Raynaud phenomenon

Raynaud phenomenon (RP) is an exaggerated vasoconstrictive response of distal arteries and arterioles (most commonly in the fingers and toes) to cold or emotional stress. Primary RP is idiopathic, whereas secondary RP is caused by underlying systemic diseases (e.g., mixed connective tissue disease, vasculitides, medications). Both types typically manifest with the sequential discoloration of fingers and/or toes from white (ischemia) to purple-blue (hypoxia) to red (reactive hyperemia). Episodes of vasoconstriction usually last for 15–20 minutes after removal of the trigger. Ischemic episodes in secondary RP can be more prolonged, leading to tissue loss (ischemic ulcers) and rarely, gangrene. Trigger avoidance is the main aspect of managing RP. In patients with secondary RP, the underlying etiology should be identified and treated. Pharmacotherapy (preferably with calcium channel blockers) may be considered for RP refractory to trigger avoidance. Intravenous prostaglandins or interventional therapy (e.g., selective digital sympathectomy) may be required for patients with severe or refractory disease.

Overview ^[1][2][3]

• Vasospastic attack triggered by cold or emotional stress
• More common in female individuals

Primary Raynaud phenomenon (previously called Raynaud disease)

• Idiopathic (no identifiable vascular changes); possible genetic susceptibility ^[1]
• Vasospasms of the digital arteries and arterioles
• Onset usually < 30 years of age

Secondary Raynaud phenomenon (previously called Raynaud syndrome)

• Vasospasms due to arteriolar changes in the fingers (and/or toes), which may be precipitated by the following:
  • Drugs: beta blockers, ergotamine, bleomycin
  • Smoking
  • Occupational trauma: from handling vibrating tools, typing
  • Hyperviscocity: polycythemia, paraproteinemias (plasmacytoma, Waldenstrom macroglobulinemia), cryoglobulinemia, cold agglutinin disease
  • Vasculitides: e.g., Buerger disease
  • Connective tissue diseases (CTDs): e.g., scleroderma (CREST syndrome), systemic lupus erythematosus, mixed CTDs, Sjogren syndrome
  • Arterial disease: e.g., peripheral artery disease
  • Frostbite
  • Neurological disease: e.g., carpal tunnel syndrome, intervertebral disc disease
• Onset usually ≥ 30 years of age

Classic presentation ^[1][4][5]

• Most commonly affects the fingers and toes bilaterally (may be asynchronous and asymmetric)
• The thumb is typically spared in primary RP. ^[1][4]
• Can also affect ears, nose, areolar tissue, tongue (uncommon)
• Classic triphasic presentation
  • Ischemic phase (white): exposure to trigger → vasoconstriction of digital arteries and arterioles → ischemia and pallor
  • Hypoxic phase (blue): deoxygenation of residual blood → cyanosis
  • Hyperemic phase (red): restoration of reduced blood flow → reactive hyperemia
• Livedo reticularis may occur during episodes.
• Rewarming is associated with transient numbness, pain, and/or paraesthesias in the affected areas.

An episode does not always involve all three phases; often, blood flow is restored without causing reactive hyperemia. ^[1]

Duration ^[1][5]

• Vasospastic episodes are usually reversible.
• Symptoms normally subside within an hour (typically 15–20 minutes after cessation of trigger exposure). ^[1]
• Can potentially last for several hours

Associated findings ^[1][5]

• In primary RP: symptoms of systemic vasospasm (e.g., migraine, irritable bowel syndrome) ^[1]
• In secondary RP:
  • Severe pain and ulcerations/necrosis due to critical ischemia
  • Signs of associated systemic disease (e.g., telangiectases, skin fibrosis, sclerodactyly, calcinosis, photosensitivity, patchy alopecia)
• Clinical features of peripheral arterial disease are absent: Pulses, Allen test, and bilateral BP readings are normal in both primary and secondary RP.

Trophic changes are uncommon in primary RP. Irreversible ischemia with tissue damage indicates secondary RP and requires further investigation to identify the underlying cause. ^[1]

General principles ^[1][4][6][7]

• RP is primarily a clinical diagnosis. ^[4][7]
• Exclude differential diagnoses of RP: E.g., See “Diagnostics” in peripheral arterial disease, acute limb ischemia, and thoracic outlet syndrome.
• Distinguish between primary and secondary RP.
  • The distinction may be clear based on medical history or clinical evidence of systemic disease.
  • In case of diagnostic uncertainty, consider diagnostic studies (i.e., antinuclear antibody, nailfold capillary microscopy).
• Secondary RP: Identify the underlying cause (see “Etiology” section for details).

Diagnostic studies ^[1][6][8]

Findings are described in the table below.

• Laboratory studies
  • CBC
  • Antinuclear antibodies (ANAs): if positive, send an ENA panel
  • Inflammatory markers (ESR or CRP)
• Nailfold capillary microscopy
  • An assessment of capillaries microvascular structure
  • One of the most sensitive methods of detecting early CTD ^[1]
• Cervical spine and upper thoracic imaging: Consider to evaluate for thoracic outlet syndrome caused by a bony cervical rib. ^[6][9]

Differentiation between primary and secondary RP

It is critical to evaluate for secondary RP because missing early CTD or other associated causes can have serious consequences.

Perniosis (chilblains) ^[11][12][13]

• Erythrocyanotic papules or nodules, predominantly on the hands, fingers, toes, legs, and face on exposure to cold
• Lesions appear 12–24 hours after exposure to cold and last for 1–3 weeks.
• Typically seasonal (colder months)
• See “Nonfreezing cold injuries” for details.

Acrocyanosis ^[14][15]

• No triphasic color response like in RP, nonparoxysmal manifestation (often persistent)
• Recurrent or frequently persistent bluish/cyanotic discoloration of the peripheral extremities
• Most commonly affects the hands; more rarely the feet, ears, nose, lips, and nipples
• Caused by decreased oxyhemoglobin due to vasospasm
• Usually triggered and/or aggravated by exposure to cold temperatures, most cases improve in summer.
• Trophic changes and ulceration are extremely rare.
• May be primary (idiopathic) or secondary to neurologic, autoimmune, infective, metabolic, or other causes

Erythromelalgia ^[16][17]

• Rare condition characterized by episodes of hyperperfusion that affect the feet and less commonly the hands
• Symptoms include intense burning pain, erythema, warmth, and swelling of the affected areas.
• Triggers include warmth and physical activity.
• May be primary (genetically determined) or secondary to myeloproliferative disorders, CTD, cancer, infections, or poisoning.

Peripheral artery disease (PAD)

• Exercise-induced pain (may also be persistent)
• Cold and pale extremities
• Diminished or absent radial or ulnar artery pulse
• Can be a cause of secondary RP (functional vasospasm), but must be considered as an independent differential diagnosis.

Acute arterial occlusion of an extremity

• Acute onset as in RP, but not episodic or self-limiting
• The “6 Ps” of clinical presentation: Pain, Pallor, Pulselessness, Paresthesia, Paralysis, Poikilothermia

Thoracic outlet syndrome ^[9][18]

• Typically unilateral
• Can be a cause of secondary RP (due to compression of the sympathetic nerves)

The differential diagnoses listed here are not exhaustive.

Approach ^[1][4]

• First line management in all patients: trigger avoidance and lifestyle measures to minimize vasospastic attacks
• Persistent symptoms
  • Consider pharmacotherapy.
  • Consider interventional therapies in patients with refractory disease and surgical treatment when indicated.
• Secondary RP
  • Identify and treat the underlying cause.
  • Specialist referral (e.g., immunology, rheumatology) for further management.

Trigger avoidance ^[1][4]

• Avoidance of cold (e.g., wearing warm gloves or multiple layers of clothing)
• Stress management (e.g., anxiety attacks, episodes of irritability/anger)
• Minimize vibration exposure (e.g., occupational use of power hand tools such as jackhammers)
• Smoking cessation (smoking promotes vasoconstriction)
• Discontinuation of medications that may trigger attacks (e.g., β-blockers, ergotamine, oral contraceptives)

Cold avoidance and stress management are key aspects of managing RP. ^[4][7]

Pharmacotherapy ^[1][4][6][7]

There is a paucity of evidence on the efficacy of pharmacotherapy in RP and currently, no drugs have received FDA approval for treatment of the condition. ^{[1][7][19][20]}

• First-line: calcium channel blockers monotherapy
  • Preferred: nifedipine ^[4][7]
  • Alternative: amlodipine OR felodipine ^[4]
• Second‑line: any of the following alone or in combination with calcium channel blockers
  • Oral: ARBs, ACE inhibitors, PDE5 inhibitors (sildenafil), SSRIs, α-blockers, nitrates
  • Topical vasodilators: glyceryl trinitrate (GTN) ^[21]
• Severe or complicated RP (e.g., refractory or recurrent digital ulcers)
  • IV prostanoid therapy (e.g., iloprost, epoprostenol) : alone or in combination with botulinum toxin
  • Endothelin-1 receptor antagonists (e.g., bosentan, macitentan): in patients with secondary RP due to scleroderma

Pharmacotherapy for RP often causes significant side effects (e.g., hypotension). Start all medications at a low dose and gradually increase as tolerated. ^[1]

Interventional therapies and surgery ^[1][4][6]

• Indications: refractory or severe RP (e.g., critical digital ischemia, as evidenced by persistent ulceration or gangrene)
• Procedures
  • Botulinum toxin injections ^[22]
  • Selective digital sympathectomy
  • Amputation when necessary