Raynaud
phenomenon
Salient
features
·
Raynaud
phenomenon is a vascular disorder characterized by recurrent episodic attacks
of digital ischemia provoked by exposure to cold or emotional stress.
·
Affects
up to 10% of the population, 4:1 female-to-male ratio.
·
Classified
as primary (idiopathic) and secondary (underlying disease or cause present)
forms; severity ranges from mild/benign to severe with loss of tissue and risk
of amputation.
·
Connective
tissue diseases, particularly systemic sclerosis, are among the most common underlying
causes of secondary Raynaud phenomenon.
·
Behavioral
modification, pharmacologic therapies, and surgical interventions are effective
at reducing the frequency and severity of attacks.
Introduction
Raynaud’s phenomenon
is defined as episodic digital ischemia occurring in response to cold or
emotional stimuli. It is characterized by sequential colour changes, white
(pallor), blue (cyanosis) and red (rubor). Pallor is essential for the
diagnosis. However, in severe recalcitrant Raynaud’s phenomenon, particularly
in association with a connective tissue disease, attacks of long duration may
occur in which the initial pallor is short-lived and succeeded by prolonged
cyanosis. Primary Raynaud’s phenomenon (also called Raynaud’s disease) is
idiopathic, common
and affects 3% to 5% of the population. In contrast, secondary Raynaud’s
phenomenon is uncommon and is associated with an underlying medical problem
and the most common cause is SSc.
Epidemiology
Primary
Raynaud phenomenon is estimated to be approximately twice as common as
secondary Raynaud. Symptoms most often first develop in the teenage years with
a female predominance (female–male = 5:1). Increases in the frequency and
severity of attacks during menses suggest that female sex hormones may be
involved in the pathogenesis.
Clinical
features
Raynaud’s phenomenon affects the hands and,
less often, the feet
The Episodic Attack: A typical attack
consists of sudden onset of well-demarcated pallor of one or more digits
extending from the tip to various levels of the digits during ischemic phase. The skin distal to the line of
ischemia is cold and pale, while the proximal skin is pink and warmer. On
rewarming, blanched digits may become cyanotic, due to slow blood flow and de-oxygenation
(local cyanosis) and then bright red, because of reactive hyperaemia. Attack
persists for minutes to hours. Episodes may occur infrequently or many times
each day.
Repeated or Persistent
Vascular Vasospasm: Patients with RP often have a persistent
vasospasm rather than episodic attacks. The digits should be carefully examined
for ischemic changes, which are the signs of prolonged or severe attack, particularly
in patients with systemic sclerosis. There is telangiectases of the nail fold, sclerosis and atrophy
of the skin of fingers (sclerodactyly) and hair loss may occur over the
dorsal surfaces. The nails may become brittle and deformed. Extremely painful
ulcers develop on the finger pads and heal slowly, leave characteristic small,
pitted scars.
In primary Raynaud’s
phenomenon the condition is usually symmetrical and involves several digits. In
secondary Raynaud’s phenomenon only one or a few digits are affected and
asymmetrical. Attacks are usually
precipitated by cold, either local or of the whole body, or by psychological
(emotional) stimuli.
In primary Raynaud’s
phenomenon the outcome is good in 80% of cases, but some disability occurs in 20%;
in secondary Raynaud’s phenomenon the prognosis is that of the underlying
disease.
Female patients with
age of onset over 25 years, no pre-existing cold intolerance, no occupational,
traumatic or drug-related aetiology, and no history of a low body weight should
be regarded as being at high risk of developing connective tissue disease. The
presence of abnormal capillaries on nail fold microscopy is suggestive of a
diagnosis of secondary Raynaud’s phenomenon. In particular, Raynaud’s
phenomenon is a common presenting symptom of systemic sclerosis, but if there
are no other signs within 2 years of onset, systemic sclerosis is less likely
to develop. The presence of circulating autoantibodies (antinuclear,
anticentromere and anti-Scl 70 antibodies) should be regarded as indicating a
connective tissue disease until proven otherwise.
Related Physical Findings
The
physical examination should pay attention to all pulses, and blood pressure
should be obtained in both arms. Allen's test is useful to assess arterial and
capillary function of the hands. Abnormal filling implies structural disease of
the microcirculation and raises the suspicion of a secondary form of Raynaud
phenomenon. In this test, the radial and ulnar arteries are simultaneously
compressed by the examiner's thumbs, while the patient opens and closes the
fist to induce blanching of the palm. Selective arterial filling is judged by
the rate of colour return as pressure is sequentially released from the radial
and ulnar arteries.
Laboratory Tests
In all
patients, a complete blood count, erythrocyte sedimentation rate, urinalysis,
and antinuclear antibody test should be obtained. Additional laboratory studies
should be directed by findings elicited by the history and physical
examination. In patients with abnormal antinuclear antibody levels, tests for
antibodies to specific nuclear antigens, such as Sm antigen or topoisomerase or
centromere antigens are helpful to detect early systemic lupus erythematosus or
scleroderma. A routine chest radiograph should be obtained to look for a
cervical rib or evidence of interstitial lung disease.
Special Tests
Nail fold capillary microscopy is
considered to be a useful procedure to distinguish primary from secondary
Raynaud phenomenon. Although mild capillary abnormalities may be observed in
patients with primary Raynaud phenomenon, patients with connective tissue
diseases may have enlarged, dilated, tortuous capillary loops surrounded by
avascular areas(capillary drop out). Serial studies reveal progressive
decreases in the total number of nail fold capillary loops in secondary, but
not primary, forms of Raynaud phenomenon. A variety of vascular imaging studies have been employed but
are not specifically useful in clinical diagnosis.
Differential Diagnosis
Raynaud
phenomenon is subdivided into primary (idiopathic) and secondary forms based on
whether an underlying cause or disease association can be identified.
Primary Raynaud Phenomenon
Primary
Raynaud phenomenon is a disorder in which known causes of attacks of peripheral
vasospasm cannot be found. Criteria for the diagnosis of primary Raynaud
phenomenon have been developed by Allen and Brown and LeRoy and Medsger.
Criteria for the diagnosis of primary
Raynaud’s phenomenon
1.
Intermittent vasospastic attacks (precipitate
by cold or emotional stimuli) of discoloration of extremities
2.
Absence of evidence of organic peripheral
arterial occlusion: Normal vascular examination with symmetric peripheral pulses and normal
nail fold capillary microscopy
3.
Symmetrical or bilateral distribution
4.
No evidence of any underlying disease,
occupational exposure, trauma or drug ingestion that could give rise to
vasospastic attacks
5.
Absence of immunological abnormalities such
as circulating autoantibodies (antinuclear, anticentromere and anti-Scl 70
antibodies)
6.
Normal ESR
7.
Female sex, age under 25 years
8.
History of cold intolerance since childhood
9. History
of symptoms for at least 2 years.
|
CLINICAL AND LABORATORY FEATURES OF PRIMARY AND SECONDARY RAYNAUD’S
PHENOMENON |
||
|
Feature |
Primary Raynaud’s |
Secondary Raynaud’s |
|
Sex |
F : M
20 : 1 |
F : M
4 : 1 |
|
Age at
onset |
<25
years |
>25
years |
|
Frequency
of attacks |
Usually
<5 per day |
5–10+
per day |
|
Precipitants |
Cold,
emotional stress |
Cold |
|
Ischemic
injury |
Absent |
Present |
|
Abnormal
capillaroscopy |
Absent |
>95% |
|
Antinuclear
antibodies |
Absent/low
titer |
90–95% |
|
Anticentromere
antibody |
Absent |
50–60% |
|
Anti-topoisomerase
I (Scl-70) antibody |
Absent |
20–30% |
Several studies have examined the
long-term outcome of patients with primary Raynaud phenomenon. Progression to a
secondary form of Raynaud phenomenon, most commonly a connective tissue disease
such as scleroderma, occurs in approximately 15% of patients during the first
decade after onset. Variables predictive of a transition to a secondary form
include nail fold capillary abnormalities, hand swelling, positive Allen's
test, and antinuclear antibodies.
Secondary Raynaud Phenomenon
The
connective tissue diseases are the most common cause of secondary Raynaud
phenomenon. Among patients with scleroderma, 80%–90% manifest Raynaud
phenomenon and/or persistent vasospasm. It is the presenting symptom in about
one-third of patients and may be the only manifestation of the disease for
years. Raynaud phenomenon occurs in about one-third of patients with systemic
lupus erythematosus, idiopathic inflammatory myopathies, and systemic
vasculitis. Arteriograms of patients with connective tissue diseases usually
show digital and sometimes, ulnar or radial artery obstructions.
Drugs and Toxins
Propranolol, one of the most widely used
β-adrenergic blockers for cardiovascular diseases and migraine headaches, is
probably the most frequently used drug responsible for Raynaud phenomenon.
Ergot preparations and methysergide used to treat migraine headaches may produce
vasospasm. Intra-arterial use of many medications and recreational drugs can
result in toxicity to endothelial cells with irreversible structural damage to
the microvasculature of the extremities and be responsible for severe Raynaud
phenomenon. The chemotherapeutic agents, bleomycin and vinblastine, also may cause the phenomenon.
Causes of secondary
Raynaud Phenomenon
|
·
Connective tissue disease ·
Scleroderma ·
Systemic lupus erythematosus ·
Dermatomyositis and polymyositis ·
Undifferentiated connective tissue disease ·
Systemic vasculitis ·
Sjögren syndrome ·
Eosinophilic fasciitis ·
Obstructive arterial disease ·
Atherosclerosis ·
Thromboangiitis obliterans (Buerger disease) ·
Thromboembolism ·
Thoracic outlet syndrome ·
Neurologic disorders ·
Carpal tunnel syndrome ·
Reflex sympathetic dystrophy ·
Hemiplegia ·
Poliomyelitis ·
Multiple sclerosis ·
Syringomyelia ·
Drugs and toxins ·
β-Adrenergic blockers ·
Ergotamines ·
Oral contraceptives ·
Methysergide ·
Bleomycin and vinblastine ·
Amphetamines ·
Interferon-α ·
Occupation/environmental exposure ·
Vibration injury (lumberjacks, pneumatic hammer
operators) ·
Posttraumatic injury (hypothenar hammer syndrome,
crutch pressure) ·
Vinyl chloride disease ·
Cold injury ·
Hyperviscosity disorders ·
Cryoproteins ·
Cold agglutinins ·
Macroglobulins ·
Polycythemia ·
Thrombocytosis ·
Miscellaneous ·
Hypothyroidism ·
Infections (bacterial endocarditis, Lyme disease,
viral hepatitis) ·
Neoplasms ·
Primary pulmonary hypertension ·
Arteriovenous fistula ·
Intra-arterial injections |
Rheumatic
disorders [systemic scleroderma (85%), SLE (35%), DM (30%), Sjogren syndrome,
rheumatoid arthritis, polyarteritis nodosa], diseases with abnormal blood proteins
(cryoproteins, cold agglutinins, macroglobulins), drugs (alfa-adrenergic
blockers, nicotine), and arterial diseases (arteriosclerosis obliterans,
thromboangiitis obliterans) are the most common.
Management
The management of Raynaud phenomenon
is guided by the frequency and severity of attacks and the complications from
ischemia. Secondary forms of Raynaud phenomenon require treatment directed at
the underlying medical disorder, discontinuation of drugs causing the
vasospasm, or occupational modifications.
Management of
Raynaud Phenomenon
|
Infrequent
or mild attacks |
Preventive
measures Cessation
of smoking |
|
Frequent
or severe attacks |
Calcium
channel blockers (nifedipine, diltiazem) Antiadrenergic
drugs (prazosin, reserpine) Topical
nitroglycerin |
|
Acute,
severe ischemia |
Intravenous
prostaglandin E1 or prostacyclin Digital
sympathectomy Microvascular
surgery |
|
Digital
ulcers |
Antiseptic
soaks, antibiotic ointments, occlusive dressing Calcium
channel blockers (maximal doses) Intravenous
prostaglandin E1 or prostacyclin |
|
Gangrenous,
infected ulcers |
Analgesics Antibiotics Surgical
debridement Amputation |
General Measures
Mild
Raynaud phenomenon is generally easy to control with lifestyle changes to
minimize exposure to the cold; dressing warmly with loose-fitting, layered
clothing; and keeping the thermostat a few degrees higher than normal. Limiting
time spent outdoors in winter, wearing insulated gloves, and using hand or foot
warmers are usually helpful. Patients should be taught to recognize and
terminate attacks promptly by returning to a warmer environment and applying
local heat to the hands (e.g., by placing their hands in warm water or by using
a hair dryer). Patients should be strongly encouraged to stop smoking and to
avoid second-hand smoke, because nicotine induces cutaneous vasoconstriction.
Stress modification and social support are valuable aspects of treatment to
minimize vasoconstriction induced by hyperactivity of the sympathetic nervous
system.
Digital ulcers from Raynaud
phenomenon can be extremely painful and typically take weeks or months to heal
completely. Pain control is an important part of therapy, because pain can lead
to additional vasospasm and more ischemia. On occasion, narcotic pain
medications may be necessary to control symptoms. The finger should be soaked
in a tepid antiseptic solution (e.g., half-strength hydrogen peroxide) twice
daily to soften or loosen the crust. After drying, an antibiotic ointment is
applied to the ulcer, and the digit is covered with an occlusive dressing.
Maximum drug therapy with a calcium channel blocker should be used throughout
treatment. Infection is a common complication of digital ulcers and is
typically manifest by increasing pain, erythema, swelling, or purulent
drainage. Cultures usually demonstrate Staphylococcus sp., and treatment
with cephalosporin is usually effective.
Drug Therapy
Various
drugs have been used to treat Raynaud phenomenon, including vasodilators,
platelet inhibitors, serotonin antagonists, and fibrinolytics. Drug therapy is
usually reserved for patients with prolonged or frequent attacks that fail to
respond to conservative measures. In general, improvements with drug therapy
are more pronounced in patients with primary Raynaud phenomenon, presumably as
a consequence of fixed, structural damage in patients with secondary forms.
The
calcium channel blockers are by far the most widely used and effective drugs
for treating Raynaud phenomenon. Vasodilating properties vary among different
agents. Nifedipine (10–20 mg tid or qid) reduces
the severity and frequency of attacks; the long-acting preparation of
nifedipine is better tolerated but may be less effective. Amlodipine 5-20 mg daily or Diltiazem (60 mg tid or qid) may be
substituted if nifedipine is ineffective or not well tolerated. Side effects of
calcium channel blockers include leg oedema, headache, and heartburn; these may
limit therapy.
Sympatholytic
drugs, including reserpine, methyldopa, phenoxybenzamine, and tolazoline, have been used
in management, although they have not been well studied. In a pilot study, the
selective serotonin reuptake inhibitor fluoxetine reduced the frequency and
severity of Raynaud attacks. Additional drug therapies reported to be
beneficial in the treatment of Raynaud phenomenon include low molecular weight
heparin, prazosin, the angiotensin II receptor
antagonist losartan, and stanozolol. Topical nitroglycerin paste (2%) and a
sustained-release transdermal glyceryl patch are helpful in selected patients;
although side effects such as headaches, dizziness, and skin irritation often
limit therapy. Newer formulations of nitroglycerin appear to show promise.
Intravenous prostaglandin E1 and prostacyclin (PGI2) and iloprost (a PGI2analog) have
been shown to have beneficial effects in patients with severe Raynaud
phenomenon; however, the vasodilatory effects are not sustained and long-term
therapy is required.
Sympathectomy
Sympathectomy
may be a consideration for the management of patients with refractory,
disabling attacks or with an acutely ischemic digit that is unresponsive to
other measures. Lumbar sympathectomy has an important role in the management of
severe Raynaud phenomenon of the feet, and selective digital sympathectomy may
be used to relieve pain and heal digital ulcers in patients with ischemic
digits.
Severe Vasospasm
Severe
vasospasm with prolonged ischemia (dead-white finger) poses a threat of
gangrene and amputation; it is considered a medical emergency. The patient
should be hospitalized and the affected extremity put to rest. Nifedipine (10–20 mg tid) should be started
immediately, as well as prostaglandin E1 (6–10 ng/kg/minute) or PGI2 (0.5–2 ng/kg), given by
continuous intravenous infusion for several hours over three consecutive days.
Intra-arterial phentolamine or tolazoline may reverse acute
vasospasm, but monitoring of vital signs is essential, and these drugs need to
be used with great caution. A digital block with lidocaine hydrochloride or bupivacaine hydrochloride (without epinephrine) relieves pain and produces a
chemical sympathectomy that may reverse vasoconstriction. Sympathectomy
(thoracic, lumbar, or digital) should be considered in patients who have a
positive response. Arterial reconstruction should be reserved for patients with
angiographically documented occlusive vascular disease.
