Pathogenesis

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 pathogenesis of Raynaud's phenomenon is complex but abnormalities of the blood vessel wall, of neural control mechanisms and of intravascular circulating factors are known to interact and contribute.^[2] 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.^[3]

Epidemiology^[4] 

• Prevalence studies have shown that 3-12.5% of men and 6-20% of women report symptoms of Raynaud's phenomenon. Prevalence is higher in colder climates.
• Family history, oestrogen exposure and emotional stress are commonly associated with Raynaud's phenomenon in women.
• Smoking and hand-arm vibration syndrome are more commonly implicated in men.
• One study of about 1,500 people found that 89% of Raynaud's phenomenon was classified as primary and 11% as secondary to an underlying cause (see 'Distinguishing between primary and secondary Raynaud's phenomenon', below).
• About 12.5% of patients with Raynaud's phenomenon develop scleroderma and 13.6% develop connective tissue diseases.

Presentation

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.^[5]
• 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.

The patient's age and sex will influence the likelihood of this being primary or secondary Raynaud's phenomenon. Enquire about any associated symptoms such as migrainous headache, recent joint or muscle pains, rashes, symptoms of infection, weight loss, etc to detect possible underlying causes.

It is important to take an occupational history and specifically ask about the use of vibrating tools at work or at home. Take a medication history, including over-the-counter/complementary preparations, and ask if anyone in the family has the same problem. Ask if the patient has ever suffered from frostbite, which is thought to increase the risk of subsequent vasomotor hyperactivity.

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. 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 - eg, chest examination if pulmonary malignancy is suspected.

Differential diagnosis

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)

Investigations

• 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/thyroid function testing as the basic screening tests in appropriate patients. The presence of specific autoantibodies - eg, antinuclear 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.
  • CXR (thoracic outlet views) may show a cervical rib.
• Refer patients with suspected secondary disease for capillaroscopy if available. Other investigations performed in secondary care include infrared thermography, laser Doppler flowmetry, portable radiometry, and digital plethymography.^[4]

Distinguishing between primary and secondary Raynaud's phenomenon^[4] 

Primary

• Younger age (<30, but can be any age); female; genetic component (30% have an affected first-degree relative).
• No symptoms/signs of underlying disease; no tissue necrosis or gangrene; normal nail fold capillaries.
• Normal ESR; negative antineutrophil antibodies.

Secondary

• Older age (>30, but can be any age); less common (10-20%).
• Symptoms and signs of underlying disease; tightness of finger skin; more severe pain; digital ischaemia (digital pitting scars, ulceration, or gangrene); abnormal nail fold capillaries.
• Raised ESR; positive antineutrophil antibodies or anti-extractable nuclear antigen antibodies.

Management of primary Raynaud's disease

General/preventative^[1]

• Self-help measures
  • Smoking cessation - this is the most important self-help measure.
  • Avoid exposure to cold 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 'Further reading & references' section, below).
  • Change occupation/DIY habits if vibration is a likely underlying cause.
• Topical agents
  • Evidence on topical nitrates is limited but studies have shown that:^[4]
    
    • Topical glyceryl trinitrate applied to the dorsum of the finger results in digital vasodilatation with fewer systemic side-effects than with oral nitrates.
    • Nitroglycerin applied to the affected finger reduces the severity of Raynaud's phenomenon, but not the duration or frequency of attacks.
• Systemic agents
  • Calcium-channel blockers: these are most widely used in the treatment of Raynaud's phenomenon. Nifedipine promotes relaxation of vascular smooth muscle cells and leads to vasodilatation. Nifidepine reduces the number of and severity of attacks but effects may be  short-lived and patients often have adverse effects such as hypotension, flushing, headache and tachycardia.^[4]
  • Apart from calcium-channel blockers, there is no evidence for any beneficial effect of other vasodilator drugs (including angiotensin-converting enzyme (ACE) inhibitors) on primary Raynaud's phenomenon.^[6]
  • Intravenous prostaglandins: intravenous iloprost has been shown to reduce the frequency and severity of attacks.^[4]
• Surgery^[4]
  • Surgical intervention may be considered for severe and disabling symptoms.
  • Surgical interventions include arterial reconstruction, peripheral sympathectomy, embolectomy and ulcer debridement, or a combination of techniques.
  • Cervical sympathectomy is no longer recommended..

Management of secondary Raynaud's syndrome

• 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/preventative measures are the same as for primary Raynaud's disease 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.^[7] 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).^[8] 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.^[8]
• A systematic trial of the alpha-blocker prazosin in this scenario has found that it is modestly effective.^[9]
• Cyclofenil (a steroid-like drug similar to clomifene) is currently under investigation as a potential therapeutic agent for Raynaud's syndrome secondary to scleroderma, but there is insufficient evidence to support its routine use currently.^[10]
• Ketanserin (a serotonin receptor antagonist) is also currently under investigation.^[11] 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 under investigation include endothelin receptor antagonists, sildenafil, fluoxetine and losartan. The effect of ACE inhibitors has been variable.^[7]
• Surgery may be necessary with digital sympathectomy ± vascular reconstruction in severe cases.

When to refer

Most patients can be managed in primary care.^[12] 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.

Prognosis

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. Primary Raynaud's disease may go into remission. Most patients have a stable course and over half improve over time.^[13]
• 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.^[14]

Complications

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 very worst cases.

Prevention of attacks

• Avoid smoking.^[12]
• Avoid beta-blocker treatment.
• Wear gloves or have them to hand at all times.
• Use specialist heated gloves if necessary.
• Anticipate exposure to cold and take appropriate ameliorative steps.
• Consider moving to warmer climes (particularly during the coldest months) if the condition is troublesome enough and the patient has the resources to do so.
• Avoid use of vibrating hand tools.