increased [24]. Furthermore, the damaged endothelium can release factor VIII von Willebrand factor antigen which can have a prothrombotic effect both by its participation in the coagulation cascade and in platelet aggregation [25]. Other manifestations of endothelial dysfunction have been detected in RP such defects in the lysis of fibrin.

The cellular elements of blood may also be abnormal in RP. Platelet aggregation is enhanced as is the platelet release reaction with increased production of vasoconstrictors such as thromboxane A2 [26]. The red blood cell appears less deformable in RP generally and the cold temperature, associated with the acidosis present in cold, ulcerated fingers will also increase red cell stiffness. An important role is also emerging for the white blood cell. Polymorphonuclear leucocyte activation with increased release of prothrombotic free radicals and increased cell aggregation has been reported in RP and these may also contribute to the decreased flow seen in this disorder [27].

It should be noted that RD patients do not usually show these blood and endothelial abnormalities whilst the majority of RS patients do. Interestingly, this is true for both CTD-associated RS and that associated with HAVS [28]. Thus whilst these changes are likely to be a consequence of the RP rather than a cause, they may worsen the symptoms of vasospasm and their attenuation is an important feature in the drug management of RP

3.3. Inflammation and immunity
The WBC has always been considered to be important as the producer and modifier of the inflammatory and immune response. The endothelium is also involved in these processes by production of its vasoactive agents, growth factors and growth inhibitors. Disordered immune/inflammatory responses occur in the majority of severe cases of RS because the patients have a CTD but also in HAVS which has no clear immune/inflammatory basis [27], classically being supposed to be due to direct vessel damage. Tumour necrosis factor and lymphotoxin, phagocyte/macrophage and T-cell derived proteins, along with immune complex deposition in the vessel wall are likely to be involved in the vascular damage seen in RS[29].


   4. Management of Raynaud's phenomenon
Top
 1. Introduction and spectrum...
 2. Characteristics of vasospasm
 3. Pathophysiology of vascular...
 4. Management of Raynaud's...
5. Conclusion
 References
 
4.1. Supportive measures
Effective lifestyle changes can be useful in patients with mild disease. Stopping smoking can be beneficial. Passive smoking may be harmful and patients should be advised of this possibility. The withdrawal of drugs known to be associated with RP or a change in occupation can also be useful. It is our policy to recommend that the contraceptive pill should be stopped only if there is a clear link with the development of RP and the introduction of the contraception pill. Likewise, RP is not a contraindication for hormone replacement therapy (HRT), as HRT may protect women against the development of vascular disease in general. Treatment using self-training bio-feedback techniques has sometimes been successful but requires a well-motivated patient. It may be that bio-feedback-induced vasodilation is mediated through a non-neural β-adrenergic mechanism [30]. The mechanism whereby benefits derived from such treatments are still not fully understood however.

Apprehension about the disease can worsen the symptomatology and reassurance is often required, plus information regarding both the disease and any local self-help group. These self-help groups provide information booklets about various disorders associated with RP which can be requested by both doctor and patient. Advice regarding maintaining warmth and the protection from cold is very important. Achieving this without subscribing to a hermit-like existence is difficult, but practical solutions to the problem do exist. Electrically heated gloves and socks are the perfect solution for some where a rechargeable battery fixed on a belt provides up to 3 hours of warmth and the wires can be concealed beneath clothing to give a normal appearance. Chemical hand warmers provide a satisfactory alternative source of heat.

Good wound care of any digital ulcers should also be undertaken. Any ulcer that is moist should be swabbed and the swab sent for culture. A major pitfall in the management of digital ulceration in severe RP is the failure of the clinician to detect infection. Significant infection can be present even in the absence of warmth, erythema and pus formation. This is due to the fact that blood flow is impaired and the inflammatory cells may not be reaching the infected digit. It may be that one should consider a trial of antibiotics in all cases prior to considering amputation of a digit. The organisms detected are usually staphylococcus, but infection by less common organisms can occur, so swab culture should also be carried out.

4.2. Sympathectomy
Operative sympathectomy of the upper limb has a high relapse rate and an especially poor response in RS. We therefore no longer recommend this treatment for RP of the upper limb. It should be noted, however, that the more selective digital sympathectomy has produced some early encouraging results [31], but these have not yet been validated by long-term follow-up assessments. In contrast, sympathectomy still has an important role in the treatment of RP effecting the lower limb where results may be rewarding.

4.3. Drug treatment of Raynaud's phenomenon
A potential treatment protocol for RP is outlined in Table 2 where the drugs most commonly used in the treatment of this disorder are delineated. Most drug treatment is directed towards one or more of the abnormalities delineated above.


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  		Table 2 Flow chart for management of Raynaud's phenomenon

 
The use of simple vasodilators in RP remains controversial as most studies have either been uncontrolled or very small. Additionally, the majority of studies in the seventies and eighties evaluated patients with RP of many different aetiologies within the same study. This includes patients with RD and RS. Thus in many cases a study would only have one or two of each type of RS plus 4 to 5 RD patients. Nevertheless, some compounds do however merit consideration. These include inositol, nicotinate [32], naftidrofuryl [33] and oxpentifylline [34]. It is interesting that the full benefit obtained from these drugs may not always become apparent until after 2 to 3 months of treatment and this raises the question that although these drugs are known vasodilators, their action in RP may be through other mechanisms. A trial of these and possibly other vasodilators given in sufficient dosages for a sufficient period of time may be worthwhile. It is unusual, however, for the more severely affected patient to benefit from these treatments, most of which will have been prescribed by the primary care physician before hospital referral. In the more severely affected group of patients, simple vasodilators are often ineffective with the limiting factor being the development of side-effects at high dosage.

Many studies have been carried out investigating the use of calcium channel antagonists in RP and nifedipine has now become the gold standard of Raynaud's treatment. Its use, however, is limited by its vasodilatory side-effects to which the RP patient appears particularly susceptible. These include facial flushing, palpitations, headache and, over the longer term, ankle swelling. To attenuate the majority of these side-effects, the patients should use the retard preparation. If side-effects require discontinuation, other calcium general antagonists such as diltiazem [35] and amilodipine can be tried.

One of the most effective approaches to RS associated with the CTD systemic sclerosis has been the development of prostaglandin treatment. Both PGE1 and PGI2 have been evaluated in RP and most studies suggest a benefit from various intravenous regimes [3]. More recently the use of these intravenously administered prostaglandins has been superseded by the development of iloprost. Iloprost is a PGI2 analogue which may also be beneficial in RP [37]. Whereas both PGE1 and PGI2 are unstable, iloprost is not and this makes it easier to handle despite the earlier work having been carried out using an intravenous administration. Iloprost has similar vasodilatory side-effects to nifedipine but, in a direct comparison, was found to be equally effective [38]. Orally administered iloprost is now being evaluated in clinical trials [39] and it is hoped that this compound might be developed into an appropriate and effective drug treatment for the long-term management of RP.

Other approaches to manipulating the body's own production of vasodilatory PGs have been evaluated in the form of administration of evening primrose oil and fish oil. Only a few well-controlled studies have been reported, however, with a mild response only being detected. As with the PGs, RP is not a licensed indication for their use.

Specific inhibition of the enzyme thromboxane synthetase results in decreased production of thromboxane A2. Theoretically, this should promote vasodilatation and platelet disaggregation which may be beneficial in RP. Nevertheless, studies of such compounds have produced disappointing results although the more recently available compounds which incorporate thromboxane synthetase inhibition with thromboxane receptor site blockade may be more promising [40].

Active research continues in the field of drug development for Raynaud's phenomenon and anti-endothelin, NO-donating drugs and calcitonin-gene-related peptide infusions[41] are all potential drugs for the future. There is no doubt that the better evaluation and understanding of the pathophysiology of RP has led to a better selection of treatment options for study, with significant advances being made in the management of RP, in particular a decreased requirement for digital amputation.


   5. Conclusion
Top
 1. Introduction and spectrum...
 2. Characteristics of vasospasm
 3. Pathophysiology of vascular...
 4. Management of Raynaud's...
 5. Conclusion
References
 
RP is a common condition and is associated with many different disorders. It should be possible, with a careful clinical history and examination and with selection of specific tests, to correctly diagnose RP and to assess the likelihood of it existing in association with another disorder. Although a cure is not possible, many patients with RP can achieve a beneficial amelioration of their symptoms using the above therapies. Nevertheless, it should be remembered that the final prognosis of RS is determined by that of the associated disorder which must first be detected, then monitored and treated independently from the vasospastic symptoms.


   Acknowledgements
 
Dr. J.J.F. Belch receives support from the Raynaud's and Scleroderma Association.


   References
Top
 1. Introduction and spectrum...
 2. Characteristics of vasospasm
 3. Pathophysiology of vascular...
 4. Management of Raynaud's...
 5. Conclusion
 References
 

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