Raynaud’s syndrome, or Raynaud’s phenomenon, is a rare disorder that affects the cutaneous arterioles and can cause them to abnormally vasoconstrict, temporarily limiting blood flow. The most common symptoms are episodes of coldness, numbness, and tingling in the fingers or toes.
First described by Maurice Raynaud in 1862 as “local asphyxia of extremities,” Raynaud’s syndrome can vary greatly in presentation from the benign and reversible primary Raynaud’s syndrome to the more severe presentation of secondary Raynaud’s syndrome.1,2 As part of the normal thermoregulation system, the body constricts blood vessels to preserve heat through the use of vasoconstricting neuropeptides.1
In primary Raynaud syndrome, this normal phenomenon is augmented and leads to blood vessel restriction with exposure to cold or stress.1 Secondary Raynaud syndrome occurs due to underlying disease that disrupts normal vessel reactivity to cold temperatures.1
Maurice Raynaud initial reporting reflected a wide spectrum of disease in describing 25 cases of varying severity, including one case with bilateral upper limb gangrene.3 This wide spectrum has led to disagreement among experts regarding disease classification, which persists to this day.3
Regarding primary Raynaud’s syndrome, a recent, broad meta-analysis showed a pooled annual incidence of 0.25% and a pooled prevalence was 4.85%.4 US-based population studies suggest a prevalence of 4% to 9% in women and 3% to 6% in men.5 Some estimates suggest a prevalence of up to 20% to 30% in women.1
The predominance of the disease in females is clear, with a 9 to 1 female-to-male ratio.1 Primary Raynaud syndrome typically onsets at age 15 to 30, affects females, is transient, and does not limit activities.2,5 In people older than 60, the prevalence is just 0.1% to 1%, and it typically occurs due to obstructive vascular disease.1,2 A prospective study found rates of remission as high as 64% in women and men.2
Primary Raynaud’s syndrome occurs when there is no underlying comorbid pathology.3 However, risk factors include:3,4
- Being female
- Having a family history of Raynaud’s syndrome
- Living in a colder climate
- Having a lower body weight
- Working in a manual occupation
- Having a history of atherosclerosis
- Having a history of cardiovascular disease
- Having a psychological impairment
- Experiencing migraines
- Taking estrogen therapy
Secondary Raynaud’s syndrome has a variety of etiologies, including rheumatologic, hematologic, endocrinologic, and vascular pathologies.3 Structural etiology may also occur.2 Common etiologies of secondary Raynaud syndrome are connective tissue disorders, such as systemic sclerosis (SSc) or systemic lupus erythematosus (SLE).2,3
In fact, Raynaud syndrome may be one of the first presenting features of connective tissue disorders,6 and identifying Raynaud syndrome in these patients presents a significant opportunity for early intervention in the course of these disorders.7 An important example of vasospastic etiology is drug-induced Raynaud syndrome due to drugs such as anti-migraine medications, interferon alpha and beta, cyclosporine, and non-selective beta-blockers, among others.1
Primary Raynaud’s syndrome is considered a benign condition.2 Typically, its attacks are completely reversible and do not lead to ulceration or gangrene.6 However, secondary Raynaud’s syndrome can be associated with complications such as digital ischemia, ulcerations, and gangrene.2
Raynaud’s syndrome is primarily a clinical diagnosis.3 The patient often self-reports symptoms because they typically occur episodically, rather than during an office visit.3 Elements of the patient’s history should include the age of onset, location of affected areas, presence of symmetry, presence of digital ulcerations, and severity of the attacks.1
Because primary Raynaud syndrome occurs as a response to stimuli, such as cold or emotional stress, the patient’s history should also include an assessment of aggravating factors. Seasonal variation may also be reported due to change in cold stimuli across seasons.3
The most common skin finding associated with Raynaud’s phenomenon is skin pallor, also called white attack, of the distal fingers lasting approximately 20 minutes, which may lead to cyanosis, followed by reactive hyperemia, or vascular reperfusion and warming, which presents as erythematous areas.1 Diagnosis typically requires a description of at least two (biphasic) color changes of the digits.3 Usually these attacks begin with one finger and spread to the others but spare the thumb.1 If the thumb is involved, secondary Raynaud syndrome is more likely.1
Report of a pins-and-needles sensation, pain, or numbness may also be associated with these attacks.1 These sensations occur due to tissue ischemia.3 Pain or more persistent sensations may be associated with secondary Raynaud’s syndrome etiologies, such as SSc.3 Additionally, patients may report that these changes and sensations occur in other parts on the body, including toes, ears, nose, knees, and areolar tissue.1,3
Since Raynaud’s syndrome may also occur secondary to another disease state, a review of systemic symptoms is also necessary.1 Questions that may elicit secondary Raynaud’s syndrome etiology include asking about symptoms that point to underlying connective tissue disorder, like photosensitivity or mouth ulcers, and symptoms that indicate severe disease, like digital ulcers.7 People with more severe Raynaud’s syndrome may also report impact on quality of life due to decreased hand function related to digital ulceration.3
A positive response to all 3 questions of the Raynaud’s syndrome screening typically confirms the diagnosis:2
- Are your fingers sensitive to cold?
- Do your fingers change color when they are exposed to cold temperatures?
- Do your fingers turn white, blue, or both?
Referral to rheumatology for further evaluation is recommended to differentiate between primary and secondary Raynaud syndrome.2 Age may suggest primary or secondary etiology, as those with primary Raynaud syndrome typically develop symptoms between age 15 and 25.3
Features that should prompt consideration of secondary Raynaud syndrome include being male, first developing symptoms after age 30, signs of tissue ischemia, abnormal laboratory parameters that suggest another disease, and having unilateral symptoms.3
The physical examination should especially focus on the hands.3 However, due to the transient nature of primary Raynaud’s phenomenon, skin findings may not be present during the physical examination.5 Therefore, periodic follow-up exams should be performed.
Physical examination findings of secondary Raynaud’s phenomenon include evidence of tissue injury, digital pitting, and gangrene.2 Other hand examinations features may include sclerodactyly, telangiectasia, calcinosis, and macroscopic nailfold capillary abnormalities.3 Livedo reticularis, a purplish, mottled or reticular pattern, may also show on the skin with Raynaud syndrome.1
Due to possible involvement of other body parts, a full physical exam that includes assessment of the toes, nose, knees, earlobes, and areolar tissue is recommended.2 Peripheral pulses should also be assessed.3 Decreased peripheral pulses may indicate underlying large vessel disease.7
A rheumatologist typically performs the detailed diagnostic workup to differentiate primary and secondary Raynaud syndrome.2 This is due to the possible connective tissue disease etiologies of Raynaud syndrome.6
A nailfold capillary microscopy analysis of microvascular and morphologic changes in peripheral vessels is a non-invasive way to differentiate between primary and secondary Raynaud syndrome.1,6 This analysis uses a dermatoscope, ophthalmoscope, or USB microscope to visualize nailfold capillaries, which run parallel, rather than perpendicular, to the nail surface.6
While the gold standard technique uses high magnification videocapillaroscopy, low-magnification techniques, such as the use of a dermatoscope, ophthalmoscope, or USB microscope can quickly and easily detect abnormalities.6 Nailfold capillary microscopy is primarily useful for excluding SSc, which features the presence of giant capillaries, microhemorrhages, or avascular areas.3
Additional analysis may include a functional assessment of digital perfusion using infrared thermography or laser-derived methods, though these techniques are primarily reserved for research settings.3 Like nailfold capillary microscopy, infrared thermography can differentiate between primary Raynaud’s syndrome and SSc by indirectly measuring digital blood flow.6 Other analysis methods that have been used, such as finger systolic pressure measurements, require further validation.7
The workup may also include laboratory investigations, which should be tailored to the clinical findings.3 Examples of relevant studies include a complete blood count, comprehensive metabolic panel, rheumatoid factor, anti-cyclic citrullinated peptide, thyroid studies, hepatitis screening, anti-neutrophil cytoplasmic antibodies, and antiphospholipid antibodies.2
Additionally, because secondary Raynaud’s syndrome is associated with connective tissue disorders, testing for autoantibodies associated with these disorders may be performed through laboratory testing for antinuclear antibody by immunofluorescence (ANA), anti-double stranded DNA, anti-SSA, anti-SSB, anti-Smith, anti-ribonucleoprotein, anti-Scl-70, anti-centromere, anti-fibrillarin, anti-Pm-Scl, and anti-RNA polymerase III.2 Finally, clinical features consistent with etiologies such as SLE or cryoglobulinemia warrant laboratory testing for creatinine kinase, immunoglobulins with protein electrophoresis, and fasting lipid profile.3
The minimal set of investigations should include nailfold capillary microscopy, complete blood count, erythrocyte sedimentation rate (ESR), and ANA.6
The differential diagnosis includes primary and secondary Raynaud’s syndrome. In one study, 13% of patients thought to have primary Raynaud syndrome were later diagnosed with secondary Raynaud syndrome.2 Progression to secondary Raynaud syndrome has typically been noted within 5 years of initial diagnosis with primary Raynaud syndrome.7
For patients who present with symptoms that are more consistent with primary Raynaud syndrome but who also have weakly positive ANA testing or borderline widened capillaries on a nailfold capillary microscopy, repeating the nailfold capillary microscopy within 6 to 12 months may help establish a more accurate diagnosis.7 Patients at higher risk of developing secondary Raynaud syndrome may need annual reevaluation for up to 5 years.7
The differential diagnosis for secondary Raynaud syndrome is very broad and includes a large number of conditions.7 As there is a high prevalence of secondary Raynaud syndrome within the population of patients with autoimmune rheumatic diseases, these conditions must be considered closely within the differential diagnosis of primary Raynaud syndrome.3 In particular, connective tissue diseases, such as SSc and mixed connective tissue disease (MCTD), should be included in the differential diagnosis, in addition to SLE, Sjogren syndrome (SS), and others.3,7
Because secondary Raynaud syndrome is common in patients with autoimmune connective tissue disorders, it is especially important to closely consider these diseases as part of the differential diagnosis.7 These connective tissue disorders can be severe and difficult to treat.7 As discussed previously, secondary Raynaud syndrome is a common presenting feature of SSc, and almost all patients with SSc have Raynaud syndrome.7 Presence of Raynaud syndrome alongside positive ANA should alert the clinician to this diagnosis.7
In SSc patients, Raynaud syndrome is especially likely to become severe and progress to ulceration and gangrene.7 Another important disease to consider is MCTD.7 As with SSc, most patients with MCTD have Raynaud syndrome.7 In fact, Raynaud syndrome may be one of the few presenting symptoms upon diagnosis of MCTD.7 In patients with MCTD, ulceration of fingers is rare when compared to the rate of this complication in patients with SSc.7 Raynaud syndrome also occurs in half of patients with undifferentiated connective tissue disease.7
SS is also commonly associated with Raynaud’s syndrome, and these symptoms may occur prior to the appearance of other symptoms more typically associated with SS.7 The prevalence of Raynaud syndrome in patients with SLE is estimated to be 18% to 40%, and its presence is a potential biomarker for internal organ complications.7
Additionally, patients with SLE who also have Raynaud syndrome are more likely to develop arterial and venous thromboses.7 Secondary Raynaud syndrome can also occur within the context of idiopathic inflammatory myopathies and may present as cutaneous ulcers.7
Additionally, conditions that lead to impaired vascular perfusion must be considered. These conditions include large vessel disease that occurs due to compressive, neurogenic, inflammatory, or atherosclerotic causes, as well as vaso-occlusive disease that may occur due to cryoglobulinemia, cryofibrinogenemia, and others.3
As mentioned previously, secondary Raynaud syndrome may also occur due to drugs or chemical exposure.3 Another occupational differential diagnosis is hand–arm–vibration syndrome, which may occur within the context of work with the use of vibratory tools.3 Finally, the differential diagnosis also includes frostbite, hypothyroidism, and fibromyalgia syndrome, among others.3
Treatment of Raynaud’s syndrome is tailored to the underlying diagnosis.3 The goal of treatment is to decrease the frequency and severity of attacks and to prevent tissue ischemia.1 Some experts advise approaching treatment under 4 distinct categories: general approach to treatment, uncomplicated Raynaud syndrome, other drug therapies, and surgical strategies.7
Response to treatment is assessed using the Raynaud Condition Score (RCS), which assesses quality of life and describes the attacks.1 Over the course of 1 to 2 weeks, the RCS diary tracks daily frequency, duration, severity, and impact of Raynaud syndrome symptoms.3
Nonpharmacologic management includes patient education regarding behavioral changes, such as avoiding cold, emotional stress, smoking cessation, and vasoconstricting medications and keeping warm, if possible.3 Strategies to keep warm may include wearing multiple layers of clothing and using hand-warmers or gloves.7 Some patients also report that running their hands under warm water or moving hands in small circular motions helps reduce attack serverity.7
With occupational etiologies, such as hand–arm–vibration syndrome, removing vibration exposure is essential.6 Patients may also seek alternative therapies and supplements, such as acupuncture, biofeedback, gamolenic acid, ginkgo biloba, and vitamins C and E, but there is no evidence base for these approaches yet.7 The importance of patient education as part of nonpharmacologic management indicates that an interdisciplinary team is necessary for appropriate care.7
Pharmacologic management with vasodilating medications is considered if nonpharmacologic management is not effective.3 Typically therapies start at the lowest possible dose and increase gradually to reduce side effects.7 After failure of one therapy, another therapy is considered.7 More research is needed in the use of combination therapy for Raynaud syndrome.7 In patients with progressive symptoms, the clinician should address reversible causes and/or treat comorbid conditions before adding additional interventions.
The first-line pharmacological treatment is dihydropyridine calcium channel blockers (DHP CCBs), and both amlodipine and nifedipine may be considered.1 CCBs should be started at the lowest dose and titrated every 4 weeks based on the patient’s response.1 The recommended amlodipine dosage is 5 mg to 20 mg daily, and the recommended nifedipine dosage is 30 mg to 180 mg daily.1 Typically slow-release or long-acting formulations are used.3 DHP CCBs reduce the number of Raynaud syndrome attacks by around one third.3
If CCBs fail to improve symptoms, then a phosphodiesterase (PDE) inhibitor may be used either in conjunction with the CCB if there is a partial response or as monotherapy.1 The recommended sildenafil dose is 20 mg daily, which may be titrated over 4 to 6 weeks to a maximum dose of 20 mg 3 times daily.1 Typically slow-release or long-acting formulations are used.3 PDE inhibitors have been shown to confer benefit in a number of randomized controlled trials.6
Other pharmacologic therapies, in case of failure of CCBs and PDE inhibitors, include topical nitrates, used as 2% nitroglycerin ointment applied to the affected areas, and the medications losartan, fluoxetine, and prazosin.1 The recommended losartan dose is 25 mg to 100 mg once daily.6 The recommended fluoxetine dose is 20 mg once daily.6 The recommended prazosin dose is 500 micrograms twice daily to 2 mg twice daily.6 The evidence base for these therapies is weaker than the evidence based for CCB and PDE inhibitor pharmacologic management.6
Due to the vasoactive properties of vasodilating medications that lead to adverse effects, including headaches and presyncope, drug intolerance may be a barrier to pharmacologic treatment.3
Table 1. Recommended starting dosages for pharmacologic management of non-ischemic Raynaud’s Syndrome.1,3,6,7
|First line: CCB|
|amlodipine||5 mg to 20 mg daily|
|nifedipine||30 mg to 180 mg daily|
|Second line: PDE Inhibitor|
|sildenafil||20 mg daily|
|2% nitroglycerin ointment||Applied to affected areas|
|losartan||25 mg to 100 mg once daily|
|fluoxetine||20 mg once daily|
|prazosin||500 micrograms twice daily to 2 mg twice daily|
If progression to ulceration or ischemia occurs, IV prostaglandin infusion may be used in conjunction with aspirin or antiplatelet therapy.1,3 It is important to note that aspirin or antiplatelet therapy can be hazardous or life-threatening in some patients, particularly in patients with SSc due to their increased risk of bleeding.7 Oral prostaglandins are not often used because they are typically not well-tolerated and confer little to no benefit.7
Medications used include iloprost, epoprostenol, treprostinil, and alprostadil. The recommended iloprost dose is a continuous dose of 0.5 ng/kg/min to 2.0 ng/kg/min titrated to the maximum dose tolerated by the patient and administered for 3 to 5 days.7 Adequate analgesia due to the pain associated with ischemia, as well as antibiotic therapy, may be required in these cases.6
Finally, surgical intervention may be considered within the context of refractory secondary Raynaud syndrome with ulceration or necrosis due to SSc.3 Surgical interventions include botulinum toxin injections and digital sympathectomy.7 Evidence to support botulinum toxin injections is limited, though some studies support their use.7
Digital sympathectomy is typically used for the treatment of critical digital ischemia, and it leads to ulcer healing within 2 weeks to 7 months, according to some studies.7 However, recurrence of ulceration and amputation can still occur in 14% to 18% of patients who undergo this surgical procedure.7
Regarding first-line therapy DHP CCBs amlodipine and nifedipine, adverse effects include peripheral edema, palpitations and reflex tachycardia, and headaches.1 Monitoring for hypotension and bradycardia is especially important.8 Contraindications include hypotension, peripheral edema, angina, myocardial infarction, flushing, and headaches, among others.1,8
DHP CCBs are contraindicated with known hypersensitivity to DHP CCBs, severe hypotension, acute myocardial infarction, and pulmonary congestion.8 These medications should be used with caution in patients with renal and hepatic impairment.8 In cases that do not involve digital ischemia, CCBs should be avoided in pregnancy.1 Due to metabolism via the CYP3A4 enzyme, there is potential for many drug-drug interactions.8
Regarding second-line therapy PDE5 inhibitor sildenafil, the most commonly reported side effects include headaches, flushing, dyspepsia, nasal congestion, back pain, myalgia, nausea, dizziness, and rash.9 Adverse events have been reported. Cases of sudden loss of hearing or decreased hearing related to the use of sildenafil have been reported, and monitoring for this adverse effect is also important.9
Sildenafil should not be administered with nitrates because the combination can produce severe, life-threatening hypotension.9 Nitrate administration is safe when 24 hours have passed since the last sildenafil dose.9 Contraindications include known hypersensitivity to sildenafil, severe hypotension, pulmonary veno-occlusion, left ventricular outflow obstruction, and pulmonary arterial hypertension associated with sickle cell anemia, among others.9
Regarding other therapy topical nitrates, adverse systemic effects, such as hypotension, dizziness, flushing, syncope, reflex tachycardia, headache, and others may occur.1,10 Monitoring for nitrate tolerance is important, as it can develop within 12 to 24 hours of use.10 For this reason, a nitrate-free period of 10 to 12 hours per day is required.10 There is the previously mentioned drug-drug interaction with PDE inhibitors, and concomitant use may result in severe hypotension, as described above.9,10
Contraindications include known hypersensitivity to nitrates, right ventricular infarction, and hypertrophic cardiomyopathy.10 Due to increased risk of hypotension, people on chronic diuretic therapy, people with low systolic blood pressure, and people with autonomic nervous system dysfunction should be monitored more closely when using nitrates.10 Nitrates should be avoided in pregnancy and breastfeeding.10
Regarding other therapy losartan, primary adverse effects include hyperkalemia, renal insufficiency, and angioedema.11 Additional adverse effects include cough, fatigue, hypoglycemia, anemia, urinary tract infection, chest pain, weakness, diarrhea, and others.11 Monitoring of blood pressure, renal function to include BUN and serum creatinine, and potassium levels is typically required.11
Losartan is contraindicated with known hypersensitivity to losartan, in pregnancy, and with the use of aliskiren in diabetes mellitus.11 Precautions are required with angioedema, hyperkalemia, hypotension, and hepatic renal impairment.11
Regarding other therapy fluoxetine, there are many common reported adverse effects, including insomnia, nausea, diarrhea, anorexia, headache, drowsiness, anxiety, decreased libido, bruising, suicidal ideation, and others.12 Some patients may experience a dramatic increase in anxiety in the initial period, including experiencing panic attacks, so including this side effect in patient education is especially important.12 Monitoring for safety due to possible increase in suicidal ideation is essential.12 No routine laboratory monitoring is recommended.12
Typically, these side effects are dose- and time-dependent and disappear with time.12 Contraindications include known hypersensitivity to fluoxetine.12 The drug should be used with caution in older adults.12 Use during pregnancy is not recommended.12 Important drug-drug interactions include contraindications with the use of monoamine oxidase inhibitors, linezolid, pimozide, thioridazine, and tamoxifen.12
Regarding other therapy prazosin, serious adverse effects include first-dose hypotension.13 Due to this adverse effect, the first dose should be administered at night.13 Similarly, patients may experience orthostatic hypotension and syncope.13 Priapism and floppy iris syndrome are other serious adverse effects.13 Other common side effects include dizziness, headaches, drowsiness, weakness, palpitations, and nausea, among others.13
Contraindications include known hypersensitivity to prazosin.13 Because of possible first-dose hypotension, caution should be used in patients with hypotension.13 Due to the risk of floppy iris syndrome, caution should be used in patients with cataracts.13 This medication is within the pregnancy category C. Drug-drug interactions can occur with the use of other vasodilating medications due to additive hypotensive effects.13 No specific laboratory monitoring is required.13
Regarding therapy for progression to ulceration or ischemia prostaglandins, some adverse effects are related to administration via IV infusion.14 These adverse effects include pain at the injection site and local site infection.14 Systemic effects can include fever, hypotension, musculoskeletal pain, and cough.14 Contraindications include known hypersensitivity to prostaglandins.14 Caution should be used in patients with hypotension due to the adverse effect of hypotension associated with these medications.14
Regarding therapies for progression to ulceration or ischemia aspirin, the most common adverse effect of aspirin is gastrointestinal upset, from more mild forms, such as gastritis, to more severe forms, such as gastrointestinal bleeding.15 Other possible adverse effects include hypersensitivity, which can range from rash to angioedema to anaphylaxis, Reye’s syndrome, and intracerebral hemorrhage.15
Contraindications include known hypersensitivity to aspirin, glucose-6-phosphate dehydrogenase deficiency, peptic ulcer disease and gastritis, and administration to children experiencing a fever, among others.15 Drug-drug interactions of note include cross-hypersensitivity with ibuprofen and increased risk of bleeding with other medications that increase risk of bleeding, such as warfarin and clopidogrel, among others.15 Laboratory monitoring is not typically required for aspirin.15
Regarding therapies for progression to ulceration or ischemia clopidogrel, mild to severe bleeding is the most common adverse effect, and it can occur at any site.16 The risk of bleeding is higher for older adults, people of low body weight, those with a history of a previous bleeding event, or those taking other medications that increase their risk of bleeding.16 Another common adverse effect is rash with pruritus.16
Contraindications include known history of hypersensitivity to clopidogrel or active bleeding. Monitoring for bleeding should occur and includes visual monitoring and laboratory testing of hemoglobin and hematocrit.16
Tissue ischemia associated with more severe Raynaud’s phenomenon may lead to necrosis and amputation.1 For this reason, for patients with connective tissue diseases like SSc, Raynaud’s syndrome is a major cause of pain and disability.7
Critical digital ischemia is a true medical emergency that occurs when digits are discolored permanently, and patients should be educated to seek urgent medical care if this symptom occurs.7 Often critically ischemic digits spontaneously auto-amputate.7
The American College of Rheumatology has not published clinical guidelines for Raynaud’s syndrome.
Based on available evidence:
- Treatment is tailored to the underlying diagnosis.3
- The goal of treatment is to decrease frequency and severity of attacks and to prevent tissue ischemia.1
- Some experts advise approaching treatment under 4 distinct categories: general approach to treatment, uncomplicated Raynaud syndrome, other drug therapies, and surgical strategies.7
- Management begins with nonpharmacologic approaches.
- Nonpharmacologic management includes patient education regarding behavioral changes, such as avoiding cold, emotional stress, and vasoconstricting medications and keeping warm.3
- Pharmacologic management is considered if nonpharmacologic management is not effective, as evaluated by the RCS.3
- The first-line pharmacological treatment is DHP CCBs, and both amlodipine and nifedipine may be considered.1
- If CCBs fail to improve symptoms, then a PDE inhibitor may be used either in conjunction with the CCB if there is a partial response or as a monotherapy.1
- Other therapies for treatment in case of failure of CCB and PDE inhibitor include topical nitrates, used as 2% nitroglycerin ointment applied to affected areas, and the medications losartan, fluoxetine, and prazosin.1
- If progression to ulceration or ischemia occurs, IV prostaglandin infusion may be used in conjunction with aspirin or antiplatelet therapy.1,3 It is important to note that aspirin or antiplatelet therapy can be hazardous or life-threatening in some patients, particularly in those with SSc due to their increased risk of bleeding.7
- Surgical intervention may be considered within the context of refractory secondary Raynaud syndrome with ulceration or necrosis due to systemic sclerosis.3 Surgical interventions include botulinum toxin injections and digital sympathectomy.7
1. Musa R, Qurie A. Raynaud Disease. StatPearls: Treasure Island (FL): StatPearls Publishing; August 11, 2021. Last updated August 11, 2021. Accessed July 5, 2022.
3. Pauling JD HM, Pope JE. Raynaud’s phenomenon—an update on diagnosis, classification and management. Clin Rheumatol. 2019:3317-3330.
4. Garner R, Kumari R, Lanyon P, Doherty M, Zhang W. Prevalence, risk factors and associations of primary Raynaud’s phenomenon: systematic review and meta-analysis of observational studies. BMJ Open. March 16, 2015;5(3):e006389.
5. Suter LG, Murabito JM, Felson DT, Fraenkel L. The incidence and natural history of Raynaud’s phenomenon in the community. Arthritis Rheum. April 2005;52(4):1259-63.
6. Herrick, AL. Evidence-based management of Raynaud’s phenomenon. Ther Adv Musculoskelet Dis. 2017:317-329.
7. Hughes M, Herrick A. Raynaud’s phenomenon. Best Practice & Research Clinical Rheumatology. 2016:112-132.
8. McKeever R, Hamilton R. Calcium Channel Blockers. StatPearls: Treasure Island (FL): StatPearls Publishing; 2022. Last updated April 30, 2022. Accessed July 5, 2022.
9. Smith B, Babos M. Sildenafil. StatPearls: Treasure Island (FL): StatPearls Publishing; 2022. Last updated May 3, 2022. Accessed July 5, 2022.
10. Lee P, Gerriets V. Nitrates. StatPearls: Treasure Island (FL): StatPearls Publishing; 2021. Last updated July 13, 2021. Accessed July 5, 2022.
11. Mulla S, Siddiqui W. Losartan. StatPearls: Treasure Island (FL): StatPearls Publishing; 2022. Last updated February 9, 2022. Accessed July 5, 2022.
12. Sohel A, Shutter M, Molla M. Fluoxetine. StatPearls: Treasure Island (FL): StatPearls Publishing; 2022. Last updated May 2, 2022. Accessed July 5, 2022.
13. Basquez R, Pippin M. Prazosin. StatPearls: Treasure Island (FL): StatPearls Publishing; 2022. Last updated May 10, 2022. Accessed July 5, 2022.
14. Malik K, Dua A. Prostaglandins. StatPearls: Treasure Island (FL): StatPearls Publishing; 2022. Last updated May 15, 2022. Accessed July 5, 2022.
15. Arif H, Aggarwal S. Salicylic Acid (Aspirin). StatPearls: Treasure Island (FL): StatPearls; 2022. Last updated May 3, 2022. Accessed July 5, 2022.
16. Beavers C, Naqvi I. Clopidogrel. Treasure Island (FL): StatPearls Publishing; 2022. Last updated May 8, 2022. Accessed July 5, 2022.