Practical Management of Raynaud’s Phenomenon - A Primer for Practicing Physicians

Abstract

Purpose of review

Raynaud’s phenomenon (RP) is a common vasospastic condition that results in digital hypoperfusion in response to cold and/or emotional stress and is associated with significant pain and disability. The aim of our review is to provide a practical approach for clinicians to inform assessment and management of patients with RP.

Recent findings

Autoantibodies and nailfold capillaroscopy are key investigations to stratify the risk of progression to systemic sclerosis SSc in patients RP, which was recently confirmed in the multi-center, very early diagnosis of systemic sclerosis ‘VEDOSS’ project. Research has explored the complex lived-patient experience of RP including digital vasculopathy in SSc and has highlighted the need for outcome measure development to facilitate research in the field. Pharmacological treatment strategies vary significantly internationally and there is continued interest in developing surgical approaches.

Summary

We provide a practical and up-to-date approach to inform the assessment and management of patients with RP including guidance on drug initiation and escalation. Calcium channel blockers are first-line treatment and can be initiated by primary care physicians. We also highlight second-line drug therapies used for refractory RP and the potential role for surgical intervention.

Introduction

Raynaud’s phenomenon (RP) is a common vasospastic condition that affects the extremities and can also involve other vascular beds (e.g., lips and earlobes) (1). Common RP triggers are exposure to cold and/or emotional stress (2, 3). A key feature is that permanent ischemic tissue loss does not occur in patients with primary RP (PRP). RP affects approximately 5% of the general population, although epidemiological estimates have varied widely e.g., due to differences in case definition and ascertainment. Although the relationship between the climate and RP prevalence is complicated, the prevalence of RP is generally higher in colder areas (4, 5). Although one study in New Zealand reported the opposite, with higher prevalence in the warmer part of the country (6). RP is often the earliest feature in patients with systemic sclerosis (SSc) and can occur many years (even decades) before the onset of other disease manifestations e.g., skin thickening, especially in limited cutaneous SSc (7, 8). The underlying pathobiology of RP is complex and differs between PRP and secondary RP (SRP). In general, episodic vasospasm is believed to be central to RP pathogenesis and therefore is primarily targeted by pharmacological treatment. Other implicated aetiopathogenic mechanisms include intravascular factors (e.g., platelet activation) and neurohormonal imbalance disturbing the delicate tone between vasoconstrictor and vasodilator factors (1).

Clinical features

RP can be considered as a ‘symptom complex’ that is characterized by episodic skin color changes (Figure 1) and sometimes other intrusive (e.g., neurosensory) symptoms. The classical triphasic skin color changes are sequential pallor (white) from vasoconstriction, cyanosis (blue) due to sequestration of deoxygenated blood, and erythema (red) due to tissue reperfusion. Not all color changes are required to diagnose RP, although experts recommend at least 2 color changes (9). In addition, the majority of the RP attacks are associated with symptoms such as pain, tingling, numbness, and discomfort.

Figure 1.

Raynaud’s phenomenon. Photographs of an RP attack with biphasic color change in a patient with SSc. There is evidence of pallor and rubor with demarcation affecting the digits.

Diagnosis

RP is a clinical diagnosis, based upon establishing the episodic features of RP, and to delineate the underlying etiology, including any secondary cause (Table 1). A comprehensive clinical assessment is required in all patients with RP.

Table 1.

Secondary causes of RP. From Reference (70).

Secondary cause of RP	Underlying aetiology
Large vessel (usually proximal large vessel disease, often unilateral symptoms)	Compressive (e.g., cervical rib) Neurogenic (thoracic outlet obstruction) Inflammatory vascular disease (e.g., thromboangiitis obliterans [Buerger’s disease] or large vessel vasculitis) Atherosclerosis
Occupational	Hand–arm–vibration syndrome (vibration white finger)
Autoimmune rheumatic diseases	Systemic sclerosis Systemic lupus erythematosus Sjogren’s syndrome Mixed connective tissue disease/overlap syndromes Undifferentiated connective tissue disease Idiopathic inflammatory Myopathies Vasculitis
Drug/chemical-related	Amphetamines Beta-blockers Bleomycin Cisplatin Clonidine Cyclosporine Interferons Methysergide Polyvinyl chloride
Vaso-occlusive disease	Cold agglutinin disease Cryoglobulinaemia Cryofibrinogenaemia Paraproteinaemia Malignancy (including as a paraneoplastic phenomenon)
Other causes and associations	Carpal tunnel syndrome Frostbite Hypothyroidism POEMS syndrome Fibromyalgia syndrome

History

A detailed history should be obtained including the extent and symmetry of the areas involved, sequence of color change/s, triggering factors, occupational history (e.g., use of vibratory tools), and potentially triggering or exacerbating drug therapies (Table 1). Age of RP onset should be established, for example, generally, PRP tends to develop before the age of 30 years. A family history of RP should be elicited, especially in young females and associated. With PRP. Thumb involvement should be identified as this is reported to be over-represented in SRP (10). Clinical features suggestive of autoimmune diseases, including SSc should be elicited.

Examination

Careful attention must be made to examination of the hands including looking for evidence of digital ulcers (DUs) and irreversible tissue loss e.g., digital pitting scars and critical digital ischemic (Figure 2). The peripheral pulses should be strong and symmetrical. Cutaneous manifestations of SSc should be identified including skin thickening, telangiectases and calcinosis. Systemic examination should be performed including the cardiorespiratory system (e.g., for evidence of interstitial lung disease in SSc) (11).

Figure 2.

Digital Ulcers in SSc.

Fig 2a. Evidence of digital ulcer on digital tip, as defined by Loss of epidermal covering with visible blood vessels, fibrin, and granulation tissue. Fig 2b. Digital ulcer on the 3^rd digital pulp with evidence of loss of epidermis and evidence of fibrin (red arrow). The 4^th digit shows mild cynosis associated with RP (blue arrow).

Investigations

Key investigations are nailfold capillaroscopy and detection of autoantibodies as they are both strongly predictive of the development of SSc or other autoimmune diseases (12, 13). Nailfold capillaroscopy can be performed using low- (e.g., handheld dermatoscope or USB-microscope) and high-magnification (e.g., videocapillaroscopy) systems. Normal nailfold capillaries in patients with RP are reassuring. Capillaroscopic abnormalities (Figure 3) seen in SSc include enlarged including ‘giant’ capillaries, microhemorrhages, and capillary drop out (14). Complete blood count, antinuclear antibody (ANA), and inflammatory markers are routinely requested. Many clinicians also request renal and liver biochemistry, thyroid function, complements (C3&4), urine analysis (UA), immunoglobulins with electrophoresis and creatine kinase (15). A chest radiograph can be performed to exclude bony cervical ribs which can result in proximal vascular compression. When the index of suspicion of SSc is high, then testing for specific disease-associated (e.g., anticentromere and anti-Scl-70) autoantibodies should be performed. Based on the clinical picture, testing for antiphospholipid syndrome and fasting lipid profile (e.g., in patients at risk of atherosclerosis) can be considered (15). Thermographic testing is performed in some specialist centers and measures skin temperature as an indirect measure of blood flow and can help to distinguish between PRP and SRP (16).

Figure 3.

Nailfold capillaroscopy. Abnormal capillaroscopy. A: ‘Active’ pattern - there are enlarged capillaries and microhaemorrhages. B: ‘Late’ pattern – significant capillary drop-out (‘desertification’) from failure of successful neoangiogenesis.

Differential diagnoses

The key to establishing the diagnosis of RP is by establishing the typical episodic symptom complex which is temporally provoked by a typical trigger (e.g., cold exposure). Acrocyanosis is characterized by persistent bluish discoloration of the peripheries (17). Frostbite is a severe thermal injury (often of the peripheries) from exposure to extremely low temperature and can result in cutaneous colour changes (e.g., initial white or blue) from cell death (18). Neurosensory symptoms from peripheral nerve conditions can be persistent (e.g., neuropathy) or more variable (e.g., carpal tunnel syndrome is often worse in the morning). Erythromelalgia is rare and is characterized intermittent by redness to the feet (and less commonly the hands) and associated with severe pain and burning of the skin (19). Colour and temperature skin changes akin to RP can be seen in patients with chronic regional pain syndrome (20).

Approach to the management of RP

An overview of a practical approach to the management of RP is presented in Figure 4.

Figure 4:

Our practical approach to the management of RP. ARB: angiotensin receptor blocker; CBT: cognitive behavioral therapy; IV: intravenous; PDE: phosphodiesterase; SSRI: selective serotonin reuptake inhibitor.

We follow a practical algorithm for the management of RP. Our initial decision point is presence of digital ischemia/ ulcers. For those with no history or current digital ulcers, we assess patient-reported burden of RP. This can be assessed by asking about number of daily/weekly attacks, duration of the attacks, associated symptoms, and impact on ADLs. For those with mild symptoms or mild RP-associated patient burden, non-pharmacologic management is advocated as initial treatment, as described below. For those with moderate-to-severe attacks and/or patient burden and/or history of or current digital ulcers, we provide both non-pharmacological treatment and add oral vasodilator therapy, usually CCB as first line therapy. More details and our treatment algorithm are provided in the text below.

Non-pharmacological management

General measures including lifestyle measures are indicated in all patients with RP. Patient education includes providing high-quality information including onward direction towards patient-led organizations (21). The hands and feet should be kept warm (e.g., by wearing multiple layers, using gloves and hand warmers). The body core temperature should also be maintained (22). Patients should avoid potential triggers including avoiding cold and/or emotional stressors (1, 23). Smoking cessation should be strongly encouraged because this reduces skin blood flow (24). Many patients elect to trial alternative or complementary therapies (e.g., antioxidants and gingko biloba). However, at present there is little evidence to support these approaches and these treatments should be actively enquired about (e.g., due to potential interactions with other medications).

Pharmacological management

There is a wide therapeutic armamentarium available for the treatment of RP and we provide some general principles to treatment:

1. Drug therapies are indicated for RP when general measures are largely ineffective. Patients have a limited ability to predict attacks of RP (25), and therefore drug treatments are administered on a regular basis.

2. Clinicians often prescribe modified (or sustained) release medications which are often better tolerated by patients.

3. Common side effects across drug therapies generally result from systemic vasodilation and include hypotension and vasoactive headache, which can limit dose-escalation or even necessitate drug discontinuation. Practical approaches to manage side effects include de-escalation to the previously tolerated dose and slower up-titration with simple analgesia (e.g., paracetamol) for vasodilatory headaches.

4. Agree personalized treatment goals with the patient e.g., a set target reduction in the frequency or severity of RP attacks (26, 27). This is challenging and concerns have been raised by experts in RP and SSc about the suitability of traditional measures to assess treatment efficacy. Patients may struggle to understand the concept of discrete RP ‘attacks’ (28).

5. Drug therapies are often more effective in PRP vs. SRP. This is understandable, for example in SSc, because there is compounding functional and structural vascular disease.

6. Previous studies have examined treatment intervention in patients with PRP and SSc-RP. Therefore, there is no specific evidence base for other causes of SRP and therefore clinicians often inform management based upon that for SSc.

7. RP ‘complicated’ by irreversible tissue ischemia (e.g., DUs and critical digital ischemia) requires prompt clinical assessment and treatment review.

8. There is often significant overlap in drug therapies used for RP and other vascular complications (e.g., pulmonary artery hypertension and scleroderma renal crisis) in SSc.

9. Anxiety-induced RP may benefit from consideration of treatment with selective serotonin reuptake inhibitors (SSRIs) and other interventions (e.g., cognitive behavioral therapy and acupuncture), although currently there is a limited evidence based to support the efficacy of non-pharmacological interventions for RP.

First-line drug therapy

Calcium channel blockers (CCBs) are generally considered first-line drug treatment for RP. Dihydropyridine CCBs are typically used (e.g., amlodipine and nifedipine). There is also some evidence for benefit with the non-dihydropyridine CCB diltiazem, but not verapamil. In a recent meta-analysis (29), CCBs decreased the RP attack frequency, duration, pain, and severity in a dose-dependent manner, with higher (compared to lower) doses being more effective.

Our approach to initial CCB therapy for RP is described below:

1. We usually recommend starting amlodipine 5 mg once daily after the patient has been counselled about potential treatment-related side effects.

2. If there are no side effects and lack of improvement in 7–14 days, then the patient has authorization to increase amlodipine to 10 mg once daily.

3. The patient is also advised to report back to us if there is no improvement in 2–6 weeks.

4. If there is no or unsatisfactory improvement in approximately 6–8 weeks, then the pharmacological management should be reviewed including consideration of a second-line agent.

As indicated above, there are other CCBs that can be considered. For example, nifedipine modified/sustained release 10 mg twice daily which can be increased in 10 mg increments to a maximum of 40 mg twice daily.

Second-line drug therapy

Given a wide range of possible second-line drug therapies, this should be informed on an individual patient basis including the potential benefits and risks of treatment. There is a limited evidence base to guide whether drug therapy should be used as sequential monotherapy (i.e., substituted) or be used in combination with current treatment. Our general approach is to add the new drug if CCBs showed some benefit, and to substitute if there was no benefit at all, or if CCBs were not tolerated or contraindicated. There is a lack of any randomized clinical trials or head-to-head comparison between these agents, although experts in RP and SSc have developed practical treatment recommendations (15, 30). We also determine if the RP is predominantly trigged by cold or emotional attack. For cold induced RP, we generally add PDE-5 inhibitors or ARBs as second line treatment. For emotion induced RP, we tend to add fluoxetine, largely based on a small, randomized trial.

Phosphodiesterase type-5 (PDE-5) inhibitors

Clinicians worldwide are increasingly using PDE-5 inhibitors as second-line therapy, particularly in the context of SSc-RP (31–33). In a meta-analysis which included six double-blinded randomized, placebo-controlled studies (16, 34–38), PDE-5 inhibitors were associated with a significant improvement in RP decreased attack frequency and duration (by 14.62 minutes) (39).

If there is no contraindication/s, we usually use PDE-5 inhibitors as our initial second line agent. We start with sildenafil 20 mg daily for 1–2 weeks, before escalating therapy, to a maximum of 20 mg three times daily, depending upon the clinical response and side effects (e.g., development of vasoactive headaches and hypotension). Concomitant prescription of PDE5 inhibitors and nitrates should be avoided as this can result is significant hypotension.

For patients with digital ulcers, we recommend continuous use of PDE-5 inhibitors. Intermittent use may be reasonable for patients with mild disease who are symptomatic only during a specific time (e.g., Winter).

Due to its long half-life (17.5 hours compared to Sildenafil, 4 hours) (40), and the possibility of once-daily administration, the use of tadalafil for RP has gained attention and several studies have evaluated its potential use in RP. When used as add on therapy, tadalafil showed improvement in RP duration, frequency and RCS (37, 41). However, the only study that evaluated tadalafil with no background vasodilator therapy or other RP treatment did not meet its primary endpoints (RP duration, frequency and RCS) (34).

Other oral drug therapies targeting the renin-angiotensin pathway include angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers. Reduction in the frequency and severity of RP has been reported with losartan (42, 43). The evidence base for ACE inhibitors for RP is limited and with conflicting evidence for treatment efficacy (44). We use Losartan 50 mg daily (maximum dose of 100 mg), and we monitor blood pressure accordingly. Renal function should be checked after commencing and regularly throughout ongoing treatment as per other indications for drugs affecting the renin-angiotensin system due to the risk of potential renal impairment (e.g., in the presence of significant renovascular disease).

Serotonin is a vasoconstrictor (45) and SSRIs inhibit platelet aggregation (46). Fluoxetine (an SSRI) has been reported to reduce the frequency and severity of attacks in both PRP and SRP (47). We recommend using fluoxetine, starting at 10 mg daily for 1 week before reaching the maximum dose of 20 mg daily. Due to the absence of significant systemic hypotension, fluoxetine can be helpful in patients who are particularly prone to vasodilatory side effects. There is limited evidence that prazosin (an alpha blocker) is modestly effective for RP, with few studies showing that it decreases the frequency of the attacks; however, side effects were not uncommon and benefits were short-lived. (48–51).

In patients who continue to have refractory RP (defined as moderate to severe symptomatic attacks that affect activities of daily living (ADLs) and which are not responding to oral vasodilatory therapies) or continuing DUs, we consider parenteral prostacyclin therapy.

Prostanoids

Prostanoids are a family of inflammation regulatory mediators that include prostacyclin, leukotrienes and prostaglandins (PG) (52). Prostaglandins (e.g., PGE2, PGI2) are potent vasodilators which is mediated by their action on the prostacyclin receptor (IP) located on vascular smooth muscle, which increases intracellular cyclical adenosine monophosphate promoting vasodilation. Furthermore, prostaglandins inhibits platelet aggregation (53) and recently have been shown to promote tubuologenesis and inhibit endothelial to mesenchymal transition (54). Prostanoid therapy is indicated for severe refractory or disabling RP including in the context of digital ischemia (e.g., ulcers). Access to intravenous prostanoid therapies for RP varies internationally and the decision about which agent to use depends on the availability and the physicians’ experience. For example, unlike epoprostenol (A prostacyclin, PGI2), iloprost (A synthetic analogue of PGI2) is currently only available in Europe and not the United States. There is significant variation in treatment regimens (dosage, duration, and frequency) used by clinicians internationally. Some have utilized continuous infusion for a total of 5 days, others used an 8-hour infusion daily for 3 consecutive days, both of which showed positive results with no head-to-head comparison (55–62). Treatment efficacy with epoprostenol has been reported in both PRP and SRP. Iloprost is effective in reducing the severity, frequency, and duration of RP secondary to SSc and promoting DU healing (63, 64). A key point with is that treatment benefit is often short-lived (weeks to months) and repeated treatment is often required (65). Side effects include flushing, headaches, GI intolerance and hypotension. Selexipag (an IP prostacyclin receptor agonist) did not reduce the number of RP attacks in patients with SSc (66).

Surgical intervention

Surgery is only indicated in refractory RP, usually in the context of DUs or critical digital ischemia, including debridement of necrotic and/or infected tissue. There is increasing worldwide experience with digital sympathectomy and botulinum injection for refractory RP. There is encouraging evidence to suggest that digital sympathectomy can foster healing of chronic DUs (67–69). Improvement in RP has been reported with botulinum injection (70–74); however, there is conflicting data and treatment benefit appears short-lived (maximum of several months).

Complicated RP

RP complicated by critical digital ischemia is a medical emergency. Patients should be educated to seek urgent medical advice if they develop permanent digital color discoloration and/or severe ischemic pain. The reader is directed to dedicated review articles and consensus guidance for overviews on the management of DUs and critical digital ischemia in SSc (15, 75, 76). To highlight, the patient is admitted to the hospital and treated with intravenous heparin, PDE5 inhibitors and intravenous prostanoid therapies along with surgical intervention, as needed. Patients with RP complicated by persistent tissue digital ischemia (e.g., ulceration or gangrene) often suffer from a significant pain that may require opioid-based analgesia. Therefore, addressing pain management in these patients is fundamental to improve treatment compliance and preserve quality of life (77).

Conclusion

RP is common and is associated with significant pain and disability including SRP which can result in irreversible ischemic tissue loss. Clinicians need to perform a comprehensive clinical assessment to identify the underlying etiology in patients with RP as this has major prognostic and treatment implications, including to establish the diagnosis of SSc. Key investigations include nailfold capillaroscopy and autoantibodies. Patient education is mandatory in all patients with RP and pharmacological management is indicated after failure of general measures. CCBs are first-line drug therapy and can be confidently initiated by primary care physicians. Internationally, PDE-5 inhibitors are increasingly being used as second-line treatment after CCB failure. There are also other oral drug treatments that can also be considered and intravenous prostanoid therapy can provide short-term RP benefit and foster DU healing in SSc. Future research is required to further understand the complex aetiopathogenesis of RP to develop new treatment approaches. Recent international research has explored the lived patient experience of RP including SSc-associated vasculopathy (78, 79). Future research should develop novel outcome measures of efficacy for clinical practice and trials and to explore the integration of microvascular assessment, including to facilitate early-stage clinical trials of promising therapies.

Key points.

• RP is common in the general population and is associated with significant pain and disability and is often the earliest feature in systemic sclerosis.

• Patients with secondary (unlike primary) RP can develop irreversible ischemic tissue loss.

• Patients with RP require a comprehensive clinical assessment and key investigations include performing nailfold capillaroscopy and requesting autoantibodies.

• Patient education and general including lifestyle measures are indicated in all patients with RP.

• Calcium channel blockers are first-line drug treatment for RP and clinicians are increasingly using phosphodiesterase type-5 inhibitors as second line therapy.