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Abstract

Raynaud’s phenomenon, which is characterized by episodic digital pallor, cyanosis and rubor upon exposure to cold environment or to stress, is relatively common, although the prevalence depends on the climate. Still, it is under-diagnosed, under-treated, and often confused with other conditions. Primary Raynaud’s phenomenon (i.e., Raynaud disease) must be distinguished from secondary Raynaud’s phenomenon (i.e., Raynaud syndrome) as long-term morbidity and outcomes differ vastly between the two conditions. Additionally, the practitioner must differentiate between Raynaud’s phenomenon and related vascular disorders, such as acrocyanosis, pernio, and livedo reticularis. In this article, we review differences between the conditions and suggest an approach to diagnosis and treatment strategy for these disorders.

Keywords

acrocyanosis livedo reticularis pernio Raynaud’s vasospasm

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Disclosures

The faculty, staff, and planning committee of the University of Virginia Office of Continuing Medical Education have no financial affiliations to disclose. The CME planning committee disclosed the following: Aditya Sharma is supported by National Institutes of Health, AstraZeneca, and Vascular Medcure; Heather Gornik and Valerie Clark have no financial affiliations to disclose. The authors have disclosed no financial relationships or interests with a proprietary entity that produces healthcare goods or services related to this article.

Introduction

Raynaud’s phenomenon (RP) is a relatively common condition with an overall prevalence of 1–8% in the general population, with higher prevalence in the colder climates.¹ It is important to distinguish RP from other disorders that cause digital discoloration, including acrocyanosis, pernio, and livedo reticularis (LR), as prognosis and treatment differ between conditions. The evaluation of an underlying cause of vasospastic disorders is challenging due to the usually gradual onset of symptoms. Not all conditions associated with digital vasospasm are benign and some are related to systemic conditions that may require urgent treatment. RP, acrocyanosis, and pernio are generally characterized by discoloration in hands or feet, with or without paresthesia. On the other hand, LR may involve lower extremities, the abdomen, or the chest. While vasospasm implies a reversible constriction of vasculature, ischemic changes seen in some of these conditions may be episodic, persistent or persistent with episodic attacks of a more severe nature depending on their etiology.² In this review, we discuss the pathophysiology, diagnosis, and treatment strategies of these disorders that are commonly encountered in vascular clinical practice.

Raynaud’s phenomenon

Raynaud’s phenomenon, named after the French physician Maurice Raynaud (1834–1881), is caused by deregulated constriction of precapillary arterioles that leads to changes in skin color, swelling, and paresthesia. It generally affects the fingers and toes, but can also affect other sites such as the nose, ears, and nipples. Primary (or idiopathic) RP, termed Raynaud disease, has a relatively benign course. Conversely, secondary RP, termed Raynaud syndrome, occurs as a consequence of a systemic disease process and may include digital pitting, ulceration or dry gangrene.³ Raynaud syndrome is indeed a syndrome of signs and symptoms related to many possible etiologies. The secondary causes include connective tissue disorders, arterial occlusive disorders, neurological disorders, compression disorders, trauma, drugs, hematologic malignancy and others (Table 1). In a study of 307 RP patients, the transition rate from primary to secondary RP was 1% per year.⁴ However, the participants were primarily patients with moderate to severe symptoms who were referred to a specialty clinic and may not represent the general population. In a retrospective study of 497 patients with primary RP in whom nailfold capillaroscopy, anti-centromere, and anti-topoisomerase I antibodies were available, 32% of patients evolved to systemic sclerosis and 49% evolved to other connective tissue disorders over the next 2.3 ± 2.9 years of follow-up.⁵ Scleroderma pattern on capillaroscopy was the most sensitive marker of scleroderma development, while absence of anti-topoisomerase I antibodies was the most specific finding. In a prospective study of 586 patients with RP, 12.6% developed systemic sclerosis during the median follow-up period of 4 years.⁶ An abnormal capillaroscopy finding at baseline with presence of systemic scleroderma-specific antibodies (anti-centromere, anti-topoisomerase I, anti-Th/To, anti-RNA polymerase I/III antibodies) indicated high probability of progression to systemic sclerosis.

Table 1.

Secondary causes of Raynaud’s Phenomenon.¹¹⁸

Collagen vascular diseases
Scleroderma
Systemic lupus erythematosus (SLE)
Rheumatoid arthritis
Dermatomyositis and polymyositis
Mixed connective tissue disease
Sjögren syndrome
Necrotizing vasculitis
Arterial occlusive disease
Atherosclerosis
Thromboembolism
Buerger disease
Neurological disorders
Carpel tunnel syndrome
Complex regional pain syndrome
Cerebral vascular accident
Intervertebral disk disease
Syringomyelia
Poliomyelitis
Trauma
Exposure to vibrating tools
Hypothenar hammer syndrome
Electric shock injury
Thermal injury
Percussive injury
Thoracic outlet syndrome
Myeloproliferative disease

Drugs and toxins
Anti-migraine medications (e.g. Ergot derivatives)
Bromocriptine
Methysergide
Vinblastine
Bleomycin
Interferons
Gemcitabine
Beta-adrenoceptor antagonists
Vinyl chloride monomer exposure
Silica and solvents
Cocaine or amphetamine abuse
Pseudoephedrine
Estrogen replacement therapy
Endocrine
Hypothyroidism
Pheochromocytoma
Blood dyscrasias
Hyperviscosity syndrome
Cold agglutinin disease
Cryoglobulinemia
Cryofibrinogenemia
Miscellaneous causes
Low body mass index
Fibromyalgia
Arteriovenous fistula
Pulmonary hypertension

Clinical presentation

The typical manifestations of RP include a characteristic ‘triphasic’ color pattern, numbness, and swelling in affected digits.⁷ The three color phases are pallor caused by vasospasm-induced ischemia, cyanosis caused by tissue hypoxia, followed by rubor caused by tissue reperfusion (Figure 1). It is important to note that some patients only show biphasic response with pallor and cyanosis. The color changes are generally well demarcated. RP can be precipitated by exposure to cold, emotional stress, medications, trauma, and repetitive use of digits. Smoking is associated with higher prevalence of RP.⁸

Figure 1.

Color change associated with Raynaud’s phenomenon. The third, fourth, and fifth digits are exhibiting pallor associated with Raynaud’s phenomenon.

Epidemiology

Primary RP affects up to 8% of the general population in the United States and is more common in women (7.8% in women vs 5.8% in men).¹ Across different countries, the lowest prevalence was seen in Japan (2.1% in women, 1.1% in men) and the highest prevalence was seen in France (11.7% in women, 6.3% in men).^1,9,10 Cold climates are associated with higher prevalence of RP.^10,11 Symptoms generally begin before the fourth decade of life; symptom onset later in life should alert the provider to look for secondary causes of RP. Family history may be helpful as more than a third of individuals with RP report a relative with RP.^12,13 However, a study exploring an association between known polymorphisms of vasoactive mediator genes and RP found no significant association.¹⁴

Pathophysiology

While the precise mechanism of RP is not clearly understood, the episodic attacks of vasospasm are likely the result of an interplay of various factors that regulate peripheral blood flow. Normal regulation of peripheral blood flow depends on intrinsic vascular tone, sympathetic nervous system activity, blood viscosity, and circulating hormonal substances. Unlike other regional circulations that are supplied by both vasoconstrictor and vasodilator sympathetic fibers, the cutaneous vessels of the hands and feet are innervated only by sympathetic vasoconstrictor fibers. Thus, vasodilation is achieved by withdrawal of such stimulus that causes vasoconstriction. Vasospasm is an excessive vasoconstrictor response causing obliteration of the vascular lumen. The balance between arterial wall tension (favoring closure of vessel) and intravascular distending pressure (favoring opening of vessel) is important in maintaining patency of a blood vessel. Interestingly, compared to controls, individuals with RP have lower brachial and digital artery pressure.^15,16 These findings are more apparent in individuals with secondary RP and may be a result of arterial occlusive disease, vasculitis, or trauma, rather than a mechanism for primary RP. Additionally, disorders that increase viscosity of blood, such as polycythemia vera, Waldenström macroglobulinemia, cryoglobulinemia, and cold agglutinin disease, may reduce blood flow velocity in digital vessels with subsequent decrease in intravascular pressure.

There are multiple theories as to potential mechanisms of RP, described in Table 2; however, the exact mechanism is unknown. Theories include local vascular hyperreactivity;^17,18 potentiation of vascular adrenoceptor response by cold exposure;^19,20 increased sympathetic nervous system activity;^21,22 and role of serotonin,^23,24 thromboxane A₂,^25,26 and endothelin 1.^27,28 Effects of beta-agonists and beta-blockers on peripheral blood flow have been studied as a response to vasoconstriction, induced exogenously (i.e., norepinephrine) or environmentally (i.e., cold).²⁹ Beta-agonists increase peripheral blood flow while beta-blockers potentiate vasoconstriction, but only during exogenously induced vasoconstriction. These findings recognize the role of beta-adrenergic vasodilation in human digits but propose that its antagonism may not be the primary mechanism by which episodic vasospasm occurs in the setting of environmental cooling.

Table 2.

Pathophysiology of Raynaud’s Phenomenon.

Postulated mechanism	Evidence
Local vascular hyperreactivity	• Cold exposure can produce vasospasm even after nerve blockade or sympathectomy^17,18
Increased sympathetic nervous system activity	• Patients with primary RP have increased concentrations of epinephrine and norepinephrine in peripheral venous blood at the wrist,²¹ although this finding has not been consistently reproduced²² • Tyramine, which stimulates norepinephrine release at the sympathetic nerve terminals, increases vasoconstrictor response in patients with RP²²
Increased adrenergic activity	• There is predominance of α₂-adrenoceptors in digital arteries and dermal arterioles^119,120 • Patients with RP are hypersensitive to the vasoconstrictor effects of α₂-adrenoceptor agonist clonidine, but not to α₁-adrenoceptor agonist phenylephrine^18,121,122 • α₂-adrenoceptor antagonist yohimbine increases finger blood flow and decreases vascular resistance during reflex sympathetic vasoconstriction caused by body cooling¹²³
Beta-adrenergic blockade	• The prevalence of RP in patients receiving beta-blocker therapy is as high as 15%¹²⁴ • Intra-arterial beta-agonist administration (isoproterenol) increases fingertip blood flow during vasoconstriction induced by infusions of norepinephrine and angiotensin, but not during reflex sympathetic vasoconstriction²⁹ • Intra-arterial beta-antagonist administration (propranolol) worsens vasoconstriction induced by norepinephrine²⁹
Serotonin (5-HT)	• Ketanserin, a non-selective antagonist of 5-HT_2A receptors, improves symptoms in patients with primary or secondary RP²³ • Serotonin reuptake inhibitors may improve RP symptoms²⁴
Thromboxane A₂ (T_XA₂)	• Increased platelet activation as measured by T_XA₂ is found in patients with primary RP²⁵ • Dazoxiben, a thromboxane synthetase inhibitor, does not improve symptoms in patients with primary or secondary RP²⁶
Endothelin-1 (ET-1)	• Bosentan, an ET-1 antagonist, reduces the risk of new ulcer formation in secondary RP caused by scleroderma^27,28,50

Diagnosis

The diagnosis of RP is primarily based on a careful history and physical examination. Allen and Brown’s classical criteria for diagnosis of primary RP include: (1) episodes precipitated by cold or emotion; (2) bilateral involvement of the extremities; (3) absence of gangrene, or, if present, limited to the skin of the finger tips; (4) no evidence of an underlying disease that could be responsible for vasospastic attacks; and (5) history of symptoms for at least 2 years.³⁰ Primary RP diagnosis is supported by age of onset (most often before the fourth decade), normal capillaroscopy, and absence of exam findings suggestive of secondary causes.

On the other hand, secondary RP should be suspected if onset of symptoms occurs later in life (generally older than 40 years of age), course is progressive, capillaroscopy is abnormal, or physical exam and/or laboratory findings are more consistent with a secondary cause (Figure 2). Additionally, evaluation of digital pressures, pulse volume waveforms, or laser Doppler skin perfusion with cold exposure and/or rewarming may be helpful, although provocative testing may not be widely available (Figure 3A–B). In primary RP, digital pressures and laser Doppler perfusion decrease with cold exposure and normalize with rewarming; conversely, in secondary RP, or fixed ischemia, findings may be abnormal at rest, and do not improve with rewarming (Figure 3C–D). Additionally, RP should be differentiated from benign blue finger syndrome (BBFS), characterized by benign, painless discoloration of digits; and Achenbach syndrome, characterized by benign but painful discoloration of digits.^31–33 Unlike RP, BBFS and Achenbach syndrome affect an older population (mean age 57 years), do not affect the tips of digits, and do not respond to changes in temperature.^34,35

Figure 2.

Digital findings concerning for secondary Raynaud’s Phenomenon. Arrows are pointing to telangiectasias in a patient with positive anticentromere antibody and diagnosis of limited scleroderma.

Figure 3.

Evaluation of primary versus secondary Raynaud’s phenomenon with measurement of digital temperatures and laser Doppler signals before and after rewarming (courtesy of Dr Paul Wennberg, Mayo Clinic, Rochester, MN, USA). (A and B) Exposure of hands to cold water or a hot environment with consequent measurement of digital temperatures, digital pressures, pulse volume waveforms, and laser Doppler skin perfusion may help to differentiate between primary and secondary Raynaud’s phenomenon. (C) Baseline digital temperatures and laser Doppler signals (black bars) are low; all digits are equally involved. After rewarming, digital temperatures and laser Doppler signals (grey bars) normalize, suggesting vasospasm as the etiology of symptoms. (D) Baseline laser Doppler signals (black bars) are low. After rewarming, laser Doppler signals (gray bars) improve in only one digit (second right digit), while remaining low in the other digits. This suggests obstruction as the etiology of symptoms.

Serological studies evaluating secondary RP should screen for vasculitis, collagen vascular disorders, and blood dyscrasias. For example, laboratory may be used to evaluate for evidence of systemic inflammation (erythrocyte sedimentation rate, C-reactive protein); scleroderma (anti-nuclear antibody, anti-centromere antibody, anti-Scl70 antibody, anti-nuclear ribonucleoprotein antibody, anti-nucleolar antigens); systemic lupus erythematosus (SLE; anti-nuclear antibody, anti-double-stranded DNA), rheumatoid arthritis (rheumatoid factor, anti-citrullinated protein peptide), dermatomyositis/polymyositis (creatinine kinase, aldolase, serum glutamic oxaloacetic transaminase, lactic acid dehydrogenase), primary Sjögren syndrome (anti-SSa/Ro antibody), and mixed connective tissue disease (anti-U1-RNP antibody). Individuals presenting with RP should be asked about history of medication changes, trauma or use of illicit substances. Medications such as beta-blockers, ergot alkaloids, certain chemotherapy drugs (vinblastine, bleomycin, gemcitabine) and methysergide can cause secondary RP. Trauma to digits, such as vibratory trauma, electric injury, thermal injury or hypothenar hammer syndrome, can precipitate secondary RP. Other conditions associated with secondary RP are listed in Table 1. Angiography is rarely indicated as diagnosis can often be made with careful history, physical examination, and selective serological studies. A diagnostic approach to RP is presented in Figure 4A–B.

Figure 4.

Diagnostic approach to RP. (A) Three-step history-taking approach to diagnosis of RP. (B) Diagnostic approach to primary versus secondary RP. (Note: the choice of serologic testing should depend on the patient’s history and physical exam findings as a work-up for secondary RP.)

Treatment

Treatment options for RP vary and depend on severity of symptoms and underlying cause. Patients with primary RP should be educated and reassured regarding the benign nature of the disease process. Importantly, all individuals with RP should be counseled about cold avoidance and the use of appropriate clothing, gloves, mittens, heat packs, and footwear to maintain core temperature within the appropriate range.³⁶ Warm water may be advised for rewarming.³⁷ However, use of hot water for rewarming should be avoided as prolonged exposure for rewarming may results in burns. Smoking cessation should be strongly encouraged as nicotine enhances vasoconstriction.³⁸

Pharmacological intervention is often initiated when conservative approaches are ineffective in improving quality of life. Nonetheless, strong data, such as large randomized controlled trials (RCTs), supporting specific drug therapy is lacking and choice of agent is often dependent on patient-specific factors. The most commonly used drug class for the treatment of RP is a long-acting dihydropyridine calcium channel blocker (CCB). Most trial data pertained to nifedipine, but amlodipine is also commonly used in practice. A meta-analysis of 18 small RCTs performed by Thompson and Pope found that CCB use in primary RP decreases the weekly number of attacks, up to five fewer attacks per week, as well as improved symptom severity.³⁹ However, the authors indicate possible bias as many of the included trials were crossover trials, in which order effects were not studied. They also note the effect size may have been small due to different dosing in studies. A Cochrane review of 38 low-to-moderate quality RCTs suggested that patients with primary or secondary RP who were prescribed CCB had fewer RP episodes and improved symptom severity, as measured by visual analogue scale (moderate quality evidence).⁴⁰ However, there were more withdrawals in the CCB treatment group due to side effects such as headache, dizziness, nausea, palpitations, and ankle edema.⁴⁰

Alpha₁-adrenoceptor antagonists (prazosin, doxazosin, and terazosin) have been shown to reduce the severity of vasospastic attacks in patients with RP.⁴¹ In a double-blind, placebo-controlled, crossover study of 24 patients, a low dose prazosin therapy reduced the number and duration of attacks and improved finger blood flow during a finger cooling test in both primary and secondary RP groups.⁴² Two randomized controlled crossover studies have shown that prazosin is more effective than placebo in the treatment of RP secondary to scleroderma.⁴³ However, its use may be limited by side effects such as fatigue, dizziness, and headache.

In cases where CCBs or α₁-adrenoceptor antagonists cannot be used due to side effects, or are ineffective, a phosphodiesterase type 5 (PDE-5) inhibitor or a topical nitrate may be used. It is important to note that data for PDE-5 inhibitors is limited to studies of individuals with secondary RP, and use in individuals with primary RP is based on extrapolation from these studies.⁴⁴ A 2013 meta-analysis of 296 secondary RP patients showed a significant improvement in RP symptoms, including severity, frequency, and duration of episodes.⁴⁴ A recent randomized, placebo-controlled study in patients with systemic sclerosis showed a significant decrease in the number of digital ulcers in patients receiving sildenafil compared to placebo.⁴⁵

A meta-analysis of topical nitrate therapy in 346 patients with primary and secondary RP showed a moderate-to-large treatment effect as compared to placebo,⁴⁶ although use of nitrates was associated with more headaches. Additionally, there has been no standardized topical nitrate across different studies. Topical nitrates seem to increase perfusion at both distal digital ulcer and extensor digital ulcer cores as compared to placebo in patients with systemic sclerosis when evaluating with laser Doppler imaging (LDI).⁴⁷ A recent study revealed that application of a nitroglycerin patch to the hand dorsum led to an increase in blood flow and hand temperature in patients with systemic sclerosis after cold challenge using LDI.⁴⁸

Bosentan, an endothelin receptor antagonist, has been used to treat refractory secondary RP and digital ulcers in patients with scleroderma.^49,50 Other endothelin receptor antagonists, such as macitentan or ambrisentan, do not improve digital blood flow.^51,52

While oral prostaglandins have not shown benefit, intravenous iloprost has been shown to decrease the frequency, duration, and severity of attacks and promote wound healing in secondary RP.^53,54

Botulinum injection into the perineurovascular tissue of the wrist, the distal palm, or along the digits has been reported to relieve symptoms in uncontrolled, open-label case series.^55,56 Digital periarterial sympathectomy may be considered when there is critical digital ischemia or resistant ulceration despite aggressive vasodilatory therapy. A long-term retrospective study of 35 patients with primary or secondary RP who underwent thoracoscopic sympathectomy had a positive response in 77%; however, symptoms recurred in 60% at a median follow-up of 5 months.⁵⁷ Therefore, there is no clear role for thoracoscopic upper limb sympathectomy, unless no other reasonable options exist.

In regards to pharmacologic treatment of primary RP, no matter the agent, we recommend starting with a low dose, and titrating the dose while monitoring for both response to therapy and side effects. Given the described limitations, it is reasonable to start with α₁-adrenoceptor antagonists or long-acting dihydropyridine CCBs in younger patients (usually < 60 years old) with symptoms not well controlled with lifestyle modifications alone. The initial choice for the specific agent depends on shared decision-making between the provider and the patient, based on discussion of the side-effect profile of each agent. In older patients, or those with higher risk of developing side effects to α₁-adrenoceptor antagonists, CCBs are preferred. We do not recommend using α₁-adrenoceptor antagonists and CCB simultaneously due to the higher risk of side effects and lack of data with this approach. Regular follow-up, every 3–6 months, assessing the response and side effects of therapy, is vital.

In patients with secondary RP, CCBs, α₁-adrenoceptor antagonists, or PDE-5 inhibitors are a reasonable first choice. In patients with persistent digital ischemia or symptoms, topical nitrate and/or intravenous prostacyclin therapy can be added. Recent meta-analysis has suggested that other drug classes do not have a significant impact on symptoms of secondary RP.⁵⁸ Digital sympathectomy may be considered when there is threatening digital ischemia or persistent ulcers despite maximal vasodilatory therapy.

Acrocyanosis

Acrocyanosis was originally described by Crocq in 1896 as a persistent blue and red discoloration of the digits, sometimes extending as far as the wrists or the ankles. The blue discoloration in acrocyanosis is relatively persistent, less episodic, and not associated with discomfort when compared to RP. Similar to RP, it is often exaggerated by exposure to cold or emotional stress; and may be idiopathic (primary) or associated with a variety of systemic disorders that require timely diagnosis and treatment (secondary). The primary form is often benign and has a favorable prognosis, while prognosis of secondary acrocyanosis depends on the underlying disorder.

Clinical presentation

The classic presentation of primary acrocyanosis is described as a symmetric, painless, and persistent bluish discoloration of hands and feet in a thin young woman. Other body parts such as the nose tip, ears, lips, or nipples can be affected, but are less common. While individuals with acrocyanosis may report a sensation of coolness in affected extremities, they typically do not experience pain or tissue injury. If pain, ulceration or gangrene is seen, an alternative diagnosis should be considered.⁵⁹ The discoloration seen in acrocyanosis may have different hues, such as bluish-pink or brownish-yellow. The affected areas may have mild swelling and frequently have hyperhidrosis. The discoloration may be exacerbated by cold or emotional stress and diminished by rewarming. Another characteristic of acrocyanosis is the slow and irregular return of the blood from the periphery to the center in the area of blanching when pressure is applied to the skin (Crocq’s sign). Acrocyanosis is distinguished from RP by the absence of episodic digital pallor, rubor, or pain.

Epidemiology

While there is limited information on the precise incidence and prevalence of the disease, acrocyanosis is known to affect younger adults (second to third decades of life), and women more frequently than men.⁶⁰ The incidence of acrocyanosis decreases with age, with almost no cases seen after menopause, suggesting hormonal influences on the underlying mechanism.^59,61 It is associated with a low body mass index, anorexia nervosa, malignancy, outdoor occupations, and cooler climates.⁶² There has been a report of genetic predisposition, with a report of first degree family history in up to 10% of patients with acrocyanosis.⁶²

Pathophysiology

Proposed pathophysiological mechanisms of primary acrocyanosis are similar to those of RP and include dysregulated arteriolar tone, autonomic nervous system imbalance, and response to circulating vasoconstrictive mediators. The fundamental abnormality in primary acrocyanosis is the persistent arteriolar vasoconstriction which leads to compensatory venular dilatation in the postcapillary vascular beds.^63,64 Hypoxia caused by precapillary vasoconstriction increases the release of vasodilatory mediators, which in turn leads to postcapillary dilation and possible arteriovenous subpapillary plexus shunting.⁶⁵ Other potential mediators of altered vasoconstriction in acrocyanosis include epinephrine, norepinephrine, serotonin, and endothelin-1.^59,66 As rewarming of a part of the affected limb produces a sharp demarcation, this suggests that the primary vessel defect is localized to distal and smaller arteries.^61,67,68

Diagnosis

The diagnosis is made clinically and typically does not require laboratory or imaging studies.⁶⁹ A careful history and physical examination should be obtained in order to eliminate an underlying disease as a potential cause of discoloration. In primary acrocyanosis, arterial pulses and pulse oximetry are normal. Elevation of a cyanotic limb over the heart produces pallor, suggesting there is no venous obstruction.

Secondary acrocyanosis can be seen with anorexia nervosa, connective tissue disorders (scleroderma, SLE, rheumatoid arthritis, mixed connective tissue disease, antiphospholipid antibody syndrome (APS)), arterial occlusive disease (including atheromatous/septic embolism), coagulopathy (disseminated intravascular coagulation, heparin-induced thrombocytopenia), malignancy (lymphoma), infection (hepatitis C), and presence of cryoglobulins and cold agglutinins.⁶⁰ Medications and toxins associated with acrocyanosis include tricyclic antidepressants, interferon-α, interferon-β, amphotericin B, arsenic, and butyl nitrite.^70,71 Chronic arsenic toxicity accompanied by acrocyanosis is known as ‘black foot disease’. This condition is thought to be caused by inhibition of prostacyclin synthetase, formation of intravascular clots, and inflammation of the vascular wall leading to subsequent gangrene and amputations of the limbs.^60,72,73 A cyanotic appearance may also be a result of systemic hypoxemia with increased deoxyhemoglobin; or due to accumulation of methemoglobin and sulfahemoglobin due to exposure to oxidizing agents (e.g. aniline, benzocaine, dapsone, phenazopyridine, nitrates, and naphthalene).^74,75 Therefore, a careful review of medications and toxins is important to investigate the cause of cyanosis. In secondary acrocyanosis, abnormalities, such as asymmetric limb involvement, hypoxemia, weak/absent pulse, pain or trophic skin changes, may be seen depending on the underlying disease. When a secondary cause is suspected, laboratory and imaging work-up is similar to that of secondary RP, as previously described. Capillaroscopy may be performed to assess capillary morphology, distribution, and blood flow.⁶⁰ Nonspecific findings such as abnormal capillary morphology, pericapillary edema, and hemorrhage may be present. Mean capillary density is reduced in patients with presumed primary acrocyanosis compared to normal subjects, although is higher than that of patients with systemic sclerosis.⁷⁶

Treatment

Primary acrocyanosis is a benign condition that usually only requires conservative measurements such as reassurance, avoidance of cold exposure, and maintenance of appropriate body temperature. Several agents such as CCBs, beta-blockers, and other adrenergic blocking agents have been tried but without clear success.⁶⁰ Nicotinic acid derivatives have been used in a clinical trial with some effect but with variable responses.^77,78 Bromocriptine has been reported to relieve acrocyanosis but may cause RP.⁷⁹ Sympathetic nerve block and sympathectomy have been used for severe cases but these are rarely appropriate for primary acrocyanosis.⁶⁰ Treatment of secondary acrocyanosis is directed against the primary cause.

Pernio

Pernio (chilblains) is an inflammatory cutaneous condition involving localized swelling and erythema caused by exposure to cold, damp, and non-freezing conditions. Hands, feet, ears, and face are most commonly affected. There are acute and chronic forms of pernio. While it is possible to have pernio without underlying vascular pathology, secondary pernio associated with other conditions also exists. Various names used in the literature to describe pernio or a pernio-like condition include dermatitis hiemalis, erythrocyanosis, nodular vasculitis, or cold panniculitis.

Clinical presentation

The initial presentation of pernio is acute pernio, where the lesions appear during the cold months and disappear when the weather warms up. Lesions vary in size, shape, color, and number, and are associated with itching, burning or pain.⁸⁰ The lesions may be red-to-purple macules, papules, or plaques on one or more body parts exposed to cold.⁸¹ Acute lesions are generally self-limiting once the exposure stops. Although infrequent, complications of acute pernio include skin breakdown, ulceration, and infection. Chronic pernio may occur when there is repeated and prolonged exposure to cold during the acute phase and/or the individual goes through several seasons of acute pernio. The chronic lesions may be associated with scarring, atrophy, permanent discoloration, and ulceration.⁸⁰ Adults tend to have more severe forms of pernio and, if untreated, could develop microvascular occlusive disease.⁸² On the other hand, children may have recurrent acute pernio over several seasons.⁸³ Conditions associated with pernio include anorexia nervosa, RP, acrocyanosis, macroglobulinemia, dysproteinemias, leukemia, cryoproteinemia, SLE, antiphospholipid syndrome, peripheral artery disease, erythromelalgia, complex regional pain syndrome, and use of sulindac.^84–88 It is important to note that RP and acrocyanosis can coexist with pernio, cause secondary perniosis or clinically manifest after the initial diagnosis of pernio.⁸⁴

Epidemiology

An epidemiologic study dating back to the Second World War reported a pernio prevalence of 50% in military participants.⁸⁹ In a more recent case series of 104 patients with pernio, a female predominance (79% of cohort) with mean age of 38 years and frequent smoking was noted.⁹⁰ While 17% of patients also had RP, only 4% had concomitant autoimmune connective tissue disease and 3% had hematologic malignant disease. Pernio is most commonly seen in the northern and western parts of the United States and during a wet, near-freezing season.^82,91 In general, the disease is becoming less common with higher standards of home and workplace heating.

Pathophysiology

While the exact pathogenesis of pernio is unknown, it has been suggested that persistent cold exposure leads to vasoconstriction, hypoxemia, and a subsequent inflammatory reaction in the affected tissue. Many studies have described histological findings of perivascular lymphocytic infiltration, and vessel wall and papillary dermal edema.^92–94 Humidity in cold temperatures is an important factor as it increases air conductivity and further promotes heat loss from the skin. In response to such conditions, the cutaneous vasculature exhibits arteriolar constriction, venular relaxation and increased blood viscosity, leading to ischemia of the tissue.⁸⁰ Individual susceptibility to cold exposure also plays a role in development of pernio, as affected individuals have been shown to have cooler skin for longer durations than controls.^82,95

Diagnosis

Diagnosis is based on the recognition of lesions and chronological correlation between the onset of symptoms and cold exposure. Extensive laboratory or imaging studies are not required to make the correct diagnosis unless a secondary cause is suspected. As with other conditions, careful physical examination is key. The differential diagnosis of pernio includes a variety of diseases, but one disorder that requires careful consideration is chilblain lupus erythematosus (CHLE) due to its association with SLE and implications of familial genetic inheritance.⁹⁶ Additionally, with the recent coronavirus (COVID-19) pandemic, there has been a report of ‘COVID toes’, which clinically appears similar to pernio. A recent study evaluated patients with CHLE compared to COVID-19.⁹⁷ Interestingly, cutaneous histologic findings of both groups are similar, with elevated expression of type-I interferon-induced protein (IFN-I). Individuals with more significant COVID-19 cutaneous symptoms had higher levels of IFN-I, suggesting that ‘COVID toes’ may occur due to an exaggerated immune response.

Although not required, biopsies may be performed to support the diagnosis.^85,93 The characteristic histopathological features of pernio include edema of the papillodermis, perivascular infiltration by mononuclear and lymphocytic cells, thickening and edema of the vascular walls, fat necrosis, and chronic inflammatory reaction with giant cell formation.⁸⁰ In a study of nine patients with pernio, histologic findings demonstrated lymphocytic vasculitis in eight of nine specimens.⁸¹ These histologic changes were consistent regardless of the clinical appearance of the lesions.

Treatment

The primary focus of treatment is prevention. Avoidance of cold and damp conditions is critical in the prevention and recurrence of pernio. A dihydropyridine CCB shortens duration of lesions, reduces severity of symptoms, and prevents development of new lesions in some studies.^98,99 Other agents such as topical nitroglycerin, oral pentoxifylline, and hydroxychloroquine have been used with variable results.^100–102 Some clinicians use topical corticosteroids (0.025% fluocinolone acetonide) but benefits are unclear.¹⁰³

Livedo reticularis

Livedo reticularis (LR) is a physical exam finding characterized by reddish purple reticular mottling that forms a net-like pattern (Figure 5). In many cases, primary LR is a benign finding aggravated by cold exposure and alleviated by warming and/or elevation. Unlike the benign presentation of LR that is often reversible, livedo racemosa is a permanent condition that is always pathologic.^104,105 Systemic diseases such as APS, Sneddon’s syndrome, connective tissue disorders, cryopathies, malignancy, neurologic disorders, infections, and embolic disease (atherosclerotic/septic emboli) are associated with secondary LR or livedo racemosa.¹⁰⁶ Medications associated with the development of LR include catecholamines, amantadine, quinidine, and bismuth.¹⁰⁷ LR is found in up to 40% of patients taking amantadine.¹⁰⁸ Ulceration formation can be seen with continued use of amantadine, but ulcers typically resolve quickly with discontinuation of the medication.¹⁰⁸ Long-term therapy with gemcitabine may lead to thrombotic microangiopathy manifested by LR and hemolytic uremic syndrome.¹⁰⁹ In heparin-induced thrombocytopenia and thrombosis, disseminated intravascular coagulation and thrombotic occlusion of cutaneous blood vessels may manifest as LR.¹¹⁰

Figure 5.

Skin discoloration consistent with livedo reticularis. There is bilateral symmetric lower extremity net-like mottling, consistent with livedo reticularis. (Please note the acrocyanosis in the feet.)

Clinical presentation

LR can present in primary or secondary form. In LR, the net-like mottling is symmetrically distributed, painless, often reversible, limited to the extremities, and rarely associated with other skin abnormalities. In contrast, livedo racemosa, a condition that is always pathologic and associated with an underlying disease, has asymmetrical distribution of irregular mottling with diffuse involvement of the trunk, buttocks, extremities, and/or face; is irreversible; can be painful; and may be associated with other skin abnormalities (e.g. purpura, nodules, or ulcers).

Epidemiology

Both physiologic and primary LR are commonly seen in young women, especially those with fair skin, between the ages of 20 and 60 years.¹¹¹ LR is a common dermatologic finding in patients with APS. It is present in approximately 25% of patients with APS and in up to 70% of patients with SLE-associated APS.^112,113

Pathophysiology

LR results from changes within the cutaneous microvascular system. The dermis is supplied by a network of perpendicularly oriented arterioles that form a capillary bed at the surface. These capillary beds then empty into a conical-appearing, peripherally located subpapillary venous plexus. Anything that increases the visibility of the venous plexus can result in net-like venous mottling. Thinning of the papillary dermal layer alone can make this venous network visible.¹¹⁴ Decreased arteriolar perfusion from vasoconstriction or other systemic condition (hyperviscosity, inflammation, embolic disease) can cause deoxygenation of the venous plexus, which in return leads to net-like mottling. Venodilatation of the venous plexus secondary to hypoxia or autonomic dysfunction is another mechanism by which mottling occurs.

Diagnosis

Similar to other vasospastic disorders, the first diagnostic step is a comprehensive history and physical exam. The location of LR, exacerbating and alleviating factors, duration of attacks, associated skin findings, and risk factors for autoimmune connective tissue disorders or other secondary causes are important factors to consider. Of note, reversible LR can be seen in RP flare. On physical examination, it is important to note the location of LR as typical mottling seen outside of extremities is consistent with livedo racemosa and is always pathologic. The presence of ulcerations or nodules is suggestive of vasculitis.¹¹⁵ Serologic testing should be directed based on the patient’s history, physical exam, and risk factors. However, an antiphospholipid antibody panel should be obtained in all patients presenting with livedo racemosa as it has been identified as a marker for predicting multisystem thrombosis in APS.^116,117 A skin biopsy is not required for diagnosis of LR but punch biopsies of a central blanched area or a peripheral bluish area may be helpful in differentiating a vasculitis, vasculopathy or normal tissue.¹¹⁵

Treatment

For primary LR, cold avoidance and limb elevation are usually sufficient. In rare cases, vasodilator therapy may be used if a patient is significantly affected by the cosmetic appearance of LR. Treatment of secondary LR and livedo racemosa is directed towards the underlying disease. Patients with livedo racemosa and APS complicated by thrombosis should be treated with therapeutic anticoagulation. However, currently there is no evidence-based practice on how to treat patients with livedo racemosa and APS without a history of thrombosis.¹⁰⁶

Summary

Comparison of clinical characteristics of primary RP, primary acrocyanosis, period, and primary LR is summarized in Table 3, and key points to remember are summarized in Table 4. A comprehensive history and physical exam remain the most important diagnostic tool for differentiating various vasospastic disorders and determining the secondary cause if one is present. Routine laboratory tests and imaging tests are not necessary in many patients with RP and related vasospastic disorders. Diagnostic tests and treatment should be guided by the individual patient’s medical history, risk factors for a secondary cause, and the extent of digital ischemia. Making the correct diagnosis is imperative in understanding the trajectory of the disease and identifying the correct treatment strategy.

Table 3.

Clinical characteristics of primary RP, primary acrocyanosis, pernio, and primary LR.

	Primary RP	Primary acrocyanosis	Pernio	Primary LR
Demographic	Female predominance Age before 40 years¹	Female predominance Age 20–30 years⁶⁰	Female predominance Any age with exposure⁹⁰	Female predominance Age 20–60 years¹¹¹
Trigger/exposure	Cold, emotional stress	Cold, emotional stress	Cold, damp, non-freezing temperature	Cold exposure
Symptom duration	Episodic	Persistent over time (not triggered); improves with rewarming and elevation of limbs	Occurs during cold months and lasts days to several weeks⁸⁴	Episodic; improves with rewarming and elevation of limbs¹²⁶
Clinical features	Bi/triphasic color change with pain/paresthesia;⁷ absence of ulcer/necrosis	Painless cyanosis; absence of ulcer/necrosis; associated with hyperhidrosis in the hands and feet⁶⁹	Erythematous or purple lesions accompanied by pain, burning sensation, ulcer or necrosis^80,81	Violaceous reticular, ‘net-like’ mottling encircling a pallor central core
Distribution	Symmetric; commonly seen in hands (thumbs are often spared) and feet; less commonly seen in tongue, earlobes, nose, nipples	Symmetric; commonly seen in hands and feet; less commonly seen in tongue, earlobes, nose, nipples	Depends on exposure; commonly seen in finger pads, toe pads, nailfolds, dorsum of the hands/feet, face, ears	Symmetric; more frequently seen in the lower limbs, but may be seen in upper limbs or torso
Treatment	Cold avoidance; dihydropyridine CCB (nifedipine, amlodipine), α₁-adrenoceptor antagonists^40,125	Cold avoidance, elevation Medications rarely indicated	Cold avoidance Medications rarely indicated	Cold avoidance, elevation Medications rarely indicated

CCB, calcium channel blocker; LR, livedo reticularis; RP, Raynaud’s phenomenon.

Table 4.

Key points to remember.

• RP is characterized by well-demarcated triphasic or biphasic color pattern and paresthesia in bilateral hands/feet.
• Contrary to primary RP, secondary RP may be complicated by digital pitting, ulceration or gangrene.
• Routine laboratory testing and imaging studies are not usually required for diagnosis of RP or other vasospastic disorders, unless a secondary cause is suspected.
• Contrary to RP, acrocyanosis is persistent and usually painless.
• Pernio is thought to be a result of vasoconstriction, hypoxemia and subsequent inflammatory reaction that takes place in cold, damp and non-freezing conditions.
• Avoidance of cold or other aggravating factors (e.g., emotional stress, repetitive injury) should be advised even when pharmacotherapy is used.
• Smoking cessation is strongly encouraged in patients with vasospastic disorders as nicotine may enhance vasoconstriction.
• Unlike primary or secondary LR, livedo racemosa is always pathologic and associated with an underlying disease.

LR, livedo reticularis; RP, Raynaud’s phenomenon.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Stanislav Henkin

References

*Garner

Kumari

Lanyon

, et al. Prevalence, risk factors and associations of primary Raynaud’s phenomenon: Systematic review and meta-analysis of observational studies. BMJ Open 2015; 5: e006389.

Coffman

Davies

. Vasospastic diseases: A review. Prog Cardiovasc Dis 1975; 18: 123–146.

*Maverakis

Patel

Kronenberg

, et al. International consensus criteria for the diagnosis of Raynaud’s phenomenon. J Autoimmun 2014; 48-49: 60–65.

Hirschl

Lenz

, et al. 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 2006; 54: 1974–1981.

Pavlov-Dolijanovic

Damjanov

Stupar

NZV

, et al. The value of pattern capillary changes and antibodies to predict the development of systemic sclerosis in patients with primary Raynaud’s phenomenon. Rheumatol Int 2013; 33: 2967–2973.

Koenig

Joyal

Fritzler

, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: A twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 2008; 58: 3902–3912.

Block

Sequeira

. Raynaud’s phenomenon. Lancet 2001; 357: 2042–2048.

Brand

Larson

Kannel

, et al. The occurrence of Raynaud’s phenomenon in a general population: The Framingham Study. Vasc Med 1997; 2: 296–301.

Iwata

Makimo

Miyashita

. Prevalence of Raynaud’s phenomenon in individuals not using vibrating tools. Sangyo Igaku 1987; 29: 500–503.

10.

Maricq

Carpentier

Weinrich

, et al. Geographic variation in the prevalence of Raynaud’s phenomenon: A 5 region comparison. J Rheumatol 1997; 24: 879–889.

11.

Plissonneau

Pistorius

Pottier

, et al. Cold climate could be an etiologic factor involved in Raynaud’s phenomenon physiopathology. Epidemiological investigation from 954 consultations in general practice. Int Angiol 2015; 34: 467–474.

12.

Jones

Herrick

Woodham

, et al. Occurrence of Raynaud’s phenomenon in children ages 12–15 years: Prevalence and association with other common symptoms. Arthritis Rheum 2003; 48: 3518–3521.

13.

Freedman

Mayes

. Familial aggregation of primary Raynaud’s disease. Arthritis Rheum 1996; 39: 1189–1191.

14.

Smyth

Hughes

Bruce

, et al. A case–control study of candidate vasoactive mediator genes in primary Raynaud’s phenomenon. Rheumatology (Oxford) 1999; 38: 1094–1098.

15.

Thulesius

. Methods for the evaluation of peripheral vascular function in the upper extremities. Acta Chir Scand Suppl 1976; 465: 53–54.

16.

Cohen

Coffman

. Reduced fingertip arterial pressure in Raynaud’s disease. J Vasc Med Biol 1989; 1: 21–26.

17.

Lewis

. Experiments relating to the peripheral mechanism involved in spasmodic arrest of the circulation in the fingers, a variety of Raynaud’s disease. Heart 1929; 15: 7–101.

18.

Freedman

Mayes

Sabharwal

. Induction of vasospastic attacks despite digital nerve block in Raynaud’s disease and phenomenon. Circulation 1989; 80: 859–862.

19.

Coffman

Cohen

. Total and capillary fingertip blood flow in Raynaud’s phenomenon. N Engl J Med 1971; 285: 259–263.

20.

Vanhoutte

Cooke

Lindblad

, et al. Modulation of postjunctional alpha-adrenergic responsiveness by local changes in temperature. Clin Sci (Lond) 1985; 68(Suppl 10): 121s–123s.

21.

Peacock

. Peripheral venous blood concentrations of epinephrine and norepinephrine in primary Raynaud’s disease. Circ Res 1959; 7: 821–827.

22.

Kontos

Wasserman

. Effect of reserpine in Raynaud’s phenomenon. Circulation 1969; 39: 259–266.

23.

Coffman

Clement

Creager

, et al. International study of ketanserin in Raynaud’s phenomenon. Am J Med 1989; 87: 264–268.

24.

Coleiro

Marshall

Denton

, et al. Treatment of Raynaud’s phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology (Oxford) 2001; 40: 1038–1043.

25.

Polidoro

Barnabei

Giorgini

, et al. Platelet activation in patients with the Raynaud phenomenon. Intern Med J 2012; 42: 531–535.

26.

Coffman

Rasmussen

. Effect of thromboxane synthetase inhibition in Raynaud’s phenomenon. Clin Pharmacol Ther 1984; 36: 369–373.

27.

Cutolo

Ruaro

Pizzorni

, et al. Longterm treatment with endothelin receptor antagonist bosentan and iloprost improves fingertip blood perfusion in systemic sclerosis. J Rheumatol 2014; 41: 881–886.

28.

Nguyen

Eisendle

Gruber

, et al. Effect of the dual endothelin receptor antagonist bosentan on Raynaud’s phenomenon secondary to systemic sclerosis: A double-blind prospective, randomized, placebo-controlled pilot study. Rheumatology (Oxford) 2010; 49: 583–587.

29.

Cohen

Coffman

. Beta-adrenergic vasodilator mechanism in the finger. Circ Res 1981; 49: 1196–1201.

30.

Allen

Brown

. Raynaud’s disease: A critical review of minimal requisites for diagnosis. Am J Med Sci 1932; 183: 187–200.

31.

DuVall

Lopez

. An unusual bruise: A case of Achenbach syndrome. Proceedings of UCLA Health 2019; 23: 1–3.

32.

Yie

. Achenbach syndrome: A benign painful blue finger with tip sparing. Vasc Specialist Int 2019; 35: 251.

33.

Godoy

Tabares

. Achenbach syndrome (paroxysmal finger hematoma). Vasc Med 2019; 24: 361–366.

34.

Manappallil

Jayaraj

. Blue finger syndrome: An unusual presentation of rheumatoid arthritis. J Clin Diagn Res 2017; 11: OD06–OD07.

35.

Weinberg

Jaff

. Spontaneous blue finger syndrome: A benign process. Am J Med 2012; 125: e1–e2.

36.

Flavahan

. A vascular mechanistic approach to understanding Raynaud phenomenon. Nat Rev Rheumat 2015; 11: 146.

37.

Jobe

Beetham

Jr Roberts

, et al. Induced vasodilation as a home treatment for Raynaud’s disease. J Rheumatol 1985; 12: 953–956.

38.

Cardelli

Kleinsmith

. Raynaud’s phenomenon and disease. Med Clin North Am 1989; 73: 1127–1141.

39.

Thompson

Pope

. Calcium channel blockers for primary Raynaud’s phenomenon: A meta-analysis. Rheumatology 2005; 44: 145–150.

40.

Rirash

Tingey

Harding

, et al. Calcium channel blockers for primary and secondary Raynaud’s phenomenon. Cochrane Database Syst Rev 2017; 12: CD000467.

41.

Landry

. Current medical and surgical management of Raynaud’s syndrome. J Vasc Surg 2013; 57: 1710–1716.

42.

Wollersheim

Thien

Fennis

, et al. Double-blind, placebo-controlled study of prazosin in Raynaud’s phenomenon. Clin Pharmacol Ther 1986; 40: 219–225.

43.

Pope

Fenlon

Thompson

, et al. Prazosin for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2000; 1998: CD000956.

44.

Roustit

Blaise

Allanore

, et al. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: Systematic review and meta-analysis of randomised trials. Ann Rheum Dis 2013; 72: 1696–1699.

45.

Hachulla

Hatron

P-Y

Carpentier

, et al. Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: The placebo-controlled SEDUCE study. Ann Rheum Dis 2016; 75: 1009–1015.

46.

Curtiss

Schwager

Cobos

, et al. A systematic review and meta-analysis of the effects of topical nitrates in the treatment of primary and secondary Raynaud’s phenomenon. J Am Acad Dermatol 2018; 78: 1110–1118.e3.

47.

Hughes

Moore

Manning

, et al. Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate. Microvasc Res 2017; 111: 32–36.

48.

Pintea Bentea

Wauters

Wautrecht

J-C

, et al. Laser Doppler imaging evaluation of nitroglycerin patch application in systemic sclerosis patients. Vasc Med 2020; 25: 559–568.

49.

Korn

Mayes

Matucci Cerinic

, et al. Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004; 50: 3985–3993.

50.

Matucci-Cerinic

Denton

Furst

, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: Results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2011; 70: 32–38.

51.

Khanna

Denton

Merkel

, et al. Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis: DUAL-1 and DUAL-2 randomized clinical trials. JAMA 2016; 315: 1975–1988.

52.

Bose

Bena

Chatterjee

. Evaluation of the effect of ambrisentan on digital microvascular flow in patients with systemic sclerosis using laser Doppler perfusion imaging: A 12-week randomized double-blind placebo controlled trial. Arthritis Res Ther 2015; 17: 44.

53.

Wigley

Korn

Csuka

, et al. Oral iloprost treatment in patients with Raynaud’s phenomenon secondary to systemic sclerosis: A multicenter, placebo-controlled, double-blind study. Arthritis Rheum 1998; 41: 670–677.

54.

Pope

Fenlon

Thompson

, et al. Iloprost and cisaprost for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2000; 1998: CD000953.

55.

Mannava

Plate

Stone

, et al. Recent advances for the management of Raynaud phenomenon using botulinum neurotoxin A. J Hand Surg 2011; 36: 1708–1710.

56.

Neumeister

. The role of botulinum toxin in vasospastic disorders of the hand. Hand Clin 2015; 31: 23–37.

57.

Thune

Ladegaard

Licht

. Thoracoscopic sympathectomy for Raynaud’s phenomenon—A long term follow-up study. Eur J Vasc Endovasc Surg 2006; 32: 198–202.

58.

Khouri

Lepelley

Bailly

, et al. Comparative efficacy and safety of treatments for secondary Raynaud’s phenomenon: A systematic review and network meta-analysis of randomised trials. Lancet Rheumatol 2019; 1: e237–e246.

59.

Davis

. Clinical aspects of acrocyanosis. Adv Microcirc 1982; 10: 101–119.

60.

*Kurklinsky

Miller

Rooke

. Acrocyanosis: The flying Dutchman. Vasc Med 2011; 16: 288–301.

61.

Hallam

. The relationship between erythema pernio and acrocyanosis. Med Press Circ 1930; 129: 408–412.

62.

Carpentier

. Definition and epidemiology of vascular acrosyndromes. Rev Prat 1998; 48: 1641–1646.

63.

Boas

. The capillaries of the extremities in acrocyanosis: Blood pressure and morphology. JAMA 1922; 79: 1404–1406.

64.

Bollinger

Mahler

Meier

. Velocity patterns in nailfold capillaries of normal subjects and patients with Raynaud’s disease and acrocyanosis. Bibl Anat 1977(16 Pt 2): 142–145.

65.

Bollinger

. Function of the precapillary vessels in peripheral vascular disease. J Cardiovasc Pharmacol 1985; 7: S147–151.

66.

Mangiafico

Malatino

Santonocito

, et al. Plasma endothelin-1 concentrations during cold exposure in essential acrocyanosis. Angiology 1996; 47: 1033–1038.

67.

Lewis

Landis

. Observations upon the vascular mechanism in acrocyanosis. Heart 1930; 15: I930.

68.

Sivula

. Vascular reactions in acrocyanosis. Angiology 1966; 17: 269–274.

69.

Heidrich

. Functional vascular diseases: Raynaud’s syndrome, acrocyanosis and erythromelalgia. Vasa 2010; 39: 33–41.

70.

Masuda

Mori

Araki

, et al. Bilateral foot acrocyanosis in an interferon-β-treated MS patient. Intern Med 2016; 55: 319.

71.

Zhang

Jin

Cai

, et al. Amphotericin B liposome-induced acrocyanosis and elevated serum creatinine. Indian J Pharmacol 2016; 48: 321–323.

72.

Engel

Hopenhayn-Rich

Receveur

, et al. Vascular effects of chronic arsenic exposure: A review. Epidemiol Rev 1994; 16: 184–209.

73.

Mak

. Prostacyclin production in vascular endothelium of patients with Blackfoot disease. Adv Exp Med Biol 1988; 242: 119–125.

74.

Eberhardt

. Acrocyanosis. In: Creager

Beckman

Loscalzo

(eds) Vascular Medicine: A Companion to Braunwald’s Heart Disease. 3rd edition. Philadelphia, PA: Elsevier Saunders, 2013: 640–643.

75.

Lata

Janardhanan

. Methemoglobinemia: A diagnosis not to be missed. Am J Med 2015; 128: e45–e46.

76.

Monticone

Colonna

Palermi

, et al. Quantitative nailfold capillary microscopy findings in patients with acrocyanosis compared with patients having systemic sclerosis and control subjects. J Am Acad Dermatol 2000; 42: 787–790.

77.

Kakimura

. Comparative studies of the effects of alpha-tocopheryl nicotinate and the combination alpha-tocopheryl acetate and nicotinic acid. J Nutr Sci Vitaminol (Tokyo) 1973; 19: 375–381.

78.

Holti

. Experimentally controlled evaluation of vasoactive drugs in digital ischemia. Angiology 1978; 29: 89–94.

79.

Morrish

Crockford

. Acrocyanosis treated with bromocriptine. Lancet 1976; ii: 851.

80.

Olin

. Vascular diseases related to extremes in environmental temperature. In: Young

Olin

Bartholomew

(eds) Peripheral Vascular Diseases. 2nd edition. St Louis: Mosby-Year Book, 1996: 607–620.

81.

Herman

Kezis

Silvers

. A distinctive variant of pernio: Clinical and histopathologic study of nine cases. Arch Dermatol 1981: 117: 26–28.

82.

Jacob

Weisman

Rosenblatt

, et al. Chronic pernio. A historical perspective of cold-induced vascular disease. Arch Intern Med 1986; 146: 1589–1592.

83.

Simon

Soep

Hollister

. Pernio in pediatrics. Pediatrics 2005; 116: e472–e475.

84.

Almahameed

Pinto

. Pernio (chilblains). Curr Treat Options Cardiovasc Med 2008; 10: 128–135.

85.

Olin

AlMahameed

. Pernio (chilblains). In: Creager

Beckman

Loscalzo

(eds) Vascular Medicine: A Companion to Braunwald’s Heart Disease. 2nd edition. Philadelphia, PA: Elsevier Saunders, 2013, 613–617.

86.

White

Rothe

Milanese

, et al. Perniosis in association with anorexia nervosa. Pediatr Dermatol 1994; 11: 1–5.

87.

Rustin

Foreman

Dowd

. Anorexia nervosa associated with acromegaloid features, onset of acrocyanosis and Raynaud’s phenomenon and worsening of chilblains. J R Soc Med 1990; 83: 495–496.

88.

Reinertsen

. Unusual pernio-like reaction to sulindac. Arthritis Rheum 1981; 24: 1215.

89.

Winner

Cooper-Willis

. Chilblains in servicewomen. Lancet 1946; ii: 663–667.

90.

Cappel

Wetter

. Clinical characteristics, etiologic associations, laboratory findings, treatment, and proposal of diagnostic criteria of pernio (chilblains) in a series of 104 patients at Mayo Clinic, 2000 to 2011. Mayo Clin Proc 2014; 89: 207–215.

91.

Purdue

Hunt

. Cold injury: A collective review. J Burn Care Rehabil 1986; 7: 331–342.

92.

Crowson

Magro

. Idiopathic perniosis and its mimics: A clinical and histological study of 38 cases. Hum Pathol 1997; 28: 478–484.

93.

Cribier

Djeridi

Peltre

, et al. A histologic and immunohistochemical study of chilblains. J Am Acad Dermatol 2001; 45: 924–929.

94.

Boada

Bielsa

Fernandez-Figueras

, et al. Perniosis: Clinical and histopathological analysis. Am J Dermatopathol 2010; 32: 19–23.

95.

Lewis

. Observations on some normal and injurious effects of cold upon the skin and underlying tissues: II. Chilblains and allied conditions. Br Med J 1941; 2: 837–839.

96.

Whitman

Crane

. Pernio. In: StatPearls. Treasure Island, FL: StatPearls Publishing, 2020.

97.

Battesti

El Khalifa

Abdelhedi

, et al. New insights in COVID-19-associated chilblains: A comparative study with chilblain lupus erythematosus. J Am Acad Dermatol 2020; 83: 1219–1222.

98.

Dowd

Rustin

Lanigan

. Nifedipine in the treatment of chilblains. Br Med J (Clin Res Ed) 1986; 293: 923–924.

99.

Rustin

Newton

Smith

, et al. The treatment of chilblains with nifedipine: The results of a pilot study, a double-blind placebo-controlled randomized study and a long-term open trial. Br J Dermatol 1989; 120: 267–275.

100.

Verma

. Topical nitroglycerine in perniosis/chilblains. Skinmed 2015; 13: 176–177.

101.

Al-Sudany

. Treatment of primary perniosis with oral pentoxifylline (a double-blind placebo-controlled randomized therapeutic trial). Dermatol Ther 2016; 29: 263–268.

102.

Yang

Perez

English

3rd . Successful treatment of perniosis with hydroxychloroquine. J Drugs Dermatol 2010; 9: 1242–1246.

103.

Ganor

. Corticosteroid therapy for pernio. J Am Acad Dermatol 1983; 8: 136.

104.

Ehrmann

. Ein gefaessprozess bei lues. Wien Med Wochenschr 1907; 57: 777–782.

105.

Kraemer

Linden

Berlit

. The spectrum of differential diagnosis in neurological patients with livedo reticularis and livedo racemosa. A literature review. J Neurol 2005; 252: 1155–1166.

106.

Dean

. Livedo reticularis and related disorders. Curr Treat Options Cardiovasc Med 2011; 13: 179–191.

107.

Fleischer

Resnick

. Livedo reticularis. Dermatol Clin 1990; 8: 347–354.

108.

Shulman

Minagar

Sharma

, et al. Amantadine-induced peripheral neuropathy. Neurology 1999; 53: 1862.

109.

Flombaum

Mouradian

Casper

, et al. Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine. Am J Kidney Dis 1999; 33: 555–562.

110.

Gross

Thompson

Arzubiaga

MDC

, et al. Heparin-associated thrombocytopenia and thrombosis (HATT) presenting with livedo reticularis. Int J Dermatol 1993; 32: 276–279.

111.

Freeman

Dover

, eds. Autonomic neurodermatology (Part I): Erythromelalgia, reflex sympathetic dystrophy, and livedo reticularis. Semin Neurol 1992; 12: 385–393.

112.

Asherson

Mayou

Merry

, et al. The spectrum of livedo reticularis and anticardiolipin antibodies. Br J Dermat 1989; 120: 215–221.

113.

Cervera

Piette

Font

, et al. Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46: 1019–1027.

114.

Ryan

. The ageing of the blood supply and the lymphatic drainage of the skin. Micron 2004; 35: 161–171.

115.

Gibbs

English

III Zirwas

. Livedo reticularis: An update. J Am Acad Dermatol 2005; 52: 1009–1019.

116.

Francès

Niang

Laffitte

, et al. Dermatologic manifestations of the antiphospholipid syndrome: Two hundred consecutive cases. Arthritis Rheum 2005; 52: 1785–1793.

117.

Toubi

Krause

Fraser

, et al. Livedo reticularis is a marker for predicting multi-system thrombosis in antiphospholipid syndrome. Clin Exp Rheumatol 2005; 23: 499–504.

118.

Henkin

Creager

. Raynaud phenomenon. In: Creager

Beckman

Loscalzo

(eds) Vascular Medicine: A Companion to Braunwald’s Heart Disease. 3rd edition. Philadelphia, PA: Elsevier, 2020, 625–639.

119.

Flavahan

Cooke

Shepherd

, et al. Human postjunctional alpha-1 and alpha-2 adrenoceptors: Differential distribution in arteries of the limbs. J Pharmacol Exp Ther 1987; 241: 361–365.

120.

Chotani

Mitra

, et al. Regulation of α₂-adrenoceptors in human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 2004; 286: H59–67.

121.

Coffman

. Pathogenesis and treatment of Raynaud’s phenomenon. Cardiovasc Drugs Ther 1990; 4(Suppl 1): 45–51.

122.

Freedman

Baer

Mayes

. Blockade of vasospastic attacks by alpha 2-adrenergic but not alpha 1-adrenergic antagonists in idiopathic Raynaud’s disease. Circulation 1995; 92: 1448–1451.

123.

Coffman

Cohen

. Role of alpha-adrenoceptor subtypes mediating sympathetic vasoconstriction in human digits. Eur J Clin Invest 1988; 18: 309–313.

124.

Mohokum

Hartmann

Schlattmann

. The association of Raynaud syndrome with beta-blockers: A meta-analysis. Angiology 2012; 63: 535–540.

125.

*Wigley

. Raynaud’s phenomenon. N Engl J Med 2002; 347: 1001–1008.

126.

*Belch

Carlizza

Carpentier

, et al. ESVM guidelines – The diagnosis and management of Raynaud’s phenomenon. Vasa 2017; 46: 413–423.

Raynaud’s phenomenon and related vasospastic disorders

Abstract

Keywords

Introduction

Raynaud’s phenomenon

Clinical presentation

Epidemiology

Pathophysiology

Diagnosis

Treatment

Acrocyanosis

Clinical presentation

Epidemiology

Pathophysiology

Diagnosis

Treatment

Pernio

Clinical presentation

Epidemiology

Pathophysiology

Diagnosis

Treatment

Livedo reticularis

Clinical presentation

Epidemiology

Pathophysiology

Diagnosis

Treatment

Summary

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

References