Assessment and management of Raynaud’s phenomenon

Raynaud’s phenomenon (RP) is commonly encountered in primary care and can either be a primary condition or occur secondary to a wide range of underlying medical conditions and drug therapies. This article discusses the assessment and treatment of RP and the GP’s role in management.

Raynaud’s phenomenon (RP) is a common vasospastic condition characterised by episodic colour change of the extremities, often triggered by exposure to cold and/or emotional stressors. The purpose of this article is to describe the clinical spectrum of RP, the potential underlying causes, and an approach to assessment and management (including first- and second-line drug treatments and the role of the GP).

Causes

The vast majority of patients with RP have primary (idiopathic) RP (PRP), which is entirely reversible and does not progress to irreversible tissue injury. However, healthcare professionals must be aware that RP can be secondary (SRP) to a wide range of underlying medical conditions and drug therapies, as outlined in Table 1.1 In particular, RP may be the first symptom of an underlying autoimmune connective tissue disease; for example, systemic sclerosis, also referred to as scleroderma.

Table 1. The differential diagnosis of Raynaud’s phenomenon1

Signs and symptoms

RP commonly affects the fingers and toes although other vascular beds can be involved as well, including the lips, nose and ears. An example of an attack of RP is shown in Figure 1. Classically, the patient’s skin progresses through a triphasic colour change (physiological mechanisms in parentheses) of white (deoxygenation), blue (cyanosis) and red (reactive hyperaemia). The hyperaemic phase may be associated with significant pain and paresthesia.

Figure 1. Photos of an attack of Raynaud’s phenomenon taken by a patient with systemic sclerosis. A. There is whiteness (pallor of the fingertips). B. Normal colour has been restored to the fingers. The time between the two photographs was approximately 16 minutes. Photos provided courtesy of Dr Graham Dinsdale, University of Manchester

Sometimes, patients may present with only mono- or biphasic colour changes of the digits. In PRP, tissue ischaemia is completely reversible; however, in SRP, permanent ischaemic tissue loss can occur. In particular, in patients with systemic sclerosis, a spectrum of potentially serious digital vascular disease may occur, ranging from digital pitting and ulcers to gangrene (see Figure 2).

Figure 2. Ischaemic digital vascular disease in secondary Raynaud’s phenomenon. Digital pitting (A), ulcer (B) and gangrene (C) in patients with systemic sclerosis. Note that ischaemic tissue loss does not occur in patients with primary Raynaud’s phenomenon

Clinical assessment

The clinician should consider the following two key questions when assessing patients with RP:

  • Why does the patient have RP? For example, could he or she have an underlying connective tissue disease?
  • How severe is the RP? This will guide management, including the need for drug therapies.

Clinicians must perform a comprehensive clinical assessment, including a detailed medical history and physical examination, supported through focused investigations. LeRoy and Medsger proposed criteria for PRP,2 which clinicians should be aware of when assessing patients with RP (see Table 2).

Table 2. Proposed criteria for primary Raynaud’s phenomenon2

History and examination

Key features to look for include any symptoms that could suggest an autoimmune connective tissue disease (eg apthous mouth ulcers and photosensitivity), and those that could reflect the severity of digital vascular disease (eg significantly impacting on activities of daily living and a history of digital ulcers).

A full systematic review and drug history must be undertaken with an awareness of the wide differential diagnosis of the secondary causes of RP (see Table 1).

An occupational history should be taken, with particular reference to the use of vibratory tools and possible chemical exposures that may be of significance (eg vinyl chloride and epoxy resins are linked to the development of systemic sclerosis-like disorders). A family history of RP (many patients with PRP have a family history) and associated conditions (eg connective tissue diseases) should be explored.

A full physical examination must be performed. In particular, attention should be paid to the fingers and toes, looking for digital pitting and ulcers (signs of ischaemic tissue damage, which does not occur in PRP), puffiness of the fingers (an early sign of systemic sclerosis), sclerodactyly (scleroderma of the digits) or any visible abnormalities of the nailfold capillaries to the naked eye (indicative of a connective tissue disease). It is also very important to examine the integrity of the peripheral pulses: reduced or absent pulses suggest proximal (large) vessel disease.

Investigations

‘Basic’ investigations consist of a full blood count, erythrocyte sedimentation rate, antinuclear antibody and nailfold capillaroscopy, all of which should be normal/negative in PRP.

Other investigations that clinicians commonly request include a biochemistry profile, thyroid function tests and a thoracic outlet radiograph (looking for a cervical rib, which can be associated with RP). If there is clinical suspicion of an underlying connective tissue disease, more specific autoantibody testing is indicated, for example testing for systemic sclerosis-specific autoantibodies.

Nailfold capillaroscopy (see Figure 3) is a noninvasive imaging tool, which allows the microcirculation to be examined. In patients with RP, normal nailfold capillaries are reassuring, whereas abnormalities (eg capillary enlargement and avascularity) are suggestive of an underlying systemic sclerosis-spectrum disorder (see Figure 3).3,4 For clinicians who do not have access to a stereomicroscope or videocapillaroscopy (the ‘gold standard’), capillaroscopy can be performed using other lower magnification techniques including a dermatoscope, USB microscope or an ophthalmoscope.5-8

Figure 3. Nailfold capillaroscopy (performed using videocapillaroscopy, magnification x300). A. Normal capillaroscopy: the capillaries are regular in appearance and this is reassuring in patients with Raynaud’s phenomenon. B. Abnormal nailfold capillaroscopy in a patient with systemic sclerosis: there are several enlarged capillaries with areas of avascularity and distortion of the normal nailfold architecture

In a study that included 586 patients who were followed up for 3197 person-years, both the presence of systemic sclerosis-specific autoantibodies and the presence of a systemic sclerosis pattern on nailfold capillaroscopy were independent predictors of the development of systemic sclerosis on multivariate analysis (hazard ratio (HR) 4.7 and 4.5 respectively). Patients with both abnormalities at baseline were 60 times more likely to develop systemic sclerosis than those with neither.9

Which patient groups are most susceptible?

RP is common, although estimates have varied between studies (likely due to differences in study design and in the definition of RP). In a systematic review that included 33 articles (33,733 participants), the pooled prevalence of PRP in the general population was 4.85% (95% confidence interval 2.08% to 8.71%).10 Risk factors and associations for RP included female gender (odds ratio (OR) 1.65), family history of RP (OR 16.6) and smoking (OR 1.27).10 PRP usually develops in the teenage years or early twenties, and later onset of RP (or worsening of the severity of existing RP) is more worrying because it is more likely to be associated with an underlying secondary cause.11 RP is common in the connective tissue diseases, especially in systemic sclerosis (approximately 95% of patients with systemic sclerosis have RP).12

Although PRP is often considered relatively ‘benign’ compared with SRP, PRP can have a significant negative impact on quality of life. In a survey that included responses from 443 subjects with self-reported RP from 15 countries, subjects with both PRP and SRP reported making at least one life adjustment due to RP (71% and 87% respectively) and impaired quality of life due to RP (mean score 6.5 and 5.2 respectively, where 10 was the best imaginable).13

First and second-line options

The UK Scleroderma Study Group best practice pathway for RP (see Figure 4)14 is a useful reference tool for clinicians to use in the daily management of all patients with RP.

Figure 4. Management of Raynaud’s phenomenon.14 This pathway was developed for systemic sclerosisrelated Raynaud’s phenomenon, but is a useful reference tool for the management of all patients with Raynaud’s phenomenon. Since this pathway was published (in 2015), phosphodiesterase type 5 inhibitors are being used increasingly in the management of secondary Raynaud’s phenomenon (often second line, after calcium-channel blockers)

Patient education is a priority in all patients with RP. General and lifestyle adaptations are first-line treatment, including avoidance of cold exposure and keeping warm (eg by using hand warmers and gloves). Patients should be counselled and supported about the importance of smoking cessation (smoking promotes vasoconstriction). Useful information about RP (for both patients and clinicians) is available from Scleroderma and Raynaud’s UK (www.sruk.co.uk). Although some patients also consider a number of complementary therapies,15 there is no strong evidence base to recommend these interventions at present.

Drug treatment is indicated if general and lifestyle adaptations are ineffective. In general, drug therapies act via systemic vasodilation in order to increase tissue perfusion, and thereby lead to fewer and less severe attacks of RP. Drug therapies are started at a low dose and gradually increased in increments. Common errors are to start at too high a dose (which may not be tolerated), or conversely not to increase the dose to the maximum tolerated. Modified-release preparations are often better tolerated by patients than shorter acting formulations.

Examples of drug therapies along with typical adult doses are presented in Table 3. First-line drug treatment for RP is usually with a calcium-channel blocker (eg nifedipine). In a systematic review that included seven randomised trials involving 296 participants with PRP, treatment with calcium-channel blockers was associated with 1.72 fewer attacks a week compared with placebo.16

Table 3. Examples of drugs used in the treatment of Raynaud’s phenomenon14

The evidence base for other drug treatments for RP is very weak.17 However, other drug therapies that are prescribed for RP include angiotensin II-receptor blockers, alpha-blockers and SSRIs (the latter can be useful in patients who are particularly susceptible to vasodilatory side-effects).14 Phosphodiesterase type 5 (PDE5) inhibitors are increasingly being used for SRP18 and with changing healthcare economics (eg sildenafil now being off patent, and tadalafil in November 2017), it is likely that in the future these drugs will be used earlier in the treatment of RP, at least in patients with SRP. Intravenous prostanoid infusions (eg iloprost and epoprostenol) therapy should be considered in patients with refractory RP (especially systemic sclerosis-related RP) or in RP with digital ischaemic complications (eg digital ulcers).

The GP’s role in management

The role of the GP is two-fold. Firstly, the diagnosis of RP (is it primary or secondary?) must be established and those patients with an underlying cause (in particular, a connective tissue disease) need to be identified and, if appropriate, referred to secondary care. Secondly, many patients with uncomplicated RP (eg without digital ulcers) can be treated successfully in primary care using conservative (nondrug) measures, with the addition of drug therapy for those in whom conservative measures are not sufficient to control symptoms.

Conclusion

RP is common and can significantly impact on quality of life. It is important to be aware that RP can be secondary due to a wide range of underlying medical conditions and drug therapies. The GP has a key role in the identification of those patients with a likely underlying cause for their RP, who warrant further investigation in secondary care. Patient education is a management priority in the treatment of all patients with RP. The majority of patients with uncomplicated RP can be successfully managed by GPs in primary care.

References

1. Hughes M, Herrick AL. Raynaud’s phenomenon. Best Pract Res Clin Rheumatol 2016;30(1):112–32.
2. LeRoy EC, Medsger TA. Raynaud’s phenomenon: a proposal for classification. Clin Exp Rheumatol 1992;10(5):485–8.
3. Maricq HR, LeRoy EC. Patterns of finger capillary abnormalities in connective tissue disease by ‘wide-field’ microscopy. Arthritis Rheum 1973;16(5):619–28.
4. Herrick AL, Cutolo M. Clinical implications from capillaroscopic analysis in patients with Raynaud’s phenomenon and systemic sclerosis. Arthritis Rheum 2010; 62(9):2595–604.
5. Anders HJ, et al. Differentiation between primary and secondary Raynaud’s phenomenon: a prospective study comparing nailfold capillaroscopy using an opthalmoscope or stereomicroscope. Ann Rheum Dis 2001;60(4):407–9.
6. Baron M, et al. Office capillaroscopy in systemic sclerosis. Clin Rheumatol 2007;26(8):1268–74.
7. Dinsdale G, Herrick AL. Vascular diagnostics for Raynaud’s phenomenon. J Vasc Diagnostics 2014;2:127–39.
8. Hughes M, et al. A study comparing videocapillaroscopy and dermoscopy in the assessment of nailfold capillaries in patients with systemic sclerosis-spectrum disorders. Rheumatology (Oxford) 2015;54(8):1435–42.
9. Koenig M, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 2008;58(12):3902–12.
10. Garner R, et al. Prevalence, risk factors and associations of primary Raynaud’s phenomenon: systematic review and meta-analysis of observational studies. BMJ Open 2015;5(3):e006389.
11. Pavlov-Dolijanovic S, et al. Late appearance and exacerbation of primary Raynaud’s phenomenon attacks can predict future development of connective tissue disease: a retrospective chart review of 3,035 patients. Rheumatol Int 2013;33(4):921–6.
12. Meier FM, et al. Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database. Ann Rheum Dis 2012;71(8):1355e60.
13. Hughes M, et al. Prediction and impact of attacks of Raynaud’s phenomenon, as judged by patient perception. Rheumatology (Oxford) 2015;54(8):1443–7.
14. Hughes M, et al. Consensus best practice pathway of the UK Scleroderma Study Group: digital vasculopathy in systemic sclerosis. Rheumatology (Oxford) 2015;54(11):2015–24.
15. Malenfant D, et al. The efficacy of complementary and alternative medicine in the treatment of Raynaud’s phenomenon: a literature review and meta-analysis. Rheumatology (Oxford) 2009;48(7):791–5.
16. Ennis H, et al. Calcium channel blockers for primary Raynaud’s phenomenon. Cochrane Database Syst Rev 2016;2:CD002069.
17. Stewart M, Morling JR. Oral vasodilators for primary Raynaud’s phenomenon. Cochrane Database Syst Rev 2012;7:CD006687.
18. Roustit M, et al. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: systematic review and meta-analysis of randomised trials. Ann Rheum Dis 2013;72(10):1696–9.

Declaration of interests

Professor Herrick has done consultancy work for Actelion, served on a Data Safety Monitoring Board for Apricus, received research funding and speaker fees from Actelion, and received speaker fees from GSK.

Dr Hughes is a clinical research fellow at the Centre for Musculoskeletal Research, University of Manchester, Salford Royal NHS Foundation Trust and Manchester Academic Health Science Centre; Professor Herrick is professor of rheumatology and honorary consultant rheumatologist at NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust and Manchester Academic Health Science Centre

Assessment and management of Raynaud’s phenomenon

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