Rheumatology

Raynaud's Phenomenon

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Does this patient have Raynaud's phenomenon?

Raynaud's phenomenon (RP) is an episodic exaggerated vascular response in which digital arteries constrict in response to cold temperatures and emotional stress. This disorder derives its name from Maurice Raynaud who described the first case in 1862. Prevalence rates in the general population range from 3-20%, with cold climates having higher rates. RP is more common in young women and in families of patients with RP.

What are the key elements in a patient's history?

A typical episode of RP is characterized by the sudden onset of sharply demarcated color changes of the fingers and/or toes in response to cold temperatures or emotional stress. These color changes include skin pallor (white) due to ischemia, followed by skin cyanosis (blue), with subsequent blushing from re-perfusion (red). Classic triphasic color changes (white, blue, red) are seen in a minority of RP cases, with some patients experiencing biphasic or monophasic color changes. Generally, however, it is accepted that at least pallor must be present for the diagnosis of RP.

RP should be distinguished from skin mottling or cyanosis in response to cold, which is a common phenomenon. RP has discrete, sharply demarcated color changes (rather than patchy discoloration), a delayed recovery phase of vascular flow, and is abrupt in onset, episodic, and usually symmetric.

RP typically initially involves a single finger (index, middle, ring finger most common; thumb spared) and spreads to involve other digits symmetrically in both hands. Early episodes may involve only a few fingers, but with time most fingers are affected. RP can occur in the toes and more rarely in the skin of the ear lobes, nose, tongue, nipples, as well as internal organs.

What are the key symptoms of Raynaud's phenomenon?

Symptoms of RP include pain, numbness and cold which are often secondary to ischemia (white and blue), and burning and tingling which can be associated with the hyperemic stage (red). RP can be uncomplicated with the ischemic phase (white and blue) lasting 15-20 minutes and being reversible with warming or stress reduction. However, complicated RP with persistent tissue ischemia can result in pain and ulceration of the digital tips, and can eventually lead to gangrene, and even loss of digits.

What are the types of Raynaud's phenomenon?

RP may be either primary, where there is no identifiable underlying cause for Raynaud attacks, or secondary, where a disease is associated with and potentially causes the attacks. Typically patients with primary RP are younger (age onset between 15 and 30 years old), are female, and have multiple family members with RP.

Criteria for primary RP have been established by LeRoy and Medsger in 1992. These include:

  • Symmetric episodic attacks.

  • No evidence of peripheral vascular disease.

  • No digital pitting or tissue injury.

  • Normal laboratory values, including a negative anti-nuclear antibody test (ANA) and a normal erythrocyte sedimentation rate (ESR).

  • Normal nailfold capillary exam.

The nailfold capillary exam, or nailfold capillaroscopy, helps distinguish between primary and secondary RP. To perform a nailfold capillary exam, drop oil in the periungual area and use a magnification tool to look at the nailbeds. An opthalmoscope with the diopter set at 40 can be used as a magnification tool in the office or hospital setting. All fingers should be inspected, but the fourth and fifth finger of both hands is the most precise, due to the highest transparency of skin in these areas.

Enlarged or distorted capillary loops, capillary hemorrhages, as well as a paucity of capillary loops suggest an underlying connective tissue disease, or secondary RP. If these changes are observed in at least two fingers, the patient's nailfold capillary exam is considered abnormal. If an abnormal nailfold capillary exam is found, patients should undergo investigation for secondary causes of RP. Patients with primary RP will have a normal nailfold capillary exam.

The number of disorders associated with secondary RP is extensive. The most common associations are connective tissue diseases, such as systemic sclerosis (90%), mixed connective tissue disease (85%), Sjogren's syndrome (33%), systemic lupus erythematosus (10-45%), dermatomyositis and polymyositis (20%), rheumatoid arthritis (10-20%), vasculitis and undifferentiated connective tissue disease.

RP might precede the clinical onset of any of these disorders and is the common presenting manifestation in systemic sclerosis, as well as other connective tissue diseases; therefore, rheumatic disorders should be ruled out upon presentation of RP.

Some clinical clues that suggest secondary RP are:

  • Late onset (age>40).

  • Male gender.

  • Painful severe events with ulceration.

  • Asymmetric attacks.

  • RP associated with abnormal laboratory parameters or signs and symptoms of another disease.

  • RP associated with ischemic signs or symptoms proximal to the fingers or toes (hand, foot, limbs).

  • Abnormal nailfold capillaroscopy.

What are the key signs and physical findings of Raynaud's phenomenon?

Often in a doctor's office, as RP can be precipitated by stress and cool temperatures, triphasic, biphasic or monophasic color changes in the digits may be present. Nailfold capillaroscopy may be abnormal indicating a secondary cause for RP. Digital pits or even ulcerations may be present on the fingertips, indicating persistent tissue ischemia and usually secondary RP.

Physical exam features can be suggestive of underlying connective tissue diseases responsible for RP. Sclerodactyly, calcinosis, telangectasias, hyperpigmentation or hypopigmentation, loud P2 (indicating pulmonary hypertension), crackles in the lungs (indicating interstitial lung disease) are features consistent with systemic sclerosis.

Dry eyes and dry mouth are consistent with Sjogren's syndrome. Discoid and photosensitive rashes, such as a malar rash, are present in systemic lupus erythematosus. Proximal muscle weakness can be suggestive of polymyositis and dermatomyositis, and arthritis and joint deformities can indicate rheumatoid arthritis. Cutaneous ulcerations and palpable purpura can be a sign of underlying vasculitis.

However, patients with RP, especially those with primary RP, may have an entirely normal physical exam.

How do you diagnose Raynaud's phenomenon?

RP is a clinical diagnosis and can be made if a patient provides a history of the sudden onset of symptoms characteristic of a RP attack. If a patient has repeated episodes of sharply demarcated color changes (at least pallor, but can also be cyanosis and hyperemia) upon exposure to cold or stress, he or she can be diagnosed with RP. Photographs of hands can be obtained during an attack and can be used to help confirm the history.

Provocative techniques such as submersion of digits in cold water are not necessary for the diagnosis of RP and are not performed in routine clinical practice. Objective measures of blood flow to the digits, including measurement of digital systolic blood pressure after cooling, thermography, radioisotope clearance and laser Doppler flowmetry are also not routinely used in clinical practice.

What is the differential diagnosis of Raynaud's phenomenon?

Complaints of cold hands or feet are very common and must be distinguished from RP. Normal individuals may experience skin mottling on exposure to the cold, but in these patients the recovery of vascular flow is not delayed and sharp demarcations of skin color changes do not exist.

Many other diseases can present with RP-like manifestations, including occupation related exposures or injuries, obstructive vascular diseases, drug-induced or systemic vasospasm, and infectious, hematologic, metabolic or immune-mediated disorders (see Table I). A thorough history and physical exam must be obtained to try to identify these contributing etiologies.

Table I.

Differential diagnosis of Raynaud's phenomenon
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 probably 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 there is no abnormal nailfold capillary exam 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 should be tested for the antinuclear antibody test (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 at minimum:

  1. Complete blood count with differential.

  2. General blood chemical analysis (comprehensive metabolic panel).

  3. Erythrocyte sedimentation rate (ESR).

  4. Urinalysis.

If a connective tissue disease is suspected as a cause of secondary RP, an ANA can be ordered. 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 there is no abnormal nailfold capillary exam 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 can be made to a rheumatologist to 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 have not developed to suggest an underlying connective tissue disease within the first 2 years, patients are very 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?

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 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. Once an underlying etiology for secondary RP is established, repeat imaging is usually not necessary. If the clinical scenario changes or lacks improvement, repeat imaging may be considered.

What are the next steps?

Once a secondary case or an alternative diagnosis for RP has been established, it is necessary to direct therapy toward treating this 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 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, usually oriented toward 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 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, 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, as they have the greatest body of evidence supporting their use and have shown about a 30-35% reduction in the frequency and severity of RP attacks in metanalyses for both primary and secondary RP.

Initial medical therapy for RP is begun with the class of calcium channel blockers called dihydropyridines, as they selectively target vascular smooth muscle and have reduced effects on cardiac function. Examples of dihydropyridines are nifedipine, amlodipine, isradipine, 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 disappear with continued treatment, and therefore, unless they are intolerable, the patient should persevere for at least 2 weeks before a decision is made to discontinue treatment.

CCBs should probably not be used during pregnancy.

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 or a phosphodiesterase type 5 inhibitor.

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. Caution should be used when using these agents with topical nitrates, and the combination of these agents should be avoided.

In severe Raynaud's refractory to calcium channel blocking agents, phosphodiesterase type 5 inhibitors can be used and should be considered. Further well-designed prospective placebo-controlled studies investigating these agents in primary and secondary RP are needed. The use of combination vasodilator therapy has not been well-studied to date.

A few small studies suggested benefit of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, as well as ketanserin, another serotonin antagonist, in the treatment of RP, but studies of angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs) have produced conflicting results.

A Cochrane review concluded that ketanserin for the treatment of RP secondary to scleroderma was not clinically beneficial. A meta-analysis showed prazosin, an alpha-1 receptor blocker, to have a modest effect in the treatment of RP secondary to scleroderma. These therapies should be reserved as potential therapeutic options for those who cannot tolerate CCBs, as their efficacy is questionable for the treatment of RP.

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

Parenteral prostaglandin and prostacyclin analogues, such as alprostadil (PGE1), 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 SSRIs, ACE inhibitors and angiotensin receptor blockers, as well as alpha-blockers, can be considered if patients are intolerant of CCBs. Parental prostaglandin and prostacyclin analogues should be considered for severe refractory RP and ischemic digital ulcerations.

Anticoagulation and antithrombotic therapy

Low dose aspirin at 81 mg 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.

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:

  1. His or her digits, as well as entire body, should of course be kept warm.

  2. If digital ulcerations appear infected, patients should be given intravenous antibiotics.

  3. An investigation with ultrasound or MRI to examine the bone and soft tissue can be obtained if there is concern for underlying osteomyelitis.

  4. 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. Given conflicting results of relatively small clinical trials, the use of topical nitrates, phosphodiesterase type 5 inhibitors, selective serotonin reuptake inhibitors, ace-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. A deficit of calcitonin gene-related peptide containing nerves has also been seen in primary RP.

The main difference between primary and secondary RP is the degree of endothelial and vascular damage, being large in secondary and not primary RP. 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.

In general, surgical amputation is avoided, as often the natural progression of Raynaud's with distal ischemia is more tissue sparing than what would typically exist if surgical amputation is undertaken. These of course are very individual decisions and are case-specific.

Nurses

Nurses can be helpful in keeping patients warm, including their entire body as well as their digits, by providing 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 can induce vasospasm.

Therapists

Occupational therapists can assist in the usage of painful digits to ensure mobility, 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:

  1. Patients should have episodes of at least sharply demarcated pallor (can have cyanosis and hyperemia as well) in response to cold or stressful stimuli.

  2. Nailfold capillary exam should be used to help distinguish between primary and secondary RP.

  3. Primary RP will be 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.

  4. 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:

  1. 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.

  2. Pharmacologic therapy should be initiated if non-pharmacologic therapy is not sufficient and for those with digital pitting and digital ulceration.

  3. Initial pharmacologic therapy should consist of calcium channel blockers.

  4. If CCBs fail, topical nitroglycerin or phosphodiesterase type 5 inhibitors can be tried.

  5. If CCBs cannot be tolerated, other agents such as SSRIs, ACE-inhibitors, angiotensin receptor blockers, or alpha-blockers can be tried.

  6. Low dose aspirin (81 mg daily) should be considered in all patients with secondary RP with ischemic digital ulcerations or a history of other thrombotic events.

  7. 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

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.

What is the evidence?

LeRoy, EC, Medsger, RA. "Raynaud's phenomenon: a proposal for classification". Clin Exp Rheumatol. vol. 10. 1992 Sep-Oct. pp. 485-8.

(This is the original article which described classification of primary RP.)

Wigley, FM. "Clinical Practice. Raynaud's phenomenon". N Engl J Med. vol. 347. 2002 Sep 26. pp. 1001-8.

Block, J, Sequeira, W. "Raynaud's phenomenon". Lancet 2001 Jun. vol. 357. 23. pp. 2042-48.

(The above two articles are excellent reviews of Raynaud's phenomenon.)

Hirschl, M, Hirschl, K, Lenz, M. "Transition from primary Raynaud's phenomenon to secondary Raynaud's phenomenon identified by diagnosis of an associated disease: results of ten years of prospective surveillance". Arthritis Rheum. vol. 54. 2006 Jun. pp. 1974-81.

(This article investigated the incidence of transitioning from primary to secondary RP and the various factors that contributed to this transformation.)

Cutolo, M, Grassi, W, Matucci Cernic, M. "Raynaud's phenomenon and the role of capillaroscopy". Arthritis Rheum. vol. 48. 2003 Nov. pp. 3023-30.

(This is a good review of the role of capillaroscopy in RP.)

Thompson, AE, Pope, JE,. "Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis". Rheumatology. vol. 44. 2005. pp. 145-150.

Thompson, AE, Shea, B, Welch, V. "Calcium channel blockers for Raynaud's phenomenon in systemic sclerosis". Arthritis Rheum. vol. 44. 2001. pp. 1841-1847.

(The above two articles are metanalyses of calcium channel blockers for primary and secondary RP.)

De LaVega, A, Derk, C. "Phosphodiesterase-5 inhibitors for the treatment of Raynaud's: a novel indication". Expert Opinion Investig Drugs. vol. 18. 2009. pp. 23-29.

(This is a review of some of the trials of phosphodiesterase-5 inhibitors for the treatment of RP.)

Suter, LG, Murabito, JM, Felson, DT. " The incidence and natural history of Raynaud's phenomenon in the community". Arthritis Rheum. vol. 52. 2005 Apr. pp. 1259-63.

Kransdorf, MJ, Turner-Stepahin, S, Merrit, WH. "Magnetic resonance angiography of the hand and wrist: evaluation of patients with severe ischemic disease". J Reconstr Microsurg. vol. 14. 1998 Feb. pp. 77-81.

Pope, K, Fenlon, D, Thompson, A. "Ketanserin for Raynaud's phenomenon in progressive systemic sclerosis. Cochrane Database Systematic Reviews Issue 2". Oxford: Update Software. 2000.

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(The above are other noteworthy references.)

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