Raynaud's Phenomenon

Synonyms: Raynaud phenomenon/disease/syndrome (American forms); primary Raynaud's; secondary Raynaud's

This condition was discovered by Maurice Raynaud (a Parisian physician) in the latter half of the nineteenth century. It is characterised by a paroxysmal vasospastic and subsequent vasodilatory chain of events affecting peripheral arterioles, usually in the hands and feet.¹ It commonly occurs as a response to cold exposure, but may also be precipitated by emotional turmoil. The process may occur as a primary entity or secondary to other disease processes.

The exact mechanism of disease is uncertain in primary Raynaud's and for some causes of secondary Raynaud's. Possible pathological mechanisms in the primary form include: increased sympathetic activity, increased sensitivity to adrenergic stimuli, an excess of alpha-receptors in the arteriolar walls or hyperactivity of, or damage to, endothelial cells, exacerbating normal vasospasm.

This clinical condition has several names. Unfortunately they are not always used consistently, leading to confusion:

• Phenomenon is the term best used to describe the characteristic symptomatic sequence as experienced by the patient, before it is classified as being a primary or secondary entity.
• Raynaud's disease is the term used to describe the primary form of the symptoms where there is no obvious underlying cause. It is a disease that predominantly affects young women in the second and third decades of life.
• Raynaud's syndrome is the name given to the symptoms when there is an identifiable underlying cause, although many use phenomenon to describe this situation too. The syndrome often occurs in later life (>30 years old), concurrently with the onset of an underlying cause. However, some patients may have this symptom as the earliest manifestation of the underlying disease, which may reveal itself at a later time.

Matters are further complicated by the fact that Monsieur Raynaud has a type of gangrene (symmetrical gangrene of the extremities) and a sign (symmetrical, mottled cyanosis of extremities with patches of erythema and excessive sweating) named after him.²

Prevalence

It is a common symptom in the general population:
A UK-based postal survey of working-age adults found that about 14% suffered it, with 11% attributing it to cold-exposure:³

• About 2% of those surveyed had seen a doctor for the problem.
• Overall prevalence was higher in women than men, but men (and presumably women) exposed to hand-transmitted vibration from tool use are 2–2.5 times more likely to experience the phenomenon than their unexposed counterparts.
• Over a third of men with symptoms who were exposed to hand-transmitted vibration had consulted a doctor about it.

Climate and ethnic factors may affect prevalence.⁴

Risk factors

More common in women, men who use vibrating tools and those who have associated conditions as outlined below. Smoking certainly exacerbates the condition and is probably an independent risk factor.

Occupational exposure to polyvinyl chloride, arsenical compounds or lead are thought to increase the likelihood of suffering the condition, as is previous frostbite.¹ Moderate red wine consumption appears to have a protective effect in men and women. Heavy consumption of other types of alcohol seems to be a risk factor for women, but moderate consumption had a protective effect in men.⁵

Symptoms

• The patient may initially notice pallor of the distal portion of one or more digits.¹ For reasons as yet unknown, the thumb is usually spared.⁶
• There is usually a clear demarcation line between affected and normal skin.
• There then follows a feeling of numbness or pain in the digit(s) accompanied by cyanosis (blueing) of the digit.
• Finally there is a hyperaemic phase where the digit becomes red and feels warm.
• Individual patients may show variation in the sequence of these three phases.

Signs

In primary Raynaud's disease there will usually be nothing to find, as patients rarely present during the event.

• To detect evidence of an alternative cause for the symptoms, or an underlying disease associated with secondary Raynaud's syndrome, look for any abnormality in pulses of the affected hand/foot.
  • Is there atrial fibrillation/other cardiac dysrhythmia or murmur, or any other evidence of a cause for embolic disease?
  • Look at the skin of the face for malar rash indicating systemic lupus erythematosus (SLE). Look for sclerodactyly, calcinosis or ulcer formation, and carefully seek evidence of vasculitic changes in the nail beds (magnification will help with this), suggesting progressive systemic sclerosis.
  • Examine any joints that are sore, palpate the abdomen to exclude hepato/splenomegaly and check the lymph fields to detect any evidence of malignancy. Examine any other relevant systems if other underlying causes are possible, e.g. chest examination if pulmonary malignancy suspected.

Many conditions may co-exist as above. The symptom complex is usually fairly distinctive, but other causes of vascular compromise may cause similar symptoms. If in doubt consider vascular flow imaging/vascular surgical advice. Possible diagnoses that are not classically associated as causative diseases but that may cause symptoms that resemble Raynaud's phenomenon are:¹

• Vasculitides
• Carpal tunnel syndrome
• Arterial thromboembolism
• Cholesterol emboli
• Thoracic outlet obstruction
• Reflex sympathetic dystrophy (algodystrophy)

• In classically presenting primary Raynaud's disease, in a young woman who is well and has no evidence of other causes on examination, you are unlikely to detect anything on investigation:¹
• It is probably worth checking FBC and ESR/plasma viscosity in this situation as basic screening for unrecognised associated disease. If there is reason to suspect an underlying cause then investigations should be directed to confirming or refuting the association as below:
  • Consider U&E/liver function tests/thyroid function tests as basic screening tests in appropriate patients. The presence of specific autoantibodies, e.g. anti-nuclear antibodies, may suggest underlying inflammatory disease. Check plasma glucose for possible diabetes.
  • Urine/serum protein electrophoresis, cold agglutinins and fibrinogen levels may identify hyperviscosity states.
  • Chest X-ray (thoracic outlet views) may show a cervical rib.
  • Vascular Doppler flow studies may help if you are not convinced this is Raynaud's but, instead, an occlusive vascular disease of different aetiology.

One large study (>1,000 patients) has shown that patients who have normal serology and ESR/viscosity, only 2–8.5% subsequently develop connective tissue or other associated disease (follow up >10 years).⁷

General/preventative¹

• Self-help measures
  • SMOKING CESSATION - this is the most important self-help measure.
  • Avoid cold-exposure and take precautionary measures before exposure to cold; use gloves or electrically-heated mittens in the winter (available from patient support groups via specialist outfitters - see Internet and further reading section below).
  • Change occupation/DIY habits if vibration is a likely underlying cause.
• Topical agents
  • GTN paste, prostaglandin analogue gels and nitrate/ascorbate gels have been advocated with some evidence of usefulness but there are no reliable trials to confirm their efficacy.⁸
  • A potential problem with their use is a stinging effect, particularly if there is any broken skin.
• Systemic agents
  • Calcium channel blockers such as nifedipine and, to a lesser degree, diltiazem, are the mainstay of medical therapy via their vasodilatory action, but their beneficial effects appear to be relatively modest and there are relatively significant adverse effects for some who take them.⁹
  • There is some limited evidence of efficacy for ACE-inhibitors and serotonin-reuptake inhibitors.¹ Further evaluation is needed.
  • Intravenous prostaglandins may be tried in more bothersome cases and appear to have long-standing effect lasting weeks to months but this usually wanes in the long-term.
  • Anti-platelet drugs and anticoagulation are ineffective in trials and are not indicated.¹
  • Surgical approaches such as sympathectomy are rarely necessary and are reserved for severe cases, as the frequency of adverse post-operative effects (mainly gustatory and compensatory sweating) can be high.¹⁰

• Optimal management of the underlying cause can alleviate the symptoms, but unfortunately many cases do not seem to respond well and persist despite best treatment of the precipitating illness.¹
• General/preventive measures are the same as for primary Raynaud's as above.
• Those cases associated with progressive systemic sclerosis are often most troublesome and may lead to severe digital ischaemia and gangrene. More aggressive therapy is used in these and other secondary cases, including prostaglandin analogues or prostacyclins.¹¹ Intravenous iloprost has been shown to be effective in treating Raynaud's syndrome due to systemic sclerosis. It reduces the frequency and severity of attacks and prevents ulceration (or promotes ulcer healing once this has occurred).¹² It seems to have a sustained effect lasting up to several months after the infusion. Its oral form appears to be less effective and oral cisoprost is thought to be virtually ineffective.¹²
• A systematic trial of the alpha blocker prazosin in this scenario has found that it is modestly effective.¹³
• Cyclofenil (a steroid-like drug similar to clomifene) is currently under investigation as a potential therapeutic agent for Raynaud's secondary to scleroderma, but there is insufficient evidence to support its routine use currently.¹⁴
• Ketanserin (a serotonin receptor antagonist) is also currently under investigation.¹⁵ It has a modest effect on attack duration but significant side-effects, and so overall is not thought to be clinically useful.
• In acute severe cases infiltration of local anaesthetic agents at the base of the finger blocks sympathetic signalling to the digital arterioles and reduces pain and improves perfusion of the digit.
• Anticoagulation and antiplatelet therapy may be used in advanced cases to reduce thrombotic complications in the severely narrowed arterioles.
• Other drugs currently under investigation include endothelin receptor antagonists, sildenafil, fluoxetine and losartan. The effect of ACE inhibitors has been variable.¹¹
• Surgery may be necessary with digital sympathectomy ± vascular reconstruction in severe cases.

Most patients can be managed in primary care.¹⁶ However, referral (usually to a rheumatologist) should be considered in the following circumstances:

• The diagnosis is in doubt.
• A cause for the Raynaud's phenomenon is suspected.
• The cause is suspected to be associated with the person's occupation, (in which case, refer to occupational health services).
• The patient is a child under the age of 12 years.
• If the symptoms are poorly controlled, despite appropriate treatment.
• Ulcers develop or cuts/sores do not heal in affected areas.

Primary cases tend to do well after diagnosis and most patients learn to adapt to the condition using basic measures ± vasodilators:

• An underlying disorder develops in 13% of cases of the primary form.¹⁷ Primary Raynaud's may go into remission.¹⁸ Most patients have a stable course and over half improve over time.¹⁹
• Secondary cases are more prone to be problematic - ulceration, scarring, or gangrene occur in 17% of people with Raynaud's phenomenon secondary to systemic sclerosis.²⁰

Severe cases may lead to digital infarction and gangrene with loss of the tissue of the finger pulp or distal phalanx. The skin may become chronically ischaemic and ulcerate. The digit(s) may lose viability and require amputation in the the very worst cases.

• Avoid smoking.¹⁶
• Avoid beta blocker treatment.
• Wear gloves or have them to hand at all times.
• Use specialist heated gloves if necessary.
• Anticipate cold-exposure and take appropriate ameliorative steps.
• Consider moving to warmer climes (particularly during the coldest months) if condition troublesome enough and patient has the resources to do so.
• Avoid use of vibrating hand tools.