The information – Raynaud’s phenomenon

The PUNs

A 20 year old lady attends very worried about her circulation. For many years she has noticed that her hands turn cold and whitish-blue when they get wet or the weather is chilly – and that they become very red and tingly when she warms up. She recently attended a music festival and while she had anticipated the ‘typical’ festival weather, she hadn’t expected a significant worsening of the symptoms in her hands – and, for the first time, in her feet, too. ‘I know I smoke, doctor,’ she says, ‘But this seems ridiculous at my age. Can you get me checked out or should I see a specialist? And is there anything I can take for it?’

The DENs

What are the characteristic features of Raynaud’s phenomenon and how can it be distinguished from ‘normal’ reactions to cool temperatures?

Raynaud’s phenomenon (RP) is an exaggeration of the normal physiological response of the extremities to cold or to emotional stress. Typically, the fingers (and often the toes) turn white (ischaemia), then blue (deoxygenation) and then red (reperfusion). Although not all patients experience a triphasic colour change, most experts agree that at least a biphasic colour change is required – a ‘normal’ reaction to cool temperature does not lead to biphasic colour change. It is the ‘red’ phase that patients tend to find most uncomfortable; this is often associated with tingling and pain.

RP is defined by these colour changes. It is not a diagnosis it itself, but rather a symptom complex demanding a diagnosis, as described below.

How often is there an underlying aetiology? What are the possible causes?

The vast majority of patients with RP (in the order of 90%) have primary (idiopathic) RP, which is very common. Estimates vary, but probably around 5% of the general population have primary RP. In a minority of patients, RP is secondary to one of a number of different diseases and conditions¹ including:

• Connective tissue diseases, for example systemic sclerosis, inflammatory muscle disease, and systemic lupus erythematosus
• Hand-arm-vibration syndrome (vibration white finger)
• Large vessel disease (e.g. atherosclerosis, thromboangiitis obliterans)
• Extrinsic vascular compression (e.g. cervical rib)
• Intravascular diseases (e.g. those causing hyperviscosity states)
• Certain drugs and chemicals (e.g. beta-blockers)

A key point is that primary RP is entirely reversible and does not progress to irreversible tissue injury. This is probably because in primary RP, the vascular abnormalities are entirely functional and structural vascular disease is not recognised. Therefore if a patient presents with any features of tissue damage, for example:

• Pitting of the tips of the fingers
• Ulcers of the fingers or toes
• Critical ischaemia of the fingers or toes

Then that patient does not have primary RP and an underlying cause must be identified.

The history and examination (especially examination of the hands) will help distinguish between primary and secondary RP, complemented by investigations listed below. Most patients present with primary RP present in their teens or twenties, and although primary RP can present at any age, an older age of onset should always raise suspicion of an underlying condition. In the case above (a 20 year old with RP for many years) the probabilities are that this will be primary RP, but nonetheless the recent worsening is of concern and so a careful evaluation is required.

In the history, ‘puffy fingers’ (patients often describe how they cannot get rings on and off) is a ‘red flag’ for underlying connective tissue disease. On examination, key signs to look for in the hands are any asymmetry in the pulses (this would point to large vessel disease), puffy fingers, sclerodactyly (skin thickening of the fingers, suggestive of systemic sclerosis), pitting of the fingertips and telangiectases (both suggestive of systemic sclerosis).

What investigations should the GP perform?

Many patients with RP will never seek medical attention. For those who do, a recommended minimal set of investigations for the GP is:

• A full blood count
• ESR or CRP
• ANA testing

All of these should be normal or negative in primary RP.

Other investigations should be requested on the basis of the clinical picture. Many clinicians will also request a biochemical profile with thyroid function tests, and a thoracic outlet radiograph (to look for a cervical rib). Nailfold capillaroscopy, which allows direct, non-invasive visualisation of the finger microvasculature, is a key investigation in the early detection of systemic sclerosis-spectrum disorders (in which the microvasculature is abnormal). However, at present this is an investigation generally performed in secondary care.

How significant is the role of smoking?

This is a difficult question, and one in need of further research. In patients with systemic sclerosis-related RP (which is often very severe) there is evidence to suggest that smoking is associated with RP severity. There is also some evidence, albeit weaker, for an association between smoking and primary RP. Given that smoking is associated with vascular disease, it seems sensible to strongly advise patients with RP, including the 20 year old described above, to stop smoking.

What simple advice should be given to help prevent the problem?

Patients with RP should be advised to try to avoid situations that trigger attacks of RP. This mainly focuses on avoiding cold exposure. Therefore patients should dress warmly, including warm gloves and a hat. It’s often changes in temperature rather than absolute temperatures that trigger attacks. For example, many patients report that they experience RP attacks in the cold aisles of supermarkets.

What treatment is available and when should referral be considered?

Many patients respond to conservative (non-drug) measures and report that their symptoms of RP become less troublesome over time. Patient education (mainly avoiding cold exposure, described above) is a key part of management – Scleroderma and Raynaud’s UK (SRUK) and Arthritis Research UK provide very helpful patient education materials.

Patients not responding to conservative measures should be offered drug treatment.^1,2 Calcium channel blockers are generally considered first-line.³ Most clinicians start at a low dose and gradually titrate up the dose as tolerated and indicated. Sustained-release preparations are often better tolerated than short-acting ones. Options include sustained-release nifedipine (initially 10mg twice daily, increasing gradually to 40mg twice daily) or amlodipine (initially 5mg daily, increasing if necessary to 10mg daily). However, a substantial proportion of patients develop vasodilatory side effects on calcium channel blockers (e.g. headaches, dizziness, flushing) requiring dose reduction, or discontinuation.

The evidence base for other vasodilators is weak⁴, although these can be used instead of (or sometimes in addition to) calcium channel blockers. Examples include angiotensin receptor blockers (e.g. losartan) or an alpha-blocker. Phosphodiesterase type 5 inhibitors are being increasingly used for RP, although at present mainly in connective tissue disease-related RP. A proportion of patients discontinue drug treatment over the summer (warmer) months when symptoms tend to be less troublesome.

The following indicate the need for referral to secondary care:

1. Any worrying features on history and examination e.g. puffy fingers, finger ulcers.
2. Abnormalities in the investigations e.g. a positive ANA.
3. Any patient in whom there is concern for other reasons e.g. late onset RP.
4. Failure to control symptoms with conservative measures and a calcium channel blocker (irrespective of whether the RP is primary or secondary).

Due to the strong association between RP and connective tissue disease, a rheumatologist is often the most appropriate specialist to whom to refer, although this will depend on the clinical situation. For example, RP affecting only one hand with reduced peripheral pulses in that limb would point to a vascular surgical referral.

Ariane Herrick is professor of rheumatology at the University of Manchester and honorary consultant rheumatologist at Salford Royal NHS Foundation Trust.

Declaration of interests: ALH has done consultancy work for Actelion, served on a Data Safety Monitoring Board for Apricus, received research funding and speaker’s fees from Actelion, and speaker’s fees from GSK.

References

1. Wigley FM, Flavahan NA. Raynaud’s phenomenom. N Eng J Med 2016; 375:556-565.
2. Hughes M, Ong VH, Anderson ME, et al. Consensus best practice pathway of the UK Scleroderma Study Group: digital vasculopathy in systemic sclerosis. Rheumatology 2015; 54: 2015-2024.
3. Ennis H, Hughes M, Anderson ME,Wilkinson J, Herrick AL. Calcium channel blockers for primary Raynaud’s phenomenon. Cochrane Database of Systematic Reviews 2016. DOI: 10.1002/14651858.CD002069.pub5.
4. Stewart M, Morling JR. Oral vasodilators for primary Raynaud’s phenomenon. Cochrane Database of Systematic Reviews 2012, Issue 7. Art. No.: CD006687. DOI: 10.1002/14651858.CD006687.pub3.