Pediatric Raynaud Phenomenon 

Updated: Jun 23, 2022
Author: Suzanne C Li, MD, PhD; Chief Editor: Lawrence K Jung, MD 

Overview

Practice Essentials

Raynaud phenomenon (RP) was first described by Maurice Raynaud in 1862 and refers to a transient vasospasm of peripheral arteries and arterioles that classically results in triphasic color changes in the affected region.[1, 2, 3, 4]  The initial artery and arteriole vasospasm causes pallor (white), followed by cyanosis (blue) due to dilation of the capillaries and venous stasis (deoxygenated blood), with continued artery and arteriole vasospasm. The arteries and arterioles then dilate, causing rapid return of blood flow (red, reactive hyperemia).[1, 2, 5]  The fingers are the most commonly affected region, and Raynaud phenomenon is typically triggered by cold exposure or stress.[2, 6, 7, 8]

See the image below.

Raynaud phenomenon showing demarcation of color di Raynaud phenomenon showing demarcation of color difference.

Raynaud phenomenon can be primary (idiopathic), meaning no associated diseases are present (about 80-90% of cases), or secondary, meaning that another condition is believed to be the cause of the Raynaud phenomenon.[2, 9, 10]  Connective tissue diseases are the most common cause of secondary Raynaud phenomenon, but several medications and many other conditions are also associated with Raynaud phenomenon.[11, 12, 13]

In the past, Raynaud phenomenon had been referred to as Raynaud syndrome, with Raynaud disease referring to primary Raynaud phenomenon, and Raynaud phenomenon referring to secondary Raynaud phenomenon; however, these terms were often used interchangeably.[14, 15, 2]  The current preferred terminology of primary and secondary Raynaud phenomenon was proposed by LeRoy and Medsger in 1992.[16]  Primary Raynaud phenomenon rarely leads to significant problems and does not usually need to be treated with medications. In contrast, secondary Raynaud phenomenon, especially when associated with scleroderma-related diseases, often causes irreversible digital ischemia, resulting in the development of digital ulcers or even digital amputation.[2, 6, 9]

Pathophysiology

The pathophysiology of Raynaud phenomenon is not completely understood; the vasospasm that occurs in the digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts involves both central and peripheral mechanisms.[2, 4, 12, 17, 18] The pathophysiology of secondary Raynaud phenomenon also involves structural changes to the vasculature that worsens the severity of the Raynaud phenomenon.

Raynaud phenomenon can be thought of as an exaggerated normal response to cold and emotional stress.[9, 19] The skin of the digits is supplied by both thermoregulatory and nutritional blood flow. Blood flow to the skin is decreased in response to cold environmental temperatures and is increased in response to warm temperatures.[5] This thermoregulation is controlled by the sympathetic nervous system, which regulates flow through the arteriovenous shunts.[5] In contrast, nutritive flow is constant and is supplied by a capillary network.[5]

Primary Raynaud phenomenon rarely affects the nutritive flow, whereas secondary Raynaud phenomenon can cause digital artery vasospasm severe enough to block the nutritive flow, leading to tissue hypoxia and ischemia.[5] Patients with Raynaud phenomenon have a decrease in digital blood flow rates and a longer lag time before peak blood flow returns following cold exposure compared with normal controls; patients with secondary Raynaud phenomenon have a greater defect than patients with primary Raynaud phenomenon.[2, 17, 12] Patients with Raynaud phenomenon have a defective pattern of flow in response to digit cooling.[18]

Structural vascular defects in patients with secondary Raynaud phenomenon who have systemic sclerosis include endothelial cell apoptosis (due to repeated ischemia and antiendothelial cell antibodies), upregulation of adhesion molecules, formation of fibrous intimal lesions, intimal proliferation, capillary enlargement and atrophy, obliteration of vessel patency by perivascular fibrosis or thrombus formation, and defective vascular remodeling and arteriogenesis.[20, 5, 21, 12, 4]

Functional vascular defects include impaired endothelial-dependent vasodilation, decreased production of vasodilator substances (increased production of endothelial nitric oxide synthetase inhibitor), and increased production of vasoconstrictors such as endothelin-1 and angiotensin II in systemic sclerosis patients.[4, 12]

A study that assessed microcapillary status and serum concentrations of chosen cytokines, adhesive molecules, and nitric oxide in pediatric patients with primary Raynaud syndrome and secondary Raynaud syndrome found that external factor-induced vasoconstrictive effects dominated in primary Raynaud syndrome, whereas in secondary Raynaud syndrome in the course of connective tissue diseases, it was accompanied by coexistent vasodilation due to endothelial dysfunction which was partially dependent on insufficient nitric oxide release.[22]

Raynaud phenomenon patients also show impairments in neural regulation of vascular tone. Both primary Raynaud phenomenon and secondary Raynaud phenomenon patients have decreased levels of calcitonin gene–related peptide (CGRP), a potent vasodilator released from sensory afferents.[12] The level of vasodilator vasoactive intestinal peptide has also been found to be lower in Raynaud phenomenon patients.[4] Systemic sclerosis patients have increased levels of one of the adrenergic a2 receptor subtypes in skin arterioles, which leads to increased reactivity and vasoconstriction in response to cold.[4, 12]

Intravascular defects associated with Raynaud phenomenon include the following[4, 12, 23] :

  • Platelet activation - Present in both primary Raynaud phenomenon and secondary Raynaud phenomenon; leads to increased levels of the vasoconstrictors thromboxane A2 and serotonin and other substances that can contribute to inflammation or angiogenesis such as platelet microparticles and platelet-derived growth factor

  • Defective fibrinolysis - Found in patients with secondary Raynaud phenomenon; can lead to fibrin deposition and obstruction of vasculature

  • WBC activation - Found in both primary Raynaud phenomenon and secondary Raynaud phenomenon; leads to damage from oxidative stress

  • Decreased RBC deformability - Found in secondary Raynaud phenomenon; can lead to impairment of blood flow

  • Increased blood viscosity - Found in both primary Raynaud phenomenon and secondary Raynaud phenomenon; can lead to impaired blood flow

  • Oxidative stress - Triggered by ischemic episodes; decreased levels of antioxidants found in both primary Raynaud phenomenon and secondary Raynaud phenomenon (Free radicals can trigger neutrophil activation, and oxidative stress can lead to further endothelial damage.)[24]

Raynaud phenomenon is thought to be a polygenic phenomenon. About one fourth of patients with primary Raynaud phenomenon have a family history of Raynaud phenomenon in a first-degree relative; secondary Raynaud phenomenon also occurs more frequently in families with a history of Raynaud phenomenon or connective tissue disease.[2] Raynaud phenomenon is also known to be associated with migraine headaches; recently, a genetic locus for migraines and Raynaud phenomenon, 3p21.1-p21.3, was identified in a Dutch family.[25] A genome screen in 6 extended families with multiple cases of Raynaud phenomenon identified 3 potential genes associated with primary Raynaud phenomenon.[26]

Etiology

Cold exposure was the reported trigger in 90% of patients with primary Raynaud phenomenon and secondary Raynaud phenomenon; 3% of patients with primary Raynaud phenomenon and 10% of patients with secondary Raynaud phenomenon reported that stress triggered the episode.[6]  Jones et al did not find any associated psychosocial or social variables, such as socioeconomic status, conduct problems, or peer problems.[27]  In addition, 5% of pediatric patients with primary Raynaud phenomenon and none of the patients with secondary Raynaud phenomenon reported episodes precipitated by exercise, and 14% of patients with primary Raynaud phenomenon and 7% of patients with secondary Raynaud phenomenon said no trigger was known for some of episodes.[28]

Besides outdoor cold exposure, cold stresses can include taking items out of the freezer, sitting in air conditioning, and coming out of an outdoor swimming pool. Combined cold and wet exposure, as occurs in spring and fall seasons, can also precipitate Raynaud phenomenon episodes.[29]

Factors reported to exacerbate or to be associated with Raynaud phenomenon include the following:

  • Immune-mediated conditions

    • Scleroderma (limited systemic sclerosis, CREST syndrome, diffuse systemic sclerosis)[11, 15, 30]

    • Mixed connective tissue disease[11, 15]

    • Systemic lupus erythematosus[11, 15, 30]

    • Dermatomyositis[11, 30]

    • Eosinophilic fascitis[31]

    • Juvenile idiopathic arthritis[15, 30]

    • Undifferentiated connective tissue disease[30]

    • Sjögren syndrome[11, 15]

    • Primary vasculitis[30]

    • Arteritis (eg, giant cell, Takayasu)[11]

    • Cryoglobulinemia, cryofibrinogenemia[11, 17]

    • Antiphospholipid syndrome[11]

    • Primary biliary cirrhosis[11]

  • Occupation/activity-related factors

    • Vibrating equipment or instruments[11, 29, 32]

    • Working in a cold area (eg, working with frozen foods or in outdoor situations)[11]

    • High level of repetitive hand movements in work[33]

    • High psychological demand of the work[33]

    • Polyvinyl chloride exposure[5, 11, 17]

  • Obstructive vasculopathy

    • Pressure from using crutches[1, 11]

    • Atherosclerosis[1, 11, 17]

    • Microemboli[11]

    • Thromboangiitis obliterans[11, 17]

    • Thoracic outlet syndrome[11, 17]

    • Carpal tunnel syndrome[1, 11]

    • Diabetic microangiopathy[11]

  • Metabolic disorders

    • Hypothyroidism [11, 17]

    • Carcinoid syndrome[11, 17]

    • Pheochromocytoma [11, 17]

    • Uremia[11]

  • Drug/chemical factors

    • Beta-adrenergic blocking drugs[11, 34]

    • Chemotherapeutic drugs (eg, bleomycin, cisplatin/carboplatin, vinblastine/vincristine)[5, 17, 35]

    • Lead[36]

    • Cyclosporine[5, 11]

    • Interferons[11, 37]

    • Estrogen[5]

    • Cocaine[5]

    • Nicotine[5, 34]

    • Ergotamine derivatives[5, 11]

    • Sulfasalazine[11]

    • Toxic oil[38]

  • Infections

    • Chronic viral liver disease[11, 39, 37]

    • Cytomegalovirus [11]

    • Parvovirus[11]

    • Helicobacter pylori [11]

  • Miscellaneous factors

    • Arteriovenous fistula[11, 17]

    • Artificial acrylic nails[11]

    • Neoplasm (Raynaud phenomenon may precede acute lymphoblastic leukemia.)[11, 17, 40]

    • Carney complex[41]

    • Complex regional pain syndrome I (reflex sympathetic dystrophy)[17]

    • Fibromyalgia [11]

    • Polycythemia [11, 17]

    • Anorexia, weight loss (underweight)[28]

    • Hypermobility[42, 43]

    • Frostbite [44]

    • Familial cold autoinflammatory syndrome (FCAS)[45]

Epidemiology

Only one pediatric study has been done to assess the prevalence of pediatric Raynaud phenomenon. Jones et al surveyed 720 British school children aged 12-15 years to determine the prevalence of Raynaud phenomenon and its association with other problems.[27] Surveys containing color pictures were shown to the students who were asked to identify which picture corresponded with their digit color during episodes of cold sensitivity. The students were required to identify a distinct demarcation of color difference and the presence of digital pallor. The students also had to answer affirmatively to the following questions:[27]

  • “Do your fingers change color in cold at least once per month?”

  • “Have your fingers become numb or felt tingly or like pins and needles in the cold?”

The overall prevalence was 14.9%; an 18% prevalence was reported in the girls, and a 12% prevalence was reported in the boys.[27] Prevalence increased with age, especially in girls (9.8-14.3% in boys; 11.4-44% in girls).[27]

A review of Raynaud phenomenon from 10 international sites reported that 2.2% of 1247 patients had onset of primary Raynaud phenomenon within the first decade of life, and 19.9% had onset within the second decade of life (2.8-55.6% range for onset within the first 2 decades of life).[46]

The pediatric prevalence is similar to that reported in adults. Overall adult prevalence ranges from 3-20%, with higher rates found in females than in males, and higher rates found in colder climates.[47] A prospective community-based adult study found an incidence of Raynaud phenomenon of 2.2% for females and 1.5% for males, and a prevalence of 11% for middle aged women and 8% for middle aged men.[48]

In a review of outpatient clinic and hospital admission records, 69% of pediatric patients had primary Raynaud phenomenon, and 28% had secondary Raynaud phenomenon.[6] One study of 250 pediatric patients with Raynaud phenomenon (mean age, 15 y) reported 76% of patients had primary Raynaud phenomenon and 24% had secondary Raynaud phenomenon.[49] An additional study of 27 pediatric patients with Raynaud phenomenon reported 33% of patients had primary Raynaud phenomenon, 15% had probable secondary Raynaud phenomenon, and 52% had secondary Raynaud phenomenon.[15]

The frequency of Raynaud phenomenon in patients with different connective tissue diseases is as follows:

  • Systemic sclerosis – 84% in the pediatric population; 90% in adults[50, 29]

  • Systemic lupus erythematosus – 10% in the pediatric population; 30% in adults[51, 29]

  • Mixed connective tissue disease – 50% in the pediatric population; 85% in adults[52, 30, 11]

Adult patients with rheumatoid arthritis were reported to have a 20% prevalence of Raynaud phenomenon, and adult patients with Sjögren syndrome had a 13% prevalence of Raynaud phenomenon.[9]

Race-, sex-, and age-related demographics

Race

Few studies have examined racial predominance in Raynaud phenomenon; Raynaud phenomenon has been reported worldwide, with no reported racial difference.[47] In one pediatric study of 27 patients, patients with primary Raynaud phenomenon were predominantly white, whereas no racial predominance was seen in patients with secondary Raynaud phenomenon.[15]

Sex

Females are more commonly affected than males. Most studies report a female-to-male ratio of 3-4:1.[15, 6, 49] No difference has been reported in the female-to-male ratio of primary Raynaud phenomenon and secondary Raynaud phenomenon incidence.[15, 6, 49]

Adult studies generally report a female-to-male ratio of 2-4:1. Some studies have reported a higher prevalence in males than in females, but this is believed to reflect secondary disease related to vibration or other occupational trauma; when these patients are excluded, females with Raynaud phenomenon greatly outnumber males with Raynaud phenomenon.[53]

The prevalence of Raynaud phenomenon in adult males and females in different countries is as follows:

  • United States - 4.3% in females, 2.7% in males;[46] 11% in females, 8% in males[48]

  • United Kingdom - 19% in females, 11% in males[54]

  • Italy - 3.4% in females, 0.5% in males[55]

  • Hungary - 5.3% in females, 7.7% in males[56]

  • Japan - 2.5% in females, 3.3% in males[46]

Age

Two pediatric studies reported a similar mean age of onset. Nigrovic et al reported primary Raynaud phenomenon had a mean age of onset of 12.2 (± 4.3) years, whereas secondary Raynaud phenomenon had a mean age of onset of 12.7 (± 4.4) years, with a range of 1-19 years.[28] Duffy et al reported a mean age of onset for their mixed population of patients with primary Raynaud phenomenon and Raynaud phenomenon of 11.7 years, with a range of 1.8-17.6 years.[15]

Adult studies have reported that Raynaud phenomenon starts at a younger age in colder regions than in warmer regions; 42.3% of patients with Raynaud phenomenon had onset at younger than 20 years in the coldest region studied compared with 20.4% of patients in warmer locations.[57, 47] A younger age of onset (< 20 y) was reported to be more common in patients with primary Raynaud phenomenon than in those with secondary Raynaud phenomenon, but a large overlap in ages was noted between these 2 groups; these authors reported that reactive hyperemia at the end of attack and discoloration of the earlobes and nose were also more likely to be associated with primary Raynaud phenomenon than with secondary Raynaud phenomenon.[58]

Prognosis

The prognosis is good for patients with primary Raynaud phenomenon. An adult community study found 36% of primary Raynaud phenomenon patients had persistent disease, while 64% of primary Raynaud phenomenon patients had resolution of this problem within 7 years.[48]

The prognosis can be poor for patients with secondary Raynaud phenomenon whose underlying disease is a scleroderma-related condition or systemic lupus erythematosus.[9]  Other connective tissue diseases may also be associated with a poor outcome.

Morbidity/mortality

Morbidity is related to the severity and duration of the Raynaud phenomenon episode. When pallor is present, ischemia is more likely than cyanosis; no ischemia is associated with the reactive hyperemia phase. Severe pain suggests that the vasospasm is affecting nutritional flow.[5]  Although patients with primary Raynaud phenomenon do not usually experience significant morbidity due to Raynaud phenomenon, pediatric studies have reported digital ulcers and even gangrene.[59, 14, 6]  Patients with limited systemic sclerosis or calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias (CREST) syndrome are at greater risk for digital ischemia than those with diffuse systemic sclerosis; 20% of patients with limited systemic sclerosis have been reported to lose at least one digit due to Raynaud phenomenon.[2]

Morbidity in patients with Raynaud phenomenon syndrome includes the following:

  • Altered sensation: Paresthesia, numbness, and pain were reported in as many as 67% of pediatric patients with primary Raynaud phenomenon and 63% of those with pediatric secondary Raynaud phenomenon.[6]

  • Digital pits: A shallow divot in the tip of the digit due to ischemia is found in 2% of pediatric patients with primary Raynaud phenomenon and 15% of pediatric patients with secondary Raynaud phenomenon.[6]

  • Digital ulcerations: A deeper and more extensive loss of tissue on the digit tip due to ischemia is found in 5% of pediatric patients with primary Raynaud phenomenon and 18% of pediatric patients with secondary Raynaud phenomenon.[28]  Digital ulcers have been reported in 30-50% of adult patients with scleroderma.[29]

  • Poor wound healing in digits: In pediatric patients with primary Raynaud phenomenon, the prevalence of poor wound healing in digits was 2%; in pediatric patients with secondary Raynaud phenomenon, a prevalence of 6% was reported.[6]

  • Digital gangrene: Severe ischemia results in tissue necrosis with gangrene; self-amputation may occur or surgical debridement may be needed. Digital gangrene is reported in 3% of pediatric patients with secondary Raynaud phenomenon and was not reported in pediatric patients with primary Raynaud phenomenon in the largest pediatric series.[6]  Early studies reported of pediatric patients with primary Raynaud phenomenon who developed digital gangrene; however, the authors did not comment on nailfold capillary examination. Therefore, some of these patients may have represented slowly evolving secondary Raynaud phenomenon.[14, 59]

  • Hospitalization for Raynaud phenomenon due to need for more intensive treatment: One percent of pediatric patients with primary Raynaud phenomenon are hospitalized for intensive treatment, and 6% of pediatric patients with secondary Raynaud phenomenon are hospitalized for intensive treatment.[28]

A higher frequency of morbidity (eg, digital ulcers, need for hospitalization) was reported in patients with primary Raynaud phenomenon who had antiphospholipid antibodies.[6]

Mortality related to Raynaud phenomenon has not been reported in pediatric patients. Severe Raynaud phenomenon is an indicator of a serious and potentially fatal underlying disease. In adult patients with mixed connective tissue disease, severe Raynaud phenomenon is associated with a higher mortality rate,[60]  whereas late onset of Raynaud phenomenon in adult patients with scleroderma is associated with an increased prevalence of renal and lung disease.[61]

Cold-induced vasospasm of blood vessels in other organs, including the lungs, heart, GI tract, cerebral vascular system, and kidneys, has also been reported in adults.[62, 63, 18]  One adult patient had severe dyspnea related to a coronary artery vasospasm that caused left ventricular heart dysfunction; his symptoms resolved with treatment using a prostacyclin analogue (iloprost).[64]  Another patient had improvement in his left ventricular dyskinesia with nifedipine treatment.[62]  Cold-induced vasospasm of heart (cardiac Raynaud phenomenon) was found to be a predictor for development of systolic left ventricular dysfunction in systemic sclerosis patients.[65]

Complications

Digital pits, digital ulcers, autoamputation or gangrene, infection, and poor wound healing are potential complications. Patients who develop digital ischemia are at risk for further ischemia due to damage to the local circulation.

Patient Education

Patients should be taught to recognize potential triggers and to avoid them when possible.

Patients should be taught to warm-up whenever they feel altered sensation or notice prolonged pallor or cyanosis.

Patients should be taught good digital hygiene and the importance of thoroughly treating peripheral injuries and wounds.

Patients should be instructed about their medications and potential side effects.

For patient education resources, see Raynaud Syndrome.

 

Presentation

History

How Raynaud phenomenon (RP) should be diagnosed is somewhat controversial. Several studies have reported that most patients with Raynaud phenomenon do not have the classic triphasic color pattern. Nigrovic et al reported that only 24% of children with primary Raynaud phenomenon and 19% of children with secondary Raynaud phenomenon had the classic 3 color changes.[6] Maricq et al reported that only 1% of adults who were cold sensitive had triphasic color changes, 37% had white or blue color only, and 6% had 2 color changes.[53]

Diagnosis requires a sharp demarcation of the border between the area affected by Raynaud phenomenon and the unaffected area, and most groups accept having only white or blue color changes with an appropriate history.[53, 18, 2, 9] However, the UK Scleroderma Study Group defined definite Raynaud phenomenon as the presence of 2 color changes in response to cold, and possible Raynaud phenomenon as the presence of uniphasic color change accompanied by numbness or paresthesia.[66] Color charts may aid in the diagnosis; patients are asked to compare their affected digits with those shown in the color chart, not all of which represent Raynaud phenomenon.[57]

Patient history should include affected sites, frequency and severity of attacks, duration of attacks, color pattern, triggers, seasonality, and associated symptoms (ie, numbness, paresthesia, pain).[29] The most commonly affected sites are the fingers, toes, ears, nose, and, rarely, nipples.[1, 18] The triggers of Raynaud phenomenon in children are similar to those described in adults. Cold and emotional stresses are the most common triggers; primary Raynaud phenomenon can also be triggered by exercise.[59, 6] Episodes are more common in the winter than in the summer, and serious ischemia is also more common in the winter.[5]

Secondary Raynaud phenomenon episodes are typically more intense, painful, asymmetric, frequent, and more likely to lead to digital ulcers and scars.[4] Thumb involvement is more suggestive of secondary Raynaud phenomenon than primary Raynaud phenomenon.[67]

Patients and their parents should be queried about changes in digits such as pits, ulcers, or poor healing, and about the presence of infection in affected digits. They should also be asked about possible associated or precipitating factors including frostbite, drug or toxin exposure, infection, vibration injury,[36] family history of Raynaud phenomenon, family history of connective tissue diseases, history of migraine,[25] weight loss or eating disorders, and cardiovascular diseases.

Patients should also be questioned for any history suggestive of connective tissue disease such as fever, weight loss, fatigue, rash (malar, vasculitic, dermatomyositis), morning stiffness, arthralgia, myalgia, dysphagia, peripheral edema, lymphadenopathy, or oral sores.

Physical Examination

A general physical examination should be performed to evaluate for signs suggestive of rheumatic disease or other conditions associated with secondary Raynaud phenomenon. Careful examination of the nailfold capillaries, digit tips, and extremities should be performed to look for signs associated with severe Raynaud phenomenon or signs associated with an increased likelihood of developing secondary Raynaud phenomenon. Pediatric patients with primary Raynaud phenomenon generally have normal nailfold capillary findings.[32]  Nigrovic et al reported that 13% of pediatric patients with primary Raynaud phenomenon had nailfold changes compared with 54% of patients with secondary Raynaud phenomenon.[28]

Digit tips should be examined for pits, ulcers, and healing problems. Other signs potentially associated with rheumatic diseases include livedo reticularis, rash (malar, vasculitic, dermatomyositis), arthritis, skin edema or tightening, abnormal peripheral pulses, weakness, and oral ulcers.

Nailfold capillaries can be examined with an ophthalmoscope set at 10-40 diopters or with an otoscope and a drop of grade B immersion oil or lubricating jelly (eg, Surgilube, K-Y Jelly) placed over the periungual area of each finger,[2]  or with a dermoscope, widefield microscope, or digital video capillaroscope. The examiner must manually zoom in until the nailfold capillaries are clearly visible.

A normal capillary pattern consists of thin, parallel vessels. The earliest feature of a scleroderma spectrum–associated nailfold capillary pattern is symmetrically enlarged giant capillaries. Later signs include microhemorrhages, loss of capillaries (decreased density to avascular areas), and neoangiogenesis.[68]  The presence of any of these features has been found to identify adult primary Raynaud phenomenon patients at high risk for developing a scleroderma spectrum condition and secondary Raynaud phenomenon.[69]  It has therefore been recommended that nailfold capillaroscopy be performed at least once a year in patients with primary Raynaud phenomenon to identify those at risk for evolving to secondary Raynaud phenomenon.[68]

A decrease in capillary density and the presence of giant loops surrounded by avascular areas were only seen in pediatric patients with secondary Raynaud phenomenon in a prospective study of 250 patients.[49]  A sclerodermalike nailfold capillaroscopy pattern was also found in many pediatric patients with dermatomyositis or mixed connective tissue disease, but rarely in those with juvenile idiopathic arthritis, systemic lupus erythematosus, or localized scleroderma.[70]  In systemic lupus erythematosus patients, the development of a sclerodermalike nailfold capillaroscopy pattern was associated with development of lung fibrosis and pulmonary artery hypertension.[69]

 

Workup

Laboratory Studies

Laboratory evaluation should be performed to better evaluate the patient for secondary Raynaud phenomenon (RP). Routine screening to look for inflammation and general organ function should include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), CBC count with differential, comprehensive metabolic panel with plasma creatinine, and urinalysis.

Autoantibody screening can include antinuclear antibody (ANA), anticentromere antibody (ACA), and anti-scl 70 antibody; these autoantibodies have the highest sensitivity for predicting evolution from primary Raynaud phenomenon to secondary Raynaud phenomenon.[71, 9] Most pediatric patients with secondary Raynaud phenomenon have a +ANA (85-100%).[15, 28, 72] However, a significant number of pediatric patients with primary Raynaud phenomenon also have a +ANA.[73, 6] The presence of ACA is associated with the development of CREST syndrome and limited systemic sclerosis in patients with Raynaud phenomenon, whereas anti-scl 70 antibody is associated with the development of diffuse systemic sclerosis.[2, 1]

In adult patients with scleroderma, the presence of ACA is associated with an increased risk for digital ischemia, including ulcers and digit loss.[2]

ACA is rarely found in pediatric systemic sclerosis patients. In adults, presence of systemic sclerosis–specific antibodies with scleroderma pattern of nailfold capillaries is highly associated with progression to systemic sclerosis, with 47% evolving by 5 years, 69% evolving by 10 years, and 79% evolving by 15 years.

Additional autoantibody and complement screening can be performed in patients suspected of having conditions that could evolve to other connective tissue diseases such as systemic lupus erythematosus, mixed connective tissue disease, or Sjögren syndrome. These include anti-Sm, anti-double stranded DNA ab, rheumatoid factor, antiribonucleoprotein, anti-Ro, anti-La, and antiphospholipid antibodies.[28] About 30% of pediatric patients with primary Raynaud phenomenon or secondary Raynaud phenomenon were found to have antiphospholipid antibodies.[28] A study of adult systemic lupus erythematosus patients did not find any association between antiphospholipid antibodies and Raynaud phenomenon occurrence.[74]

Imaging Studies

Nailfold capillaries can be visualized with digital video capillaroscopy, dermoscope, widefield microscope, or handheld ophthalmoscope. An abnormal pattern is more often present in patients with secondary Raynaud phenomenon than in patients with primary Raynaud phenomenon.[15] Nigrovic et al reported that 13% of pediatric patients with primary Raynaud phenomenon had an abnormal pattern compared with 54% of patients with secondary Raynaud phenomenon.[28]

If digital video capillaroscopy is available, then changes in the pattern can be followed because progressive worsening is associated with development of connective tissue disease.[49, 69]

Other imaging techniques include laser Doppler fluxometry (LDF), laser Doppler imaging (LDI), infrared thermography (IT), and Doppler ultrasound. LDF and LDI monitor superficial blood flow; scanning LDI has the advantage over LDF of allowing a large area to be evaluated without requiring surface contact.[75] IT measures surface temperature, which can serve as an indirect assessment of changes in blood flow in response to treatment or cold challenge.[75] A study comparing nailfold capillaroscopy (NFC), LDI, and IT evaluation of primary Raynaud phenomenon, secondary Raynaud phenomenon, and control subjects found all these techniques could differentiate patients with systemic sclerosis secondary Raynaud phenomenon from primary Raynaud phenomenon from control subjects after a cold challenge test.[76] NFC showed the highest level of discrimination, but each test provided additional information.[76]

Doppler ultrasound may be useful for identifying Raynaud phenomenon patients and differentiating primary from secondary Raynaud phenomenon. In one color Doppler study, the authors could distinguish acute vascular occlusion (eg, from antiphospholipid antibodies) from chronic occlusion as would be found in Raynaud phenomenon. Six percent of primary Raynaud phenomenon patients were found to have narrowing or occlusion of some proper digital arteries, compared with 63% of secondary Raynaud phenomenon patients; secondary Raynaud phenomenon patients also had more global involvement than primary Raynaud phenomenon patients.[77]

Another study reported different power Doppler patterns for primary Raynaud phenomenon and secondary Raynaud phenomenon, and that the power Doppler score was better than NFC at identifying secondary Raynaud phenomenon patients (86% vs 50%).[78]

In another study, secondary Raynaud phenomenon patients were found to have narrower radial and digital artery diameters, lower flow volumes at baseline and after cold provocation, and longer times for normalizing flow volumes in digital, ulnar, and radial arteries; these differences had moderate to high sensitivity and high specificity for differentiating primary Raynaud phenomenon from secondary Raynaud phenomenon.[79]

Other Tests

Other testing methods for Raynaud phenomenon include finger systolic blood pressure measurements, Doppler ultrasonography, plethysmography, and cold challenge testing.[15, 75, 32, 9] None of these tests is needed for standard office assessment or monitoring of patients with Raynaud phenomenon.

Other tests, such as chest radiography, pulmonary function tests, ECG, echocardiography, high-resolution lung CT scanning, or GI evaluation, may be needed to evaluate a patient with potentially evolving secondary Raynaud phenomenon.

Procedures such as cold challenge testing are not needed in evaluating or monitoring most patients with Raynaud phenomenon.

Histologic Findings

No permanent pathology is generally associated with primary Raynaud phenomenon except in rare severe causes.[75, 18]

Among patients with secondary Raynaud phenomenon, those with scleroderma have the most severe and most studied pathology. Arterioles and capillaries of 50-500 μm in diameter are affected; the number of capillaries decrease.[80] Vasculature shows endothelial cell swelling, fibrous intimal lesion formation with narrowing of the lumen, inflammatory cell infiltrates, and thickening of the basement membrane; intravascular thrombi may also be present, causing further vessel occlusion.[80, 20] Other changes seen in the skin include cytoskeletal alterations, junctional separation between cells and between cell and matrix, perivascular edema, platelet aggregation, and infiltration of T lymphocytes, mast cells, and dermal dendrocytes.[80]

 

Treatment

Medical Care

Patients with Raynaud phenomenon (RP) should avoid situations and stressors that aggravate the disease (eg, vibration, cold exposure, digital trauma).[5]  Patients should avoid medications and drugs that aggravate the disease (eg, smoking, cocaine, other medications listed above).

Patients need to adequately cover themselves in cold weather by covering core areas (head, trunk) and extremities using hats, layers, mittens, thick socks, and boots. Patients should come in from the cold when they feel a change in digit sensation or when prolonged pallor or cyanosis of the extremities occurs.

Digital wounds should be carefully treated and monitored. Clean wounds twice daily with soap and water, cover with a topical antibiotic ointment (eg, bacitracin, mupirocin [Bactroban]) and then with a light bandage.[5] Systemic antibiotics may be required if the infection worsens. Digital ulceration should be treated in a similar fashion.[5]

The feet should be evaluated for any problems; approximately 10% of adult patients with systemic sclerosis have foot ulcers.[7]

Biofeedback was reported to enable a pediatric patient to raise her digit temperature by 12o C and to aid some adult patients.[1, 17] Trials of biofeedback have yielded mixed results with some reporting benefits and others not. Part of the issue may be that biofeedback can be slow to learn so lack of efficacy may be partly related to patients failing to learn to do it effectively.[7, 5, 81, 82]

Auricular electroacupuncture was reported to decrease the frequency and severity of attacks in primary Raynaud phenomenon patients in an uncontrolled study.[83]

Low-level laser irradiation has also been reported to significantly reduce the frequency and severity of attacks in primary Raynaud phenomenon and secondary Raynaud phenomenon compared with sham irradiation.[84]

Botulinum toxin injection, typically in the vicinity of the palmar digital neurovascular bundle, has been used in both primary and secondary Raynaud syndrome. Improvement in symptoms and healing of digital ulcers has been reported. In one study, some patients derived long-term benefit from a single treatment, whereas in patients with systemic sclerosis, repeat treatments were administered after an average of 6 months.[85, 86]

Surgical Care

Surgical care is needed for serious morbidity problems, including the following[7, 87] :

  • Debridement of necrotic tissue, including infected wounds and osteomyelitis, may be necessary.

  • Amputation of gangrenous digit may be required.

  • Different surgical techniques have been used to improve Raynaud phenomenon symptoms, including balloon angioplasty, venous or arterial grafting, and digital or thorascopic sympathectomy.[88, 82] Sympathetic block can help improve blood flow and is useful for threatened severe digit ischemia.[29]

  • Sympathectomy may be required for intractable ischemia not responsive to medical treatment. Digital artery sympathectomy is more commonly advised compared with cervical sympathectomy because of lower morbidity.[7, 89]

Consultations

A pediatric rheumatologist should be consulted to evaluate patients suspected of having or developing secondary Raynaud phenomenon.

Other subspecialists, such as a hematologist, oncologist, or endocrinologist, should be consulted if the underlying condition for Raynaud phenomenon falls in their domain.

Consultation with a surgeon may be needed for patients with threatened digit ischemia.

Diet and Activity

Diet

No specific diet recommendations are necessary.

Supplements such as fish oil and evening primrose have been reported to be beneficial in limited studies, but additional trials are needed for better evaluation of the effectiveness of these products.[29, 90]  In placebo-controlled trials, neither gingko biloba nor St. John’s Wort were found to provide any significant efficacy.[87]

Activity

Patients should carefully monitor symptoms in situations that may precipitate an episode.

If the patient is involved in winter sports, limiting the duration of continuous cold exposure, wearing layers, and using hand warmers may help.

In the spring and fall seasons, outdoor activity may also precipitate episodes during damp or rainy days.[9]

Patients who participate in activities that may result in digital injury (eg, skateboarding, mountain biking) should wear protective gloves to minimize abrasions and deeper injuries.

 

Medication

Medication Summary

Medications are used to reduce severity of Raynaud phenomenon (RP) episodes if modifications in lifestyle are ineffective. Medications are more likely to be used to treat secondary Raynaud phenomenon rather than primary Raynaud phenomenon. Adult patients with scleroderma and systemic lupus erythematosus generally have the highest risk for developing digital ischemia.[9]

A Cochrane review of oral vasodilators did not find evidence to support the use of any other class of medications besides calcium channel blockers for treating primary Raynaud phenomenon.[91] This was largely due to limited methodology of studies and small number of studied patients.[91] A EULAR review recommended that dihydropyridine-type calcium channel blockers (usually nifedipine) be first-line treatment for Raynaud phenomenon in systemic sclerosis patients, intravenous prostanoids considered for treatment of systemic sclerosis patients with severe Raynaud phenomenon, and bosentan considered for those in whom both calcium channel blockers and prostanoids fail.[92]

A recent report from scleroderma experts found high agreement on using phosphodiesterase inhibitors to treat secondary Raynaud phenomenon not sufficiently responsive to calcium channel blockers.[93]

General categories of medications used to treat Raynaud phenomenon include the following:[17, 7]

  • Vasodilators (eg, calcium channel blockers, nitric oxide [NO] supplementation/NO donors/L-arginine (includes phosphodiesterase inhibitors, topical nitroglycerin), prostanoids, calcitonin gene–related peptides [CGRP], phosphodiesterase inhibitors)

  • Drugs that reduce vasoconstriction (eg, ACE inhibitors, angiotensin II receptor antagonists, α-adrenergic blockers, endothelin-1 receptor antagonists, serotonin reuptake inhibitors)

  • Other drugs with effects on vasculature (eg, antioxidants, statins, rho-kinase inhibitors)

  • Platelet inhibitors affect blood viscosity (eg, salicylates, dipyridamole, prostaglandins, pentoxifylline)

  • Miscellaneous agents (eg, rituximab, anakinra, botulinum toxin A)

Details for the most commonly used drugs (ie, calcium channel blockers, α-adrenergic blockers, nitroglycerin ointment, nitroprusside) are described in the specific medication tables provided below.

Angiotensin inhibitors

ACE inhibitors and angiotensin II receptor blockers can affect endothelial function but randomized placebo-controlled trials of 3 ACE inhibitors (quinapril, captopril, enalapril) have not shown any significant benefit for Raynaud phenomenon patients.[93, 91]

Selective serotonin receptor inhibitors

Serotonin receptor antagonists have been studied in patients with Raynaud phenomenon. Fluoxetine (Prozac) administered at a dose of 20 mg PO qd decreased frequency and severity of primary Raynaud phenomenon and secondary Raynaud phenomenon in adult patients in some studies but did not in others.[7, 5] Their use has not been reported in pediatric patients with Raynaud phenomenon. Dosing for children older than 5 years for other conditions has been 5-10 mg orally daily, not to exceed 20 mg/day.[94]

Ketanserin was not shown to be beneficial for patients with secondary Raynaud phenomenon (patients with systemic sclerosis) in a meta-analysis and is not marketed in the United States or United Kingdom.[7]

Sarpogrelate hydrochloride administered 3 times per day was reported to reduce digital ulcers in systemic sclerosis patients after 3 months in an open-label study.[87]

Prostaglandins

Prostanoids can have several beneficial effects in patients with Raynaud phenomenon including vasodilation, inhibiting platelet aggregation, suppressing profibrotic cytokine connective tissue growth factor, and affecting vascular remodeling.[7]

The prostacyclin analogue iloprost has been shown to be beneficial in reducing the frequency and severity of ischemic attacks and in digital ulcer healing in adult patients with Raynaud phenomenon but only via the intravenous route.[2, 7, 5] Iloprost has been shown to be beneficial in children with Raynaud phenomenon at doses of 2 (±0.3) ng/kg/min IV for 6 h/d for 10.7 (±5.7) days for each cycle.[95] Intravenous iloprost is not available in the United States; only the inhalation product (Ventavis) is available in the United States and is indicated for pulmonary hypertension.[5, 96]

Prostaglandin E1 (alprostadil [Prostin VR]) administered at 6-10 ng/kg/min IV for 72 hours was not found to have a clear benefit in adults with Raynaud phenomenon.[5] However, another study comparing iloprost with alprostadil (20 mcg/h for 5 d, then 1 d/mo) showed similar efficacy between the 2 medications.[97]

Epoprostenol was reported to be beneficial in treating pediatric patients with severe Raynaud phenomenon digital ischemia when administered at 4-20 ng/kg/min IV.[14] The cost and complicated continuous IV infusion limits the clinical use of this agent.

A transdermal prostaglandin analogue, CL115.347.cyanamid (500 mcg q12h) was reported to be helpful in children with Raynaud phenomenon.[14] In adults, 1000 mcg was optimal for treating primary Raynaud phenomenon and secondary Raynaud phenomenon.[98]

Phosphodiesterase inhibitors

Nitric oxide (NO) is a strong vasodilator. Phosphodiesterase inhibitors increase the availability and/or effect of NO and several studies have evaluated their effectiveness for Raynaud phenomenon, primarily secondary Raynaud phenomenon.[87] Most report improvement during the 4- to 6-week treatment periods. A meta-analysis of 6 randomized clinical trials found moderate but significant improvement in symptoms, with insufficient data to evaluate their effectiveness for treating or preventing digital ulcers.[99]

Sildenafil (Revatio, Viagra) has been reported to decrease the frequency, severity, and duration of Raynaud phenomenon attacks and aids in the healing of digital ulcers in adults.[100, 101] Two randomized, double-blind, placebo-controlled trials have been conducted, one using sildenafil 50 mg PO bid in 15 secondary Raynaud phenomenon patients for 4 weeks and another using a modified-release sildenafil at 100 mg PO once a day for 3 days and then dosed at 200 mg/day for a total of 4 weeks in 57 patients with limited systemic sclerosis. Both studies reported improvement, either a decrease in in Raynaud phenomenon symptoms or in frequency of attacks.[100]

Randomized, double-blind, placebo-controlled trials have been conducted of 2 other phosphodiesterase inhibitors, vardenafil and tadalafil. Vardenafil was dosed at 10 mg PO bid in 6 primary and 47 secondary Raynaud phenomenon patients for 6 weeks after being studied in an open-label trial. Both studies reported benefit.[102, 103] Two randomized, double-blind, placebo-controlled trials of tadalafil reported different findings. In one trial, tadalafil dosed at 20 mg/day in 39 secondary Raynaud phenomenon patients for 4 weeks was reported to have no benefit, while in the other, tadalfil was dosed at 20 mg on alternate days in 24 seondary Raynaud phenomenon patients for 6 weeks and reported to decrease symptoms and improve ulcers.[104, 105] Adverse effects of these medicines include flushing and headache.[87]

Dosing of sildenafil for pediatric patients has not been established. A recent study reported a mean dose of 3.4 ± 1.1 mg/kg/d to treat children (aged 4-18 y) with pulmonary hypertension.[106] Tadalafil was given at 1 ± 0.4 mg/kg/day in these patients.[106]

Endothelin inhibitors

Bosentan may be most helpful for secondary Raynaud phenomenon patients with severe vascular disease. It was found to prevent the occurrence of digital ulcers in systemic sclerosis patients in 2 randomized placebo-controlled clinical trials, reducing the occurrence rate by 30% compared to placebo.[107, 108] Bosentan, however, did not improving healing of existing ulcers.[107, 108] Potential adverse effects include liver toxicity and teratogenicity, and it may reduce the effectiveness of hormonal contraceptives.[92]

In adults, it has been dosed at 62.5 mg PO bid for 4 weeks initially, then 125 mg bid for 12 weeks.[107, 108] No information on its use in pediatric Raynaud phenomenon has been reported. Three different dosing regimens were used to treat children (aged 3-15 y) who had pulmonary hypertension.[109] Children who weighed 10-20 kg were treated with 31.25 mg PO bid, those who weighed 20-40 kg were treated with 62.5 mg PO bid, and those who weighed more than 40 kg were treated with 125 mg PO bid.[109] It was used to treat an 11-year-old girl with systemic sclerosis with Raynaud phenomenon and pulmonary hypertension with improvement in both conditions; dosing was begun at 62.5 mg/day, increased to 125 mg/day, and then to 250 mg/day.[110]

Another ET1A-R inhibitor, ambrisentan, was reported effective in a small open-label study and is currently being evaluated in a larger trial.[4]

Antioxidants

Limited studies have been done of antioxidants. Probucol (Lorelco) given at 500 mg PO qd for 12 weeks decreased the frequency and severity of primary Raynaud phenomenon and secondary Raynaud phenomenon episodes in adults and increased their low-density lipoprotein oxidation lag time compared with nifedipine.[111] N -acetylcysteine (NAC) increases levels of glutathione, an endogenous antioxidant, and has also been reported to have vasodilation effects.[112] In an open-label prospective study, 50 systemic sclerosis patients received intravenous NAC 15 mg/kg/hour x 5 hours every 14 days for a median of 3 years and were reported to have a significant decrease in the number of ulcers, decrease in attack symptoms, and over 50% decrease in attack frequency.[112] No major adverse effects were reported.

Miscellaneous agents

Statins may improve endothelial dysfunction, reduce the coagulation of blood, and have anti-inflammatory effects.[113] One randomized placebo-controlled trial has been conducted in 84 systemic sclerosis patients who either received atorvastatin 40 mg/day or placebo for 4 months. Patients who received atorvastatin had a significant decrease in developing new digital ulcers, improved patient function, and showed improvement in endothelial markers of activation.[113] More study is needed to evaluate this class of drugs.

RhoA/Rho kinase inhibitor

A double-blind, placebo-controlled, randomized, cross-over study of a Rho kinase inhibitor did not find a significant difference in digital blood flow between a single dose of fasudil and placebo following a cold challenge.[114]

Other drugs, such as pentoxifylline (Trental), decrease blood viscosity and may help in mild, but not severe, Raynaud phenomenon.[2] An older study reported a reduction in adult Raynaud phenomenon symptoms with subcutaneous low molecular weight heparin, but no follow-up studies have been done.[4]

A few studies have reported that botulinum toxin A can improve blood flow and reduce ischemia, ulceration, and pain in secondary Raynaud phenomenon associated with systemic sclerosis, but studies have been done without controls and using a range of doses.[115] Botulinum toxin may block smooth muscle depolarization and vasoconstriction.[115]

Treatment of the underlying disease can improve Raynaud phenomenon symptoms. Rituximab (Rituxan) was found to decrease severe Raynaud phenomenon symptoms in an adult female with mixed connective tissue disease who had failed treatment with iloprost, bosentan, and tadalafil, and digital sympathectomy. She was treated with rituximab (1000 mg) and had good response with retreatment when her symptoms flared.[116]

The interleukin1-receptor antagonist anakinra was reported to decrease Raynaud phenomenon symptoms in a patient with familial cold autoinflammatory syndrome (FCAS); the anakinra controlled the FCAS symptoms, and no further Raynaud phenomenon episodes occurred while taking anakinra.[45]

Calcium channel blockers

Class Summary

A meta-analysis of all studies using calcium channel blockers (most commonly nifedipine) to treat Raynaud phenomenon reported a benefit, with a moderate reduction in mean number of attacks and a 35% improvement in severity in systemic sclerosis–related Raynaud phenomenon. A smaller, but significant, benefit was observed for primary Raynaud phenomenon.[117, 118] The primary Raynaud phenomenon trials did not use maximum dosage, which may have caused the lesser response.

Most studies involve the dihydropyridine class of calcium channel blockers (eg, amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine).[2, 5] Limited studies suggest felodipine, amlodipine, and isradipine may be as effective as nifedipine, whereas diltiazem and verapamil are less potent.[5] Adverse effects (eg, edema, flushing, tachycardia, headache, hypotension) may occur in 15% of patients.[7, 5, 9]

The adult dose for nifedipine is typically 10-30 mg PO tid/qid for the prompt release formulation or 30-90 mg PO qd for sustained release.[5] In pediatric patients, nifedipine doses may range from 0.2-1 mg/kg/d PO divided tid/qid. Initiate with small doses and increase as tolerated and needed.[14, 119, 1]

Doses of other calcium channel blockers include the following:

- Amlodipine: Administer 2.5-10 mg PO qd initially and adjust as needed up to 20 mg/d in adults.[5] Pediatric dosing for hypertension is 0.1-0.2 mg/kg PO qd but may increase up to 0.3 mg/kg/d.[94]

- Felodipine: Administer 2.5-10 mg PO qd in adults.[120, 5]

- Isradipine: Administer 2.5-10 mg PO qd bid in adults.[5]

- Nicardipine: Administer 50 mg PO qd in adults.[5]

Nifedipine (Procardia)

Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Also causes peripheral vasodilation.

Alpha-adrenergic blockers

Class Summary

Smooth muscle α2-adrenergic receptors respond to the cold and were found to have increased reactivity in patients with systemic sclerosis.[7, 121] A randomized placebo-controlled trial of an α2C -adrenoreceptor antagonist was recently completed. No benefit on digital rewarming following a cold challenge was found from administering a single oral dose of 30 or 100 mg of ORM-12741 to 12 systemic sclerosis patients, with blow flow assessed by temperature probe, LDI, and IT.[122] Other studies on medications that block these receptors are limited.[5, 7]

Phenoxybenzamine was reported to be beneficial in a case series of Raynaud phenomenon in children who were given 0.25-1 mg/kg/d PO divided tid.[14] Adult doses of phenoxybenzamine range from 10 mg PO qid to 30 mg PO tid.[5] Adult doses of prazosin range from 1-3 mg PO bid or tid.[5, 123]

Prazosin (Minipress)

Prazosin treats prostatic hypertrophy. Improves urine flow rates by relaxing smooth muscle, which is caused by blocking α 1-adrenoceptors in the bladder neck and prostate. When increasing dose, administer first dose of each increment at bedtime to reduce syncopal episodes. Although doses >20 mg/d usually do not increase efficacy, some patients may benefit from as much as 40 mg/d.

Phenoxybenzamine (Dibenzyline)

Long-acting, adrenergic, α -receptor blocker that can produce and maintain a chemical sympathectomy. Lowers supine and upright blood pressures. Does not affect the parasympathetic nervous system.

L-arginine and nitric oxide pathway supplementation

Class Summary

NO is a strong vasodilator, L-arginine is precursor for NO, and topical glyceryl trinitrate is an NO donor.[7]

Topical nitrates have been used to decrease frequency and severity of primary Raynaud phenomenon and secondary Raynaud phenomenon.[9] Nitroglycerin 1% ointment has been applied to affected fingers in children with Raynaud phenomenon (< 4 mm/kg) bid or tid as tolerated.[1] In adults, nitroglycerin 2% ointment (0.25-0.50 inch) has been applied locally.[5] The topical glyceryl trinitrate patch can be effective in adults but has a high frequency of systemic adverse effects, which limits its use.[124] A topical preparation of a novel formulation of nitroglycerin MQX-503 was found effective for reducing symptoms in a placebo-controlled trial in secondary and primary Raynaud phenomenon patients, but it is not commercially available.[87, 125]

Intravenous L-arginine and sodium nitroprusside were effective in patients with secondary Raynaud phenomenon.[7] In pediatric patients with Raynaud phenomenon, nitroprusside has been anecdotally given at 0.5-5 mcg/kg/min IV.[14] No benefit was found for PO L-arginine in a trial of adult patients with primary Raynaud phenomenon and secondary Raynaud phenomenon (scleroderma-related).[7]

Nitroglycerin topical (Nitro-Bid ointment)

Causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. The result is vasodilation and decreased blood pressure.

Nitroprusside (Nitropress)

Rapidly acting, easily titrated, antihypertensive. Produces vasodilation and increases inotropic activity of the heart. At higher dosages, may exacerbate myocardial ischemia by increasing heart rate.

Platelet inhibitors

Class Summary

Salicylates are administered to decrease platelet aggregation and activation. No adult trial has shown a clear benefit for their use, but they are still recommended for adult patients with systemic sclerosis (80-975 mg aspirin/d).[5]

Salicylates have also been administered to children with Raynaud phenomenon. Nigrovic et al reported that low-dose aspirin was given to patients with Raynaud phenomenon who had antiphospholipid antibodies.[28] Burns et al reported that salicylates were used in patients whose platelets showed spontaneous aggregation (2.5 mg kg/dose PO every other day or dipyridamole 5 mg/kg/d PO divided tid).[14]

No clear benefit has been demonstrated for low molecular weight heparin in adult studies.[5]

Aspirin

Odorless, white, powdery substance available in 81 mg, 325 mg, and 500 mg for oral use. When exposed to moisture, aspirin hydrolyzes into salicylic acid and acetic acids.

Stronger inhibitor of both prostaglandin synthesis and platelet aggregation than other salicylic acid derivatives. Acetyl group is responsible for inactivation of cyclooxygenase via acetylation. Aspirin is hydrolyzed rapidly in plasma, and elimination follows zero-order pharmacokinetics.

Irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to PGI2 (potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (potent vasoconstrictor and platelet aggregate). Platelet-inhibition lasts for life of cell (approximately 10 d).

May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. Reduces likelihood of myocardial infarction. Also very effective in reducing risk of stroke. Early administration of aspirin in patients with AMI may reduce cardiac mortality in first month.

Dipyridamole (Persantine)

Platelet adhesion inhibitor that possibly inhibits RBC uptake of adenosine, itself an inhibitor of platelet reactivity. In addition, may inhibit phosphodiesterase activity, leading to increased cyclic-3',5'-adenosine monophosphate within platelets and formation of the potent platelet activator thromboxane A2. May enhance effects of aspirin.

 

Follow-up

Further Outpatient Care

Patients with secondary Raynaud phenomenon (RP) should be monitored by a pediatric rheumatologist if their underlying disease is related to a connective tissue disease.

Patients suspected of having a condition that may potentially evolve to secondary Raynaud phenomenon require more careful monitoring than patients with primary Raynaud phenomenon.

In adults, 12-20% of patients whose condition was initially classified as primary Raynaud phenomenon evolved into secondary Raynaud phenomenon over 10 or more years.[126, 127] Nailfold capillary abnormalities, strongly positive ANA, elevated ESR, and additional autoantibodies such as ACA are associated with a 30% frequency of development of secondary Raynaud phenomenon in adult patients within 5 years.[9]

A 20-year prospective study of 586 consecutive patients with Raynaud phenomenon who had no definite rheumatic disease at presentation found 12.6% developed definite systemic sclerosis. A positive systemic sclerosis–specific autoantibody (anticentromere antibody, anti-topoisomerase I, anti-RNA polymerase III, or anti-TH/To) and nailfold changes of enlarged capillaries or capillary loss were independent predictors of progression to definite systemic sclerosis; 79.5% of patients with one of these autoantibodies and abnormal nailfold changes at baseline developed systemic sclerosis.

Another adult study of over 3000 primary Raynaud phenomenon patients found progression from primary to secondary Raynaud phenomenon was associated with older age of Raynaud phenomenon onset (>40 y) and worsening attacks (more frequent, last longer).[19] In children, a similar frequency of conversion has been reported (18-23.6%), but over a shorter period (mean, 1.3-2.4 y).[6, 49]

Further Inpatient Care

Patients with Raynaud phenomenon (RP) who have severe digital ischemia, uncontrolled pain, or impending digital amputation should be hospitalized.[7, 5]

Patients who are hospitalized should receive aggressive vasodilator therapy; patients should have doses increased as tolerated while monitoring vital signs and symptoms.

Combination of different classes of vasodilators or other classes of medications may be needed to control symptoms (eg, calcium channel blocker and phosphodiesterase inhibitor).

Patients may need intravenous prostanoid treatment.

Sympathetic block or sympathectomy may be needed to improve blood flow. Sympathetic block may be repeated intermittently as needed.

Patients should be kept in a warm environment, with warm covering of affected area (eg, socks, warm blanket).

Infusion of heparin for 24-72 hours has been used for rapidly progressing ischemia, but no trials have evaluated this treatment.

Patients may need to be treated with antibiotics if infection of the ischemic area is suspected.

Surgical debridement of necrotic or infected tissue may be needed.

Patients should be evaluated for other potential problems, such as coagulopathy or worsening of underlying vasculitis.

Transfer

Patients with secondary Raynaud phenomenon should be monitored by a pediatric rheumatologist if the Raynaud phenomenon is due to a connective tissue disease. Patients with secondary Raynaud phenomenon from other underlying problems should be referred to other specialists as appropriate.

Patients may need to be referred to a surgeon for debridement of necrotic or infected digits or for a sympathectomy if digital loss is a risk.

Deterrence/Prevention

Patients should stay warm by avoiding cold situations or dressing adequately in cold situations. Appropriate garb for cold weather includes a hat, mittens, boots, and layered clothing on the trunk. Other recommendations include the following:

  • Advise patients to avoid or stop medications and drugs that can aggravate the Raynaud phenomenon.

  • Advise patients to avoid continued trauma to the affected region.

  • Patients who have very low body weight may have decreased symptoms with weight gain.

  • Patients should avoid prolonged ischemia by promptly warming up whenever they feel altered sensation in their digits.