Epidemiology and Etiology
- Primary Raynaud’s phenomenon (PRP): Idiopathic, with no identifiable cause
- Much more common than secondary RP (SRP)
- Highly prevalent in the general population: 3%–21% depending on the climate (higher prevalence in colder climates)
- 9 times more common in women than men
- 25% of patients have a positive family history of the condition
- Begins at a younger age than SRP, typically starting at 15–25 years; unusual over the age of 40 years, but can occur at any age, even in infants
- Migraine and variant (Prinzmetal’s) angina are overrepresented in this population.
- May precede SRP by 2 decades; in 1 metanalysis, 13% of primary RP patients eventually developed an autoimmune rheumatic disease.
- Secondary Raynaud’s phenomenon
- Refers to the presence of the phenomenon in association with an underlying illness, most commonly an autoimmune disease such as systemic sclerosis or systemic lupus erythematosus; or with drug use, from occupational hazards, etc.
- Trophic changes in skin and subcutaneous tissue may be seen in SRP (but not in PRP)
The causes of secondary Raynaud’s phenomenon are outlined in the table below.
Mnemonic for secondary Raynaud’s phenomenon: I, COLD HAND
- Cold agglutinins/Cryoglobulinemia/Cryofibrinogenemia
- Lupus erythematosus, other autoimmune/connective tissue diseases
- Diabetes mellitus, other endocrinologic diseases
- Hematologic disorders
- Arterial occlusive diseases
- Neurologic disorders
|Hematologic and hyperviscosity syndromes|
|Autoimmune disorders/connective tissue diseases|
|Arterial occlusive disease|
Three basic pathophysiologic mechanisms have been proposed:
- Seen in both PRP and SRP
- High levels of vasoconstrictors (e.g., nitric oxide) plus low levels of vasodilators (e.g., endothelin 1) cause vasoconstriction of digital arteries and cutaneous arterioles.
- Diminished calcitonin-secreting neurons in both primary and secondary disease (calcitonin is a potent vasodilator)
- Increased contractile response as a result of increased protein tyrosine kinase activity in PRP
- Increased neuropeptide-Y, a potent vasoconstrictor, in PRP secondary to systemic sclerosis
- Increased platelet aggregation and increased thromboxane A2 secretion in PRP and in SRP secondary to systemic sclerosis
- Fibrotic proliferation in systemic sclerosis
Clinical features seen in both primary and secondary Raynaud’s phenomenon
- Ischemic phase: Arterial vasospasm in the digits, and much less commonly on the tip of the nose, tongue, ear lobes, and nipples, occurs with exposure to cold or emotional stress, causing distal blanching and, usually, transient numbness.
- Hypoxic phase: Dilation of capillaries and venules containing deoxygenated blood causes subsequent cyanosis.
- Hyperemic phase: With rewarming and resolution of vasospasm, oxygenated blood flows into the dilated capillaries and venules, causing hyperemia and erythema. This phase may be accompanied by a painful pulsating sensation.
Features of PRP
- Mild and reversible benign condition, symmetric, usually lasting less than 20 minutes
- Often goes into remission
- Nailfold capillary microscopy: normal (no enlarged, distorted, or absent capillary loops) (note: Nailfold capillaroscopy is the procedure most commonly used in clinical practice to differentiate PRP from SRP)
- No trophic changes (no skin or subcutaneous changes, ulcers or gangrene); if present, workup needed to exclude SRP
- Migraine headaches and variant (Prinzmetal) angina have higher prevalences in PRP, but it is not known if they share a common pathogenetic mechanism.
Features of SRP
- More severe form than PRP, so trophic changes in digits can occur, including sclerodactyly (puffy fingers with skin tightening), pitting scars, and ulcers; rarely, gangrene occurs
- Remission is not common.
- If absent pulses and/or asymmetrical presentation, suspect non-reversible vascular occlusion, which may be primary or superimposed on SRP
- May also show ischemic changes in the more proximal segments of the limb
- Nailfold capillary microscopy:
- Often abnormal
- Enlarged, distorted, or absent capillary loops suggest an autoimmune rheumatic disease (loss of loops suggests scleroderma).
- Features warranting further investigation for SRP include:
- Older age at onset
- Male patient
- More severe symptoms or fixed, irreversible lesions
- Asymmetric involvement
- Systemic signs
- Abnormal capillary microscopy
- Abnormal laboratory findings
- Laboratory workup for secondary causes is directed by history and physical examination and may include:
- Autoantibody investigations, including antinuclear antibody (ANA), cyclic citrullinated peptide antibodies/immunoglobulin G (IgG), and scleroderma-related autoantibodies, including anticentromere (anti-CENP-B), anti-Th/To, antitopoisomerase I (Scl-70), and anti-RNA polymerase III
- Complete blood count
- Erythrocyte sedimentation rate
- C-reactive protein
- Cessation of tobacco smoking
- Keeping warm by avoiding cold exposure and wearing proper clothes, not only for hands and feet but the whole body, to prevent cold-induced reflex vasoconstriction
- Avoiding or managing emotional stress
- Avoiding vasoconstrictive drugs (nasal decongestants, amphetamines, methylphenidate sumatriptan, herbal drugs with ephedra)
- Dihydropyridine calcium channel blockers (CCBs) such as oral nifedipine and amlodipine (non-dihydropyridine CCBs such as diltiazem are less effective). If CCBs not tolerated or contraindicated, then one or more of the following can be prescribed:
- Alpha-1 adrenergic antagonists such as prazosin, doxazosin, and terazosin
- Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, tadalafil, and vardenafil
- Topical nitrates (not in conjunction with PDE5 inhibitors because of the risk of severe hypotension)
- Angiotensin II receptor blockers
- Selective serotonin reuptake inhibitors
- If severe acute ischemia threatening digital loss: Start and keep on anticoagulation therapy until a thrombotic cause is excluded, then start a CCB, followed by IV prostaglandin (prostacyclin/PGI2 preferred) if no response to CCB, then local or regional block if IV prostaglandin unavailable or there is insufficient response.
Cases refractory to medical therapy and lifestyle modifications
- Digital sympathectomy
- Local injection of botulinum toxin may be effective but not in all patients.
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- Winter A R, Camargo Macias K, Kim S, et al. (May 22, 2020) The Effect of Abobotulinum Toxin A on the Symptoms of Raynaud’s Phenomenon: A Case Series. Cureus 12 (5): e8235. DOI 10.7759/cureus.8235
- Bello RJ, Cooney CM, Melamed E, et al. The Therapeutic Efficacy of Botulinum Toxin in Treating Scleroderma‐Associated Raynaud’s Phenomenon: A Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial. Published: April 20, 2017. Retrieved from: https://doi.org/10.1002/art.40123