Raynaud’s Phenomenon
Kyriakos A. Kirou
KEY POINTS
Raynaud’s phenomenon (RP) is characterized by episodic vasospasm and occlusion of the digital arteries in response to cold and emotional stress. This manifests as the sequential change of digital skin color from pallor to cyanosis and then to rubor, but often not all three color changes are observed.
Primary RP (PRP) is symmetric and occurs in the absence of any known specific RP-associated disorder, peripheral pulse abnormalities, digital pitting/ulceration/gangrene, abnormal nailfold capillaries, and positive antinuclear antibody (ANA) test or a high erythrocyte sedimentation rate (ESR).
PRP is common in the general population, occurs in young women, has a familial predisposition, and carries an excellent prognosis.
Possible secondary RP (SRP) consists of those patients with some isolated laboratory or clinical abnormality that do not fulfill the diagnostic criteria for any specific RP-associated disorder. Most of them are patients who are ANA positive and those who have a relatively low progression rate (10% to 30%) to a connective tissue disorder.
SRP in the context of systemic sclerosis (SSc) is characterized by a structural micro- (and sometimes macro-) vasculopathy, which often leads to severe digital ischemia.
The management of RP includes general measures of protection from cold exposure and trauma, avoidance of drugs that promote vasospasm, and use of vasodilatory medications with a calcium channel blocker as the usual first choice.
Refractory SRP due to SSc will often respond to prostaglandin infusions but may require digital sympathectomy, microsurgical revascularization, or amputations.
Raynaud’s phenomenon (RP) is characterized by episodic vasospasm and occlusion of the digital arteries, resulting in a well-demarcated ischemic blanching of the involved digits. This may be followed sequentially by cyanosis and rubor. Tingling may occur during the reactive hyperemia phase (rubor).
Exposure to cold or emotional stress is the typical inducer of RP. The duration of an attack may vary from several minutes to hours (usually 10 to 30 minutes). Upper extremities are most frequently involved, but 40% of patients have symptoms in their lower extremities.
Primary RP (PRP) is the RP that occurs in otherwise healthy individuals while secondary RP (SRP) is observed in association with other disorders.
Proposed criteria for diagnosing PRP include the following:
Appearance of symptoms with exposure to cold or emotional upset.
Bilateral symmetric involvement of hands.
Table 17-1 Characteristics of Primary and Secondary RP
Primary
Secondary
Women
Women (i.e., SSc or SLE) or men (i.e., HAVS and Buerger’s disease)
Onset often in teens or 20s (<40)
Onset in 3rd and 4th decade (i.e., SSc) or even later (i.e., atherosclerosis)
Familial aggregation
Familial and nonfamilial, depending on the cause
Digital ischemia is episodic (vasospasm in response to cold or emotional stress)
Digital ischemia is episodic but can also occur at rest because of structural vascular abnormalities (i.e., SSc and vasculitis)
Symmetric
Symmetric (i.e., SSc) or asymmetric (i.e., atherosclerotic artery occlusion)
Normal pulse
Pulse can be absent or diminished
No significant tissue ischemic changes
Digital pitting, fingertip ulcerations, and gangrene may occur
Absence of an underlying RP-associated disorder
Underlying SSc, MCTD, SLE, vasculitis, etc.
Serologic tests for ANA and RF are negative and ESR is low
Positive ANA (i.e., SLE and SSc) or RF (SS, RA, and MC); high ESR (i.e., vasculitis and multiple myeloma)
Normal nailfold capillaroscopy
Abnormal nailfold capillaries (i.e., SSc, DM, and SLE)
ANA, antinuclear antibodies; DM, dermatomyositis; ESR, erythrocyte sedimentation rate; HAVS, hand–arm vibration syndrome; MC, mixed cryoglobulinemia; MCTD, mixed connective tissue disease; RA, rheumatoid arthritis; RF, rheumatoid factor; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; SSc, systemic sclerosis.
Normal pulse.
Absence of digital gangrene, or if present, only superficial.
Absence of an underlying disorder commonly associated with the symptom complex.
Symptoms present for longer than 2 years without the appearance of an underlying cause.
In 1992, a stricter definition of PRP was developed that excluded all patients with evidence of digital pitting, ulcerations, or gangrene; abnormal nailfold capillaries; a positive antinuclear antibody (ANA) test; or an abnormal erythrocyte sedimentation rate (ESR) upon presentation.
The main characteristics of PRP and SRP are summarized in Table 17-1.
ETIOPATHOGENESIS
PRP is caused by vasospasm of the digital arteries and cutaneous arterioles. Its familial predisposition may be due to shared genetic or environmental factors.
Vascular tone is determined by the balance of vasoconstrictor and vasodilatory mediators that act on the vascular smooth muscle cells.
Vasodilatory neuromediators from sensory (i.e., calcitonin gene-related peptide) and parasympathetic terminals (acetylcholine), as well as vasoconstrictor mediators from sympathetic fibers (i.e., norepinephrine), act on vascular smooth muscle cells to modulate vascular tone.
The endothelium plays a central role in mediating the effects of several neurotransmitters (i.e., acetylcholine and neurokinin A), circulating factors (i.e., thrombin and histamine), as well as mechanical shear stress on smooth muscle cells, by producing relaxing (i.e., nitric oxide and prostacyclin or PGI2) or constricting (i.e., endothelin-1) products.
Exposure to cold activates vasoconstriction of cutaneous blood vessels by amplifying the effect of norepinephrine on the α2C-adrenoreceptors of the vascular smooth muscle cells.
The excessive vasoconstrictive response to cold in RP may be due to increased α2C-adrenoreceptor sensitivity to cold. Other factors likely include a loss of vasodilatory sensory fibers or an overactivity of vasoconstrictive neuromediators. Interestingly, living in cold climates may predispose to PRP.
The etiopathogenesis of SRP varies according to the specific associated disorder (Table 17-2).
In systemic sclerosis (SSc) or scleroderma, the RP is due to a vasculopathy that mainly affects the cutaneous arterioles/capillaries and the proper digital arteries but often also larger vessels such as the ulnar artery and the superficial palmar arch.
Endothelial cell damage or dysfunction is a prominent and early characteristic of this vasculopathy. Reactive oxygen species (ROS) generated during the reperfusion injury from repeated ischemic attacks, as well as antiendothelial antibodies, have been implicated.
Histologically, intimal hyperplasia and fibrosis that may be accompanied by thrombosis occur. Adventitial fibrosis and telangiectasias of the vasa vasorum are also common and the former has been implicated in digital ischemia by virtue of external compression.
SRP due to mixed connective tissue disease (MCTD) and other scleroderma-overlap syndromes share the same pathogenesis.
The SRP associated with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome, and polymyositis is usually benign and vasospastic in nature. However, when caused by vasculitis or thrombosis in the context of the antiphospholipid syndrome, it can lead to tissue damage and gangrene.
Table 17-2 Causes of Secondary Raynaud’s Phenomenon
Connective tissue diseases
- Systemic sclerosis
- Mixed connective tissue disease
- Polymyositis and dermatomyositis
- Systemic lupus erythematosus
- Sjögren’s syndrome
- Rheumatoid arthritis
Systemic vasculitis
- Polyarteritis nodosa
- Takayasu’s arteritis
- Giant cell arteritis
- Wegener’s granulomatosis
- Microscopic polyangiitis
Traumatic vasospastic/occupational
- Hand–arm vibration syndrome
- After frostbites
Occlusive/structural arterial diseases
- Atherosclerosis
- Atheroemboli
- Hypothenar hammer syndrome
- Thrombangiitis obliterans (Buerger’s disease)
Nerve compression
- Thoracic outlet syndrome
- Carpal tunnel syndrome
Hematologic disease
- Cryoglobulinemia
- Cold agglutinin disease
- Polycythemia vera
- Waldenström’s macroglobulinemia
Drugs and chemicals
- Ergot alkaloids
- Methysergide
- Vinyl chloride
- Chemotherapy agents (e.g., bleomycin, vinblastine, and cisplatin)
- β-Blockers
- Sympathomimetics
- Anticholinergics
- Cyclosporine A
- Interferon-α
Other disorders
- Hypothyroidism
- Complex regional pain syndrome type 1
- Paraneoplastic
- Systemic sclerosis
In systemic vasculitis, the inflammatory occlusion of vessels usually leads to severe digital ischemia and gangrene.
The hand–arm vibration syndrome (HAVS) or vibration-induced white finger (VWF) occurs in workers who use vibratory tools such as pneumatic hammers and chain saws.Related posts:
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