Raynaud's Phenomenon

Table I.

Categories	Individual Types
Occupation-related	– Vibration-induced- Cold injury
Obstructive vascular diseases	– Thromboangiitis obliterans (Buerger’s disease)- Atherosclerosis- Thoracic outlet syndrome
Drug-induced vasospasm	– Beta-blockers- Amphetamines, cocaine, nicotine- Anti-migraine compounds- Cytotoxic drugs- Immune modulators- Bromocriptine, clonidine- Vinyl chloride
Systemic vasospasm	– Migraines- Prinzmetal’s angina
Infectious	– Viral hepatitis- Parvovirus B19- Cytomegalovirus (CMV)
Hematologic	– Cryoglobulinemia, cryofibrinogenemia- Cold agglutinin disease- Paraproteinemia- Polycythemia vera
Metabolic	– Hypothyroidism- Carcinoid syndrome- Pheochromocytoma
Immunologic	– Antiphospholipid syndrome

Controversies in the differential diagnosis

It is important to identify underlying etiologies that cause RP-like manifestations, as attacks can improve with removal of inciting triggers, such as drugs or occupation-related exposures, or with therapy directed at the underlying cause. For instance, thyroid replacement should be instituted for hypothyroidism, smoking cessation for Buerger’s disease, and anti-coagulation for antiphospholipid syndrome.

Often these etiologies can co-exist with patients with primary and secondary RP, and care should be taken to ensure that they are not contributing to worsened RP attacks.

What tests to perform?

Which tests should I order?

All patients with RP should undergo nailfold capillary examination. A detailed history and physical exam is the most important tool in assessing whether RP is likely secondary to an as yet undiagnosed underlying primary rheumatologic or hematologic disorder. Other potential contributing factors or etiologies listed in Table I, such as medications or toxic agents, vibration tools, and cold injury should also be investigated.

If the nailfold capillary exam is normal and there is low suspicion for secondary causes of RP, a diagnosis of primary RP can be made. If nailfold capillaroscopy cannot be performed or the physician is unsure whether secondary causes of RP exist, blood testing for the antinuclear antibody (ANA) and an erythrocyte sedimentation rate (ESR) should be performed.

Those that have signs or symptoms of systemic disease (such as myalgias, muscle weakness, arthralgias, arthritis, weight loss, fever, rash, dry eyes, dry mouth, fatigue, as well as organ-specific symptoms) and/or abnormal capillary nailfolds should be tested for the following:

• Complete blood count with differential.
• Comprehensive metabolic panel.
• Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
• Urinalysis.
• ANA

More than 50% of patients with RP who have a positive ANA may be diagnosed with an underlying connective tissue disorder at presentation, and a substantial number of the remaining patients will develop a rheumatologic disease.

In a patient with new onset RP or rapidly accelerated severity of RP, a more extensive serologic evaluation should be considered, even if there are no other strong clinical clues to suggest an underlying primary diagnosis.

More detailed testing should be directed toward specific suspected underlying connective tissue diseases. Referral to a rheumatologist should be made if patients with RP have an abnormal history, physical exam or laboratory values that suggest an underlying connective tissue disease.

Further testing can include: anti-centromere, anti-topoisomerase and anti-RNA polymerase antibodies (scleroderma), rheumatoid factor and anti-citrullinated protein antibodies (rheumatoid arthritis), complement, double-stranded DNA, anti-Sm, and anti-ribonucleoprotein antibodies (systemic lupus erythematosus, mixed connective tissue disease), myositis- and vasculitis-specific antibodies, among others. Other considerations are also thyroid function tests, serum protein electrophoresis, and cryoglobulins.

How do I interpret test results?

If the nailfold capillary exam is normal and there is low suspicion for secondary causes of RP, a diagnosis of primary RP can be made. If the history and physical exam and/or laboratory results (including abnormal ESR and/or ANA) suggest an underlying connective tissue disease, referral to a rheumatologist for further testing should be made.

It is important to note that low titers of ANA (1:40 to 1:80) are less likely to indicate an underlying connective tissue disease than high titer ANAs. When in doubt, however, a referral to a rheumatologist can help clarify the meaning of a borderline positive ANA test.

How often should I order tests?

If a diagnosis of primary RP has been made, no further testing is necessary unless new signs or symptoms of a systemic disease arise. Patients with primary RP should undergo nailfold capillaroscopy every 6 months for the first 2 years. If there is no evidence of abnormal nailfold capillaroscopy and clinical or laboratory signs do not suggest an underlying connective tissue disease within the first 2 years, patients are unlikely to progress to develop secondary RP. The annual incidence of transitioning from primary to secondary RP is 1%, with a median duration of 5 years.

If an ANA is positive, it is unnecessary to repeat this test, as it usually persists in systemic autoimmune diseases. Further repeat testing should be directed by a rheumatologist.

What are the next steps?

If history, physical exam and/or laboratory values (including abnormal ESR and/or ANA) suggest an underlying connective tissue disease and therefore secondary RP, a referral to a rheumatologist should be made for further testing.

Which imaging studies should I order?

There is no specific imaging study indicated to make the diagnosis of Raynaud’s phenomenon. Patients with atypical symptoms, i.e. absent pulses, asymmetry of blood pressure, or evidence of critical ischemia should undergo arterial imaging with arterial Doppler ultrasound, magnetic resonance angiogram (MRA) or angiography. The underlying etiologies in these situations could be thromboembolic disease, vasculitis, atherosclerosis, or Buerger’s disease, among others.

Does the imaging modality matter?

Arterial Doppler ultrasound has limited utility in detecting low blood flow in small arteries of the fingers of the hands and toes. This imaging modality is useful to detect medium to large vessel atherosclerosis. Angiography can be used to detect digital arterial disease, but is invasive and requires a dye load. This imaging modality should not be used in patients with renal insufficiency, as it can worsen underlying renal disease.

MRA, if available, is the preferred method for imaging the small vessels of the digits. MRA of the digits is usually performed using gadolinium contrast dye. Because of this, MRA with contrast dye should not be used with patients with a glomerular filtration rate (GFR) less than 30, as they are at risk of developing nephrogenic systemic fibrosis.

How do I interpret imaging results?

Lack of blood flow to the distal digits in MRA or angiography in a male smoker is suggestive of Buerger’s disease. Aneurysms, occlusions or vessel wall irregularities can be suggestive of vasculitis. Arterial Doppler ultrasound can be used to determine if there is medium to large vessel atherosclerotic disease in the upper or lower extremities. Thrombotic occlusions can be seen on imaging and may direct therapy toward anticoagulation.

If secondary Raynaud’s phenomenon is severe, it can cause single digit critical ischemia. If MRA or angiography confirms a lack of digital blood flow, in addition to pharmacologic measures, a digital sympathectomy may be indicated.

How often should I order imaging tests?

Routine imaging for RP is not indicated or necessary. If the clinical scenario changes or lacks improvement, imaging may be considered.

What are the next steps?

Once a secondary cause or an alternative diagnosis for RP has been established, it is necessary to direct therapy toward treating the underlying cause or diagnosis.

Biopsy

A biopsy is not necessary for the diagnosis of RP.

What is the overall interpretation of test results?

Abnormal nailfold capillary exam and abnormal laboratory values, including an abnormal ESR, ANA, complete blood count, comprehensive metabolic panel and urinalysis, can point toward an underlying connective tissue disease causing secondary RP. Further testing should be directed by a rheumatology consultant.

Abnormal MRA and angiography with lack of blood flow to digital arteries can be seen temporarily in patients with RP due to intermittent vasospasm, therefore, routine imaging is not recommended in these patients. Patients with a history of single-digit or asymmetric attacks, absent pulses, asymmetry of blood pressure, or evidence of critical ischemia should undergo arterial imaging, as these findings may indicate underlying diagnoses of thromboembolic disease, vasculitis, atherosclerosis, or Buerger’s disease, among others, and the presence of these diagnoses would alter management.

What are the controversies in diagnostic testing?

A positive ANA can be present in up to 20% of the healthy population and caution should be used when interpreting a positive test result. In addition, low titer ANA positivity (1:40 to 1:80) is less likely to represent an underlying connective tissue disease than high titer positivity.

Factors such as age and anemia can lead to an increase in the ESR. Infections and malignancy often cause elevated ESRs as well. It is important to understand the limitations of ANA and ESR testing when using them to help determine whether a patient has secondary RP.

How should patients with Raynaud’s phenomenon be managed?

Key treatment concepts

All patients with both primary and secondary RP should start with non-pharmacologic therapy. If not controlled with conservative or non-pharmacologic therapy, pharmacologic therapy may be necessary.

If there is evidence of digital pitting or ulceration, this indicates more severe Raynaud’s disease and pharmacologic therapy should be considered early in the treatment course, with the goal of promoting vasodilation.

Non-pharmacologic therapy

• Avoid cold exposures, especially sudden changes such as walking into the freezer section of the supermarket or air-conditioning.
• Protect exposed skin during cold weather. The entire body (use layers to protect the body, facemasks, hats, scarves) should be kept warm in addition to the digits (use gloves, socks, heat warmers). If hands become cold and a RP attack occurs, it is important to try to re-warm them under warm water or by placing hands in the axilla.
• Avoid smoking, including second-hand smoke.
• Avoid trauma and vibrating tools.
• Avoid drugs that cause vasoconstriction and could trigger RP (i.e. beta-blockers, ergotamines, sumatriptan, decongestants, diet pills).
• Avoid illicit drugs that cause vasoconstriction and could trigger RP (i.e. cocaine, amphetamines)
• Avoid emotional stress with relaxation techniques.

Pharmacologic therapy

Vasodilator therapy

In general, vasodilatory therapy is more effective in primary RP than secondary RP, possibly because of the greater vascular structural damage in secondary disease.

Calcium channel blockers

Calcium channel blockers (CCBs) are the mainstay of medical therapy for RP, and have shown a 30-35% reduction in the frequency and severity of RP attacks in meta-analyses for both primary and secondary RP.

Initial medical therapy for RP is begun with the dihydropyridine class of calcium channel blockers, as they selectively target vascular smooth muscle and have reduced effects on cardiac function. Examples of dihydropyridines are nifedipine, amlodipine, nicardipine and felodipine. Nifedipine and amlodipine are the most commonly used CCB agents in RP.

Typically, CCBs are started at a low dose with gradual dose escalation, with nifedipine doses ranging from 30-180 mg/day (typically 10-30 mg 2-3 times a day) and amlodipine doses ranging from 5-20 mg/day. Sustained-release nifedipine (30-120 mg/day) can also be used and has been shown to reduce attacks in patients with primary RP.

Dosage escalation of CCBs may be limited by vasodilatory side effects, including hypotension, headaches, light-headedness, peripheral edema, flushing and tachycardia. These side effects can improve with continued treatment, and therefore, unless they are intolerable, the patient should continue treatment for at least 2 weeks before a decision is made to discontinue treatment.

What to do next if calcium channel blockers fail?

If a CCB fails, options include switching to another CCB, as individual responses may vary, or adding another vasodilator, such as topical nitroglycerin (NTG) or a phosphodiesterase type 5 inhibitor (PDE5i).

Topical nitrates can provide symptomatic relief and are of some benefit in reducing the severity and frequency of attacks in both primary and secondary RP, although extensive evidence for their efficacy does not exist, and adverse effects such as headache often limit their use. Nitroglycerin 1/4 to 1/2 inch of 2% ointment can be applied topically to the fingertips daily.

Phosphodiesterase type 5 inhibitors (sildenafil, tadalafil and vardenafil) have shown some promise in decreasing RP attack frequency and duration, but with mixed results in clinical trials. Typical dosages used are sildenafil 25-100 mg daily and tadalafil 10-20 mg daily. Side effects include headache, flushing, dizziness, and dyspepsia. These agents should not be used with topical nitrates.

In severe Raynaud’s refractory to calcium channel blockers, often the combination of a phosphodiesterase type 5 inhibitor with a calcium channel blocker is indicated.

In patients who do not tolerate a CCB, PDE5i or topical NTG, some other therapeutic agents could be considered. These agents include the alpha adrenergic receptor antagonists, selective serotonin reuptake inhibitors (SSRIs), angiotensin II receptor blockers (ARBs). The clinical data on these agents, however, is far less robust.

Prazosin, an alpha-1-adrenergic receptor antagonist has been studied in 2 small randomized trials with some improvement in RP. The effect of prazosin over time, however, has been reported to wear off.

Fluoxetine, a selective SSRI may benefit patients with RP, however, the effect may be less robust than originally thought. Serotonin mediates vasoconstriction via 5HT 2A, 2B and 1B receptors, and also mediates vasodilation by 5HT7 and 5HT 2B receptors. A small open label cross-over study comparing nifedipine and fluoxetine in 56 patients with primary or secondary RP showed that there was significant improvement in the Raynaud’s condition score and in daily frequent attacks. Though, further sub-group analysis showed a less robust effect in secondary RP.

Losartan an angiotensin II receptor blocker showed some improvement in the frequency of attacks in primary RP compared to Nifedipine. Studies, however, have been limited.

These therapies should be reserved as potential therapeutic options for those who cannot tolerate CCBs, as their efficacy is overall questionable for the treatment of RP.

Some other agents that are being used for refractory RP include bosentan and the prostanglandin analogs.

Bosentan, an endothelin-1 receptor antagonist is being used for the treatment of pulmonary hypertension in scleroderma and can reduce the frequency of new digital ulcers, although randomized controlled trials have not shown benefit for RP.

Parenteral prostaglandin and prostacyclin analogues, such as epoprostenol (PGI2 analog), iloprost (PGI2 analog) and treprostinil (PGI2 analog), are effective for severe refractory RP and ischemic digital ulcers. These infusions must be given in a hospital setting. Side effects include flushing, diarrhea, headache, hypotension and rash.

Oral prostaglandins and prostacyclin analogues have led to mixed results and their role in the management of severe RP and ischemic digital ulcers must await additional clinical evidence.

Summary for vasodilator therapy

In summary, CCBs are the mainstay of therapy for RP and if they fail, addition of vasodilating agents, such as topical nitrates or phosphodiesterase type 5 inhibitors, can be considered. Other vasodilating options such as alpha adrenergic receptor antagonists, SSRIs, angiotensin receptor blockers, can be considered if patients are intolerant of CCBs. Parenteral prostaglandin and prostacyclin analogues should be considered for severe refractory RP and ischemic digital ulcerations.

Anticoagulation and antithrombotic therapy

Low dose aspirin at 81mg daily should be considered in all patients with secondary RP with digital pitting, ischemic digital ulcerations, or a history of other thrombotic events. The role of aspirin and dipyridamole has not been extensively studied in RP.

Anticoagulation with heparin should be limited to embolic or vascular occlusive disease with new thromboses. Use anticoagulants cautiously in patients with limited scleroderma, in whom gastric antral vascular ectasia may result in significant bleeding in the context of anticoagulation.

Procedures

Anesthetic blocks can be helpful in alleviating painful symptoms and reversing vasoconstriction.

If conservative treatment has failed and ischemia persists and digits are threatened, localized digital artery sympathectomy can be used. In this procedure, the common digital artery is separated from the adjacent digital nerve and the artery is stripped of its adventitia. Surgical localized digital artery sympathectomy should only be considered for patients with severe RP where ischemia threatens the involved digit.

Botulinum toxin A is another agent that is being evaluated in RP. Intra-digital and palmar injection of Botulinum toxin A has been shown to improve blood flow in small studies. Further studies are needed to define its role in RP.

Special circumstances

Severe ischemia

When a digit is “at risk” (ischemia persists with cyanosis, pallor and/or pain, with or without ulceration), hospitalization may be warranted. The following steps should be considered:

• Warming measures for entire body.
• If digital ulcerations appear infected, patients should be given intravenous antibiotics.
• An investigation with ultrasound or MRI to examine the bone and soft tissue can be obtained if there is concern for underlying osteomyelitis.
• The patient should be evaluated for potentially reversible processes, such as medications or underlying secondary causes, including an evaluation for macrovascular disease, vasculitis, or a hypercoagulable state. Vascular imaging can be helpful in trying to sort out these underlying etiologies.

The key to successful treatment is early intervention.

Treatment should be initiated with a CCB and a baby aspirin. If no benefit is seen, topical nitroglycerin or phosphodiesterase type 5 inhibitors can be added. Heparin should be considered for 24-72 hours if ischemia develops during vasodilator therapy or if thrombosis/embolism is thought to be contributing to the underlying etiology of ischemia.

Anesthetic blocks, as well as parenteral prostaglandin and prostacyclin analogues can be tried. Surgical localized digital arterial sympathectomy is indicated if symptoms persist despite these treatments. Patients may have severe pain despite these attempts, and opiates are often required to control their pain.

Controversies in patient management

As there is ample literature to support their use, CCBs are first line agents in the treatment of RP. Second line agents include topical nitrates and phosphodiesterase type 5 inhibitors. Given conflicting results of relatively small clinical trials, the use of selective serotonin reuptake inhibitors, angiotensin receptor blockers and antiplatelet agents in RP are more controversial.

What happens to patients with Raynaud’s phenomenon?

Natural history and prognosis

Spontaneous remission of primary RP may occur in up to 64% of patients. About one third of patients with primary RP have persistent symptoms and an even smaller fraction of those with persistent symptoms (about 10%) have increased severity. Thirteen percent of primary RP patients may develop a connective tissue disorder, with abnormal capillary nailfold exam being the best predictor of this. One percent may transition from primary to secondary RP each year.

Approximately 15-20% of patients with RP who have autoantibodies, abnormalities of nailfold capillaries, or both, and who initially do not meet criteria for a well-defined connective tissue disease ultimately develop such a disease within 2 years.

Pathophysiology

RP is manifested as vasospasm of the small muscular arteries and arterioles of the digits. The pathophysiology of the triphasic color changes is constriction of the digital vessels leading to pallor of the digits, followed by cyanosis secondary to deoxygenation of static venous blood, and then a reactive hyperemic stage with resulting erythema. Vasomotor homeostasis is maintained by interactions between the endothelium, smooth muscle, and autonomic and sensory nerves that innervate the vessels.

There is evidence to suggest that neurogenic mechanisms contribute to RP. In primary RP, physiologic cold-induced vasoconstriction of the cutaneous vessels is mediated in part by the sympathetic nervous system through alpha-2 receptors of the vascular smooth muscle. In primary RP, the mechanism of vasospasm seems to be related to smooth muscle contraction.

Stress-induced vasoconstriction has suggested that there is central nervous system involvement, with selective serotonin reuptake inhibitors potentially acting within the central nervous system to achieve beneficial effects.

The main difference between primary and secondary RP is the degree of endothelial and vascular damage, with secondary RP having more extensive damage. Endothelial cells regulate vascular tone by synthesizing and releasing mediators of vasodilation, such as prostacyclin and nitric oxide, and vasoconstrictors, such as endothelin-1. A reduction in nitric oxide, a potent vasodilator produced by the endothelium, is believed to be involved in the pathogenesis of secondary RP. Levels of other substances produced by the endothelium, such as endothelin-1, von Willebrand factor, and thromboxane A2 have been reported to be abnormal in secondary RP.

In secondary RP, damaged endothelial cells become activated and induce proliferation of smooth muscle cells, promote formation of intravascular microthrombi and pro-coagulant activity, and trigger an inflammatory process. Disordered inflammatory processes occur in the majority of severe cases of RP, with activation of leukocytes, macrophages, and immune complex deposition in vessel walls.

Therefore, the interaction between neurogenic, endothelial and immune mediated mechanisms contribute to the pathogenesis and propagation of RP, with neurogenic mechanisms being predominant in primary RP and endothelial and immune mediated ones more important in secondary RP.

How to utilize team care?

Specialty consultations

Often a team of consultants is needed to manage patients with RP, especially those with severe disease. Rheumatologists can help in the diagnosis, work-up and management of patients with RP. Radiologists can help interpret arterial imaging. In those with severe RP and digital ischemia, anesthesiologists can perform local blocks by injecting anesthetic into the digital, wrist, cervical, or lumbar spine sympathetic ganglia. Hand surgeons should be consulted if surgical sympathectomy is required. Wound care specialists can at times be helpful in topical management of open ulcerations.

Nurses

Nurses are helpful in maintaining patient warmth through use of blankets, socks, and gloves or mittens.

Pharmacists

Pharmacists can be helpful as intravenous fluids and various medications should be warmed if possible to keep the body temperatures of patients from becoming cool.

Dieticians

Dieticians can advise against the use of dietary supplements that induce vasospasm.

Therapists

Occupational therapists can assist with mobility of digits, especially in patients with systemic sclerosis and skin thickening.

Are there clinical practice guidelines to inform decision making?

There are no official clinical practice guidelines to inform decision making for the diagnosis and treatment of Raynaud’s. We offer the following clinical guidelines:

To diagnose Raynaud’s phenomenon:

• Patients should have episodes of at least sharply demarcated pallor (can have cyanosis and hyperemia as well) in response to cold or stressful stimuli.
• Nailfold capillary exam should be used to help distinguish between primary and secondary RP.
• Primary RP is defined as symmetric episodic attacks, no evidence of peripheral vascular disease, no digital pitting or tissue injury, normal laboratory values including negative antinuclear antibody test (ANA) and normal erythrocyte sedimentation rate (ESR), and a normal nailfold capillary exam.
• Nailfold capillary exams should be repeated every 6 months in patients with primary RP for the first 2 years to identify those at risk for secondary RP.

To treat Raynaud’s phenomenon:

• Non-pharmacologic therapy should be initiated in all patients with RP, including whole body and digital warming, as well as avoidance of cold exposures, emotional stress, smoking, vibration tools, and drugs that trigger RP.
• Pharmacologic therapy should be initiated if non-pharmacologic therapy is not sufficient and for those with digital pitting and digital ulceration.
• Initial pharmacologic therapy should consist of calcium channel blockers.
• If CCBs fail, topical nitroglycerin or phosphodiesterase type 5 inhibitors can be tried.
• If CCBs cannot be tolerated, other agents such as SSRIs, angiotensin receptor blockers, or alpha-blockers can be tried.
• Low dose aspirin (81mg daily) should be considered in all patients with secondary RP with ischemic digital ulcerations or a history of other thrombotic events.
• For severe digital ischemia and a finger “at risk,” hospitalization with initiation of heparin, anesthetic blocks, intravenous prostaglandin or prostacyclin analogues, and even surgical digital arterial sympathectomy should be considered.

These clinical guidelines have not been validated and are merely at the authors’ suggestions. Further formal clinical guidelines should be developed.

Other considerations

ICD-10 codes

• I73.0 Raynaud’s syndrome
• L98.491 Ulcer – skin, chronic
• M35.9 Connective tissue disease
• M34.9 Scleroderma
• M35.9 Mixed connective tissue disease
• M32.9 Systemic lupus erythematosus
• M35.0 Sjogren’s syndrome
• M05.9 Rheumatoid arthritis
• M33.2 Polymyositis
• M33.9 Dermatomyositis
• I77.6 Vasculitis – disseminated

Typical lengths of stay

If a patient has a digit “at risk”, hospitalization may be required. If intravenous prostaglandin or prostacyclin analogues are administered, they are usually given for 2-5 days. Hospitalization length will depend on how a patient responds to individual therapy but is rarely longer than 1-2 weeks for this indication.