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Joint Bone Spine 74 (2007) e1ee8
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Review
Raynaud’s phenomenon
Martine Gayraud*
Internal Medicine Department, Institut Mutualiste Motnsouris, 42 boulevard Jourdan, 75014 Paris, France
Received 2 November 2005; accepted 26 July 2006
Available online 4 December 2006
Abstract
Vascular acrosyndromes constitute a common reason for physician visits. They are associated with connective tissue disease; for example,
90% of patients with scleroderma experience Raynaud’s phenomenon. The rheumatologist must strive to establish the diagnosis, to identify a potential underlying cause, and to prescribe effective treatment when the symptoms are incapacitating. Raynaud’s phenomenon is the acrosyndrome most commonly encountered by rheumatologists. The diagnosis of Raynaud’s phenomenon rests on clinical grounds. Nailfold
capillaroscopy and immunological tests are useful chiefly for determining the cause. Calcium-channel antagonists are the treatment of reference
for Raynaud’s phenomenon. Drugs introduced over the last few years for severe refractory forms include prostacyclin and its derivatives, endothelin receptor antagonists, and phosphodiesterase inhibitors. These drugs were developed as a result of new knowledge on the pathogenesis
of Raynaud’s phenomenon. Acrocyanosis, which is extremely common, and erythromelalgia are the other main vascular acrosyndromes.
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: Raynaud’s phenomenon; Scleroderma; Calcium-channel antagonists
1. Definition
In 1862, Maurice Raynaud described a paroxysmal phenomenon that included three phases: ischemia, with pallor of the
digits due to vasoconstriction of the digital arteries, precapillary
arteries, and cutaneous arteriovenous shunts; hyperemia with
redness of the digits; and a return to normal (Fig. 1). Whereas
the ischemic phase is required for the diagnosis, the hyperemic
phase may be lacking. The abnormalities usually spare the
thumb but involve most of the other digits, although they may
start in a limited number of digits. The nose, ears, and tongue
may be affected. The attack resolves within an hour after the
end of cold exposure [2,3]. Raynaud’s phenomenon is associated with migraine and chest pain (usually from the chest
wall, an association with spastic angina being controversial) [4].
2. Epidemiology
Raynaud’s phenomenon may be primary or secondary. It
may occur as the first manifestation of an underlying disease,
* Tel.: þ33 1 56 61 67 24; fax: þ33 1 56 61 67 29.
E-mail address: [email protected]
most notably scleroderma [1e3]. A 7-year study conducted in
Caucasians in the United States showed baseline prevalences
of 11% in women and 8% in men and incidences of 2.2% in
women and 1.5% of men [5]. The rate of remission during
the study period was 64% in both women and men [5]. Variations in prevalence occur across climates [6]. In a study of
teenagers, the prevalence was 15% with a predominance in females [7]. The attacks occur when the ambient temperature
drops below a cutoff, which is specific of each individual patient. The cutoff temperature may be relatively high, with attacks occurring even during the summer months.
3. Pathogenesis
New insights into the pathogenesis of Raynaud’s phenomenon have led to the development of specific treatment approaches [8] (Fig. 2). Primary Raynaud’s phenomenon is
related to functional alterations alone. Secondary Raynaud’s
phenomenon, in contrast, also reflects structural microvascular
abnormalities, most notably in patients with scleroderma or
vibration injury [8,9].
Factors that promote vasoconstriction include a2-adrenoceptor overactivity, increased endothelin-1 production [10]
1297-319X/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.jbspin.2006.07.002
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M. Gayraud / Joint Bone Spine 74 (2007) e1ee8
α2
Adrenoceptor
activity
smooth muscle cells
α blockers
Selective α2c adrenoceptor blockade
endothelin
angiotensin II
tyrosine
kinase activity
serotonin
neuropeptides
vasodilators
- CGRP
- VIP
- Neurokinine A
- Substance P
nerve fibers
CGRP
Phosphodiesterase inhibitors
Calcium-channel antagonists
NO
prostacyclin or
resistance
endothelial cells
Endothelin-1 antagonists
Angiotensin II receptor antagonists
Selective serotonin reuptake inhibitors
L arginine
Transdermal NO
Phosphodiesterase inhibitors
Calcium-channel antagonists
VASOCONSTRICTION
VASODILATATION
Intravascular mechanisms
-
platelet aggregation
leukocyte activation
erythrocyte deformation
hyperviscosity
Fibrinolytic agents, antiplatelet agents, smoking cessation
Fig. 1. (a, b) Ischemic and hyperemic phases of Raynaud’s phenomenon.
and tyrosine kinase overactivity in endothelial cells [11,12].
Furthermore, there is probably a role for angiotensin II and serotonin. The endothelium releases vasodilating substances
such as nitric oxide (NO) and prostacyclin. L-arginine, which
increases NO production, has been reported to improve Raynaud’s phenomenon [13]. Loss of nerve fibers supplying the
capillaries leads to decreased production of vasodilating substances such as neuropeptides (calcitonin gene-related peptide,
substance P, neurokinin A, neuropeptide Y, and vasointestinal
peptide) whose effects are mediated by NO production. The
role for intravascular alterations is less clear.
4. Identifying the cause
Primary Raynaud’s phenomenon, also called Raynaud’s
disease, is defined as Raynaud’s phenomenon with no identifiable underlying disease. A family history supports a diagnosis
of Raynaud’s disease, particularly in younger individuals [14].
Among women with Raynaud’s phenomenon, 85% have the
primary form and 15% the secondary form, whereas the distribution is balanced in men. Table 1 lists the diagnostic criteria
for primary Raynaud’s phenomenon.
The causes of secondary Raynaud’s phenomenon are listed
in Table 2. In a study of 639 patients, 12.6% developed
Fig. 2. Pathogenic mechanisms and therapeutic targets in Raynaud’s
phenomenon.
symptoms of an associated disease within 24 months [15].
Of 142 patients followed up for 12.4 years on average,
14.1% experienced progression to connective tissue disease
[14]. Capillaroscopy, tests for antinuclear factor, and tests
for inflammation should be performed routinely in patients
with Raynaud’s phenomenon [9]. Capillaroscopy is crucial
[16,17]. It consists in examination of the nailfold capillaries
under a light microscope (10 to 300 magnification) with
cold light illumination. Capillaroscopy is difficult to perform
in patients who have pigmented thick skin (manual laborers).
Nailfold capillaries are normally horizontal. Capillary enlargement, which is the most specific finding, occurs in three connective tissue diseases: scleroderma, mixed connective tissue
disease, and dermatomyositis (Figs. 3, 4). The enlarged
Table 1
Diagnostic criteria for primary Raynaud’s syndrome (Raynaud’s disease)
Attacks triggered by exposure to cold and/or stress
Symmetric bilateral involvement
Absence of necrosis
No detectable underlying cause
Normal capillaroscopy findings
Normal laboratory tests for inflammation
Negative tests for antinuclear factors
M. Gayraud / Joint Bone Spine 74 (2007) e1ee8
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Table 2
Causes of secondary Raynaud’s phenomenon
Prevalence
CONNECTIVE
TISSUE DISEASE
DRUGS AND
TOXIC AGENTS
Systemic sclerosis
CREST syndrome
Mixed connective
tissue disease
SLE
Sjögren’s syndrome
Dermatomyositis
90e95%
100%
70e85%
10e30%
5e15%
15e35%
b-Blockers (including those
in ocular solutions)
Ergot derivatives
Cancer chemotherapy
Cyclosporine
Interferons a and b
Exposure to vinyl polychloride
Cocaine
Smoking (probable)
ENDOCRINE
DISORDERS
Hypothyroidism
Pheochromocytoma
Carcinoid syndrome
TRAUMA
(unilateral Raynaud’s)
Vibration injury
Ulnar aneurysm (hypothenar
hammer syndrome)
Repetitive stress injury
(thoracic outlet syndrome)
ARTERIAL DISEASE
(often unilateral)
Thromboangiitis obliterans
Atheroma
Peripheral embolism
Vasculitides (giant-cell
arteritis, Takayasu)
HEMATOLOGICAL
DISORDERS AND
CANCER
Cryoglobulinemia
Cold agglutinin disease
Myeloproliferative and
lymphoproliferative disorders
Cancers
capillaries may be visible to the naked eye (Fig. 5). Digital ulcers may develop, making the diagnosis obvious to inspection
(Figs. 6, 7). Joint lesions are common in patients who have
digital ulcers.
Fig. 3. Enlarged capillaries in a patient with scleroderma.
Fig. 4. Capillaroscopic abnormalities (petechiae, edema, and capillary loop
enlargement).
Unilateral Raynaud’s phenomenon suggests an arterial lesion or an occupational injury [3,18,19]. Vibration injury occurs in workers who use jackhammers, chisels, rivet presses,
drills, compacters, chain saws, buffers, or sanders. Longer exposure times and vibration frequencies in the 25e250 Hz
range are associated with an increased risk of vibration injury
[19]. Hypothenar hammer syndrome is related to dysplasia of
the ulnar artery anterior to the superficial palmar arch. An aneurysm develops then undergoes thrombosis, and emboli are
released. Construction workers, carpenters, metal workers,
and mechanics are at highest risk. Hypothenar hammer syndrome has been reported in association with several sports
(e.g., karate, mountain biking, hockey, and golf). Vascular
Doppler ultrasound and angiography establish the diagnosis
[18] (Fig. 8). Workers with hypothenar hammer syndrome
are eligible for compensation (in France, Table 69 for salaried
workers and number 29 for farmers). Thoracic outlet syndrome, which manifests chiefly as neurological symptoms, is
associated with Raynaud’s phenomenon in 45% of cases.
The link between vessel and nerve compression in the thoracic
outlet and Raynaud’s phenomenon is unclear. When the diagnosis is suspected, a radiograph of the cervical spine and clavicles should be obtained to look for a cervical rib or elongated
Fig. 5. Enlarged capillaries visible around the nails.
M. Gayraud / Joint Bone Spine 74 (2007) e1ee8
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Fig. 6. Digital ulcers in a patient with scleroderma.
transverse process [20]. Arterial lesions due to mechanical factors or inflammatory disease (vasculitis or thromboangiitis obliterans (Fig. 9) manifest chiefly as symptoms of digital
ischemia. Fig. 10 summarizes the diagnostic process.
5. Treatment
Pharmacotherapy is usually unnecessary in patients with
primary Raynaud’s phenomenon [21].
5.1. Functional factors
Exposure to cold should be avoided. Warm loose clothing
with thermal gloves and socks is often sufficient. Appropriate
clothing can often be found in mountain sports stores. Hand
Fig. 8. Digital arteriogram: obstruction of the ulnar artery and interdigital arteries of the first and second rays.
warmers are useful. Patients should not use medications or
other substances that induce vasoconstriction, such as ergot
derivatives, b-blockers, caffeine, and nasal vasoconstrictors
[2,3,21]. Smoking cessation is essential in patients with thromboangiitis obliterans.
5.2. Medications (Fig. 2)
5.2.1. Calcium-channel antagonists
Calcium-channel antagonists are the most widely used
medications in patients with Raynaud’s phenomenon [2,3,21].
Fig. 7. Phalangeal tuft resorption in a patient with scleroderma.
Fig. 9. Necrosis of the toes in a patient with thromboangiitis obliterans.
M. Gayraud / Joint Bone Spine 74 (2007) e1ee8
History:
- Intermittent attacks
- Ischemic phase
- Triggered by cold and
stress
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Other acrosyndromes:
- erythromelalgia
- acrocyanosis
- frostbite
- carpal tunnel syndrome
Raynaud's phenomenon
- Drugs or toxic agents
- Work-related exposures
- Clinical evidence of connective
tissue disease
- Malignancy
- Evidence of endocrine disease
- Evidence of vascular disease
(pulses, Allen's maneuver)
- Antinuclear factors
- Capillaroscopy
Drugs
Endocrine diseases
Negative
Positive
Cryoglobulinemia
Blood disorders
Secondary Raynaud's
phenomenon
Evidence of connective
tissue disease
Immunologic workup
X-rays hands and chest
Proteinuria
Capillary enlargement
yes
Raynaud's disease likely
(2 years' follow-up
required)
no
Scleroderma
Mixed connective
tissue disease
Dermatomyositis
Unilateral attacks
Abnormalities of
peripheral vessels
X-rays chest, cervical spine
Doppler
Angiography
AngioCT or MRI
Echocardiography
Lupus
Rheumatoid arthritis
Sjögren's syndrome
Polymyositis
Work-related
Embolism
Vasculitides
Atheroma
Thoracic outlet syndrome
Arteriovenous aneurysm
Shunt for dialysis
Fig. 10. Diagnosis of Raynaud’s phenomenon and investigations for an underlying cause.
In addition to relieving vascular spasm, they decrease superoxide anion production by monocytes and limit the progression of
endothelial lesions in patients with scleroderma [22,23]. A
meta-analysis of 17 studies showed that calcium-channel antagonist therapy was associated with a 33% reduction in attack
severity and with a reduction in the number of attacks from 5 to
2.8/week [24]. In 130 patients given nifedipine 30 mg b.i.d. for
1 year, the number of attacks decreased by 66%, and 15% of
patients experienced adverse effects requiring discontinuation
of the drug [25]. Similar results were obtained in patients
who had Raynaud’s phenomenon associated with scleroderma
[26]. Amlodipine is as effective as nifedipine, diltiazem is less
effective, and verapamil has no effect [27]. Delayed-release
once-daily formulations have been suggested based on their
better safety profile. The dosage should be increased gradually
until a response is achieved. Raynaud’s phenomenon often requires a higher dosage than hypertension (up to 60 mg of nifedipine or 20 mg of amlodipine).
5.2.2. Nitrate derivatives
Evidence that nitrate derivatives administered transcutaneously may improve Raynaud’s phenomenon comes from
only a small number of studies [3,28]. The gel is no longer
marketed in France. A preparation containing 2 g of nitroglycerine per 100 g of vaseline and lanolin ointment with 18 g of
lactose monohydrate can be used.
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M. Gayraud / Joint Bone Spine 74 (2007) e1ee8
5.2.3. a-Adrenoceptor antagonists
Prazosine, which inhibits the a1-adrenoceptors, has been
proved effective [3]. A selective inhibitor of the a2c-adrenoceptors, which play a pivotal role in vessel reactivity, was
found to improve digital blood flow in patients with scleroderma who were exposed to cold temperatures [29].
used in a few patients to treat digital ulcers associated with severe Raynaud’s phenomenon (due to connective tissue disease
or cancer) that was unresponsive to calcium-channel antagonists and ilomedin. Improvements were noted within a few
days, and tolerance was good [46e48]. Similar results were
obtained with tadalafil [49,50].
5.2.4. Buflomedil and naftidrofuryl
The effectiveness of these agents remains controversial, and
the number of studies is small [3,30,31]. However, buflomedil
is widely used in everyday practice.
5.2.8. Selective serotonin reuptake inhibitors
Serotonin has vasoconstricting effects. This mediator is released by nerve terminals and by platelets undergoing activation. The selective serotonin reuptake inhibitor fluoxetine
induced improvements in small studies. Fluoxetine (20 mg/
day) was significantly more effective than nifedipine (40 mg/
day) in decreasing attack frequency and severity, and the difference was particularly marked in the subgroup with primary
Raynaud’s phenomenon [51].
5.2.5. Prostaglandins
Prostaglandins are potent vasodilating agents that also inhibit platelet aggregation, decrease leukocyte margination,
and exert fibrinolytic effects [2,3]. Ilomedin, a synthetic analog of prostaglandin I2, has been evaluated in Raynaud’s phenomenon secondary to connective tissue disease [32e36]. The
drug was given as 6-h infusions in doses of 0.5 to 2 ng/kg/min
for 3 to 6 days [32]. In a study of 114 patients with scleroderma, ilomedin therapy decreased attack frequency and severity and improved skin healing, compared to a placebo
[32]. The 0.5 ng/kg/min and 2 ng/kg/min dosages were similarly effective, and the lower dosage induced fewer side effects
(headache, hot flashes, and gastrointestinal symptoms). Despite the short half-life of ilomedin, the beneficial effects
lasted several weeks, suggesting endothelial and cellular effects in addition to the vasodilating effect [33]. In comparisons
of ilomedin infusions to nifedipine per os in patients with
scleroderma, ilomedin was at least as effective as nifedipine
[34,35]. Oral prostaglandins have not been proved effective
[36]. A placebo-controlled study of beraprost for 6e12 months
in 107 patients with digital ulcers showed no difference in
attack frequency or severity but revealed a trend toward
decreased ulcer size [37].
5.2.6. Endothelin receptor antagonists
Endothelin, which is released by endothelial cells, induces
vasoconstriction. Endothelin receptor antagonists are approved
for use in primary arterial hypertension and in arterial hypertension associated with scleroderma functional class III
[38,39]. In a placebo-controlled study of bosentan 25 mg
b.i.d., there were fewer new ulcers with the drug, and this effect was most noticeable in patients who had numerous ulcers
at baseline [40]. Hand function improved, but there was no effect on healing of preexisting ulcers [40]. Other studies
showed rapid ulcer healing, even in patients who were previously treated with ilomedin [41e44].
5.2.7. Phosphodiesterase inhibitors
The phosphodiesterase-5 inhibitor sildenafil increases guanosine monophosphate levels in vascular smooth muscle cells,
inducing vasodilation. Sildenafil, which is used to treat erectile
dysfunction, has been evaluated in primary and sclerodermaassociated pulmonary arterial hypertension [45]. The results
showed that sildenafil improved Raynaud’s phenomenon. Sildenafil (12.5 to 150 mg once to three times a day) has been
5.2.9. Angiotensin II receptor antagonists
Results obtained with angiotensin II receptor antagonists to
treat Raynaud’s phenomenon have been inconclusive. Losartan 50 mg/day was better than nifedipine 40 mg/day in decreasing attack frequency and severity and also improved
vascular parameters, most notably in patients who had primary
Raynaud’s phenomenon [52].
5.2.10. Fibrinolytic agents, anticoagulants,
and platelet inhibitors
The evidence is not sufficient to support the use of these
medications. Controlled studies are needed to determine their
role in Raynaud’s phenomenon.
5.2.11. Medications approved for use in France
Nifedipine and ilomedin are approved for the treatment of
Raynaud’ s phenomenon. Several vasodilating agents are approved as adjunctive treatments; they include buflomedil, naftidrofuryl, and dihydroergocriptine. Other medications are not
approved for Raynaud’s phenomenon and should be used only
when the condition is severe and refractory to the above-listed
drugs, after a careful review of the literature. Ilomedin is
costly and is reimbursed by the French healthcare system
when used in hospitalized patients. The 3- to 6-day treatment
duration is well-suited to 1-week hospitalization.
5.3. Nonpharmacological treatments
The level of proof is inadequate to support the use of biofeedback, acupuncture, low-frequency laser therapy, cord
stimulation, or sympathetic block [2,3,21,53]. Surgery is
rarely appropriate, despite the introduction of thoracoscopy.
Thoracoscopic sympathectomy induced rapid improvements,
with healing of the ulcers within 1 month, but the recurrence
rate was high (82%) [54]. Digital sympathectomy with periarterial denervation also carried a high recurrence rate and also
induced postoperative complications in 37% of patients with
scleroderma [55].
M. Gayraud / Joint Bone Spine 74 (2007) e1ee8
Acknowledgments
We are grateful to Professors Guillevin and Hachulla for allowing us to reproduce Figs. 1, 6, and 7.
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