Raynaud’s Phenomenon: A Brush Up! : Indian Dermatology Online Journal

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Raynaud’s Phenomenon: A Brush Up!

Swarnkar, Bhavya1; Sarkar, Rashmi2,

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Indian Dermatology Online Journal 14(2):p 248-255, Mar–Apr 2023. | DOI: 10.4103/idoj.idoj_311_22
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Raynaud’s phenomenon manifests as episodic vasospasm leading to acral vascular compromise following emotional stress or exposure to a cold environment. It usually manifests in three phases: pallor (vasospasm), cyanosis (blood stasis), and rubor (reperfusion). Occasionally, only two phases may also be present.[1] Maurice Raynaud was the first to describe this entity in 1862 and it was called Raynaud’s disease.[2] Later, Hutchinson and others suggested the title ‘Raynaud’s phenomenon’ as there are various causes of this phenomenon. It is of two types, idiopathic/primary (Raynaud’s disease) and secondary which occurs due to some underlying cause.

Primary: Out of all the cases of Raynaud’s phenomenon, the primary type forms the majority of it (80-90%). Occurs in younger females (<30 years) often with positive family history. Sir Thomas Lewis described the physiological and structural differences between both types of Raynaud’s phenomenon.[3]

The distinction between Raynaud’s disease and secondary Raynaud’s phenomenon is of utmost importance because of differences in pathophysiology and hence natural course, prognosis, complications, associations, and treatment.


Raynaud’s phenomenon is quite frequent in the general population with a prevalence of about 5%. The prevalence of idiopathic Raynaud’s is reported to be higher in women (2-20%) than in men (1-12%) and almost 50% of them have a positive family history, especially in females and those with early onset disease.[1]

The prevalence of this entity in various connective tissue diseases is shown in Table 1 below.[4]

Table 1:
Prevalence of Raynaud’s phenomenon in various connective tissue disorders


Primary Raynaud’s phenomenon has no underlying cause while secondary has various etiologies as depicted in Table 2 below.[5] Autoimmune connective tissue diseases are the commonest causes of secondary Raynaud’s with Systemic sclerosis, Mixed connective tissue disease, Sjogren syndrome, and Systemic lupus erythematosus being the most common among them.[6]

Table 2:
Causes of secondary Raynaud’s phenomenon

Pathogenesis underlying Raynaud’s phenomenon had not yet been properly elucidated. Initially, Raynaud hypothesized that these vasospastic episodes develop secondary to irritability of the spinal cord affecting vascular innervation. Around 70 years later, Lewis and Pickering suggested that local effects cause vascular spasms, not CNS abnormalities.[5] Multiple factors including mediators released by blood cells, blood vessels, hormones, and probably neuronal factors control blood vessel reactivity. Herrick divided pathophysiological mechanisms into three major parts, abnormalities in vessels, abnormalities in the nervous system, and abnormalities within the vessels.[7] Some more factors may also play a role.

  • Abnormalities in vessels:
  • In Raynaud’s disease, the vascular abnormality is mostly functional while in secondary cases, the abnormality is both structural and functional leading to compromise in vascularity.
  • Endothelial dysfunction- Disturbance of homeostasis of endothelial cells may cause vasoconstriction.
  • A deficiency of nitric oxide (NO), a vasodilator may also be a contributory factor. In a study, a higher level of asymmetric dimethylarginine (inhibitor of NO synthase) was noted in secondary Raynaud’s cases.[8] Endothelin-1 (a potent vasoconstrictor) and angiotensin (vasoconstrictive and profibrotic) are also found to be increased in some cases.[9]
  • Structural abnormalities- They are present in secondary cases of Raynaud’s but not the primary. In systemic sclerosis cases, fibrotic intimal proliferation and minimal proliferation of tunica media of vessels have been observed. Small arterioles and capillaries may also develop intraluminal thrombi affecting the vascularity of the area.[10] Concurrent with intimal proliferation and because of anti-endothelial cell antibodies, there is endothelial cell damage as well. These damaged endothelial cells may exacerbate vasospasm by perturbing the smooth cell function of blood vessels, increasing the inflammatory process by releasing adhesion factors, and by promoting procoagulant activity within the vessels.[11]
  • Other factors like pericyte activation and growth factors and cytokines expression may also form a part of the pathogenetic pathway for vessel wall abnormality.[12] All these factors leading to vascular compromise with incomplete compensation lead to hypoxia of tissue.
  • Abnormalities in nerves:
  • The tone of cutaneous vessels is adjusted by the transmitters released by sensory and autonomic nerves. In Raynaud’s case, vasoconstriction is mediated by neuropeptide dysregulation and α2-adrenoreceptors upregulation.[5]
  • Central mechanisms- Stress-induced Raynaud’s phenomenon suggests the involvement of our nervous system in its pathophysiology. Edwards et al. suggested that individuals with Raynaud’s phenomenon do not acclimatize to response (cutaneous vasoconstriction) induced by emotional stress while healthy individuals do. Hence, the abnormal modulation of the brain stem, where the cardiovascular response to acute emotional stress is integrated, leads to the non-habituation of vascular response to repetitive stress. This leads to cutaneous vasoconstriction to each emotional stimulus in such patients while there is habituation with no such cutaneous changes, except after the first stimulus, in healthy individuals.[13]
  • Impaired vasodilatation: In Raynaud’s patients, calcitonin gene-related peptide (vasodilatory) release from neurons supplying vessels is diminished.[14] In systemic sclerosis cases, the level of neuropeptide Y, a vasoconstrictor, anti-angiogenic, and a very effective stimulator of the smooth muscle cell, is increased which might be a responsible factor for Raynaud’s phenomenon.[15]
  • Increased vasoconstriction- The ability of sympathetic nerves to get stimulated to cause vasoconstriction on the cooling of the body is augmented in Raynaud’s patients.
  • The pathway leading to vasospasm is mentioned below in Figure 1.[5]
  • Intravascular abnormalities:
  • Various intravascular circulatory factors might cause/exacerbate Raynaud’s phenomenon, especially in secondary cases.
  • Platelet activation- Platelet activation and aggregation has been noticed in Raynaud’s cases. The release of thromboxane A2 (vasoconstrictor, platelet aggregator) and serotonin (vasoconstrictor) is increased from these activated platelets leading to Raynaud’s.[16,17]
  • Decreased fibrinolysis- It is probably normal in idiopathic Raynaud’s, while in systemic sclerosis fibrinolysis is impaired leading to the formation of intravascular thrombi.[18] There are contradictory studies with some showing increased tissue plasminogen activator antigen levels while others showed increased tissue plasminogen activator inhibitor levels.
  • Reactive oxygen species- Recurrent episodes of vasospasm lead to reperfusion injury of endothelial cells by augmenting the production of reactive oxygen species. This leads to further vasospasm.[19]
  • Other factors like estrogen and genetics might play a role. The familial nature of the disease (primary > secondary) might point towards the genetic component of the disease. Various genes like those encoding acetylcholine and serotonin receptors might have a role to play.[20]

Figure 1:
Sequence of events leading to vasospasm

The pathogenesis is summarized below in Figure 2.

Figure 2:
Pathogenesis of Raynaud’s phenomenon

Clinical Manifestations and Evaluation


There is a triphasic/biphasic vascular response over hands, feet, nose, ears, lips, and nipples on cold exposure/emotional stress, in cases of Raynaud’s phenomenon [Figure 3]. In idiopathic cases, there is symmetrical involvement with minimal pain while in secondary Raynaud’s usually there is asymmetrical involvement with intense pain.[5] More cyanosis, less rubor, and more thumb involvement have been reported in secondary cases as compared to primary cases. Differential diagnoses include acrocyanosis (persistent symmetrical cyanosis exacerbated on cold exposure) and erythromelalgia (erythema and pain exacerbated on heat exposure rather than cold).[1]

Figure 3:
Cyanosis of the distal end of fingers on cold exposure representing Raynaud’s phenomenon (Credits: Dr. M. Ramam, Professor, Department of Dermatology, AIIMS, New Delhi)

LeRoy and Medsger suggested the following criteria for diagnosing Raynaud’s disease (idiopathic)[21]

  • Episodes of acral cyanosis/pallor
  • Symmetrical involvement and peripheral pulses are strongly felt
  • Absent digital pitting/ulceration/gangrene
  • Normal erythrocyte sedimentation rate (ESR)
  • Normal nail fold capillaroscopy
  • Negative antinuclear antibodies (titer <100).

Rarely, fingertip ulceration and pitted scars can be seen.

It usually has a benign course with a good prognosis but has a remote possibility of evolving to secondary Raynaud’s. Based on a population-based study, a remission rate of 3% per year was found.[22] According to a study by Gerbracht et al., 5% of patients with Raynaud’s disease developed clear evidence of connective tissue disease after a mean follow-up of 8.8 years (range 2-34.5 years). The authors concluded that the evolution of primary Raynaud’s to secondary is rare in the first decade of their disease. In those situations of transition, a mean duration of around nine years is usually required.[23] According to other studies, the frequency of the development of connective tissue disease varied from 10-30%.


Patients with secondary Raynaud’s might also have a digital ulcers, pitted scars, acro-osteolysis, nail dystrophy, onycholysis, inverse pterygium, osteomyelitis, etc.[5] Digital ulcers, pitted scars, dry gangrene, and loss of digits occur as a complication of Raynaud’s phenomenon.

Examination of peripheral pulses and Adson’s maneuver (to rule out scalenus anticus syndrome/cervical rib) are of utmost importance, especially in asymmetrical involvement. The cardiovascular and respiratory examination should be done to rule out associated diseases like interstitial lung disease in the case of systemic sclerosis. Nail fold capillaroscopy should be done using a dermatoscope. Figure 4 shows normal nail fold capillaroscopy findings with uniform distribution of hairpin-shaped capillaries. Abnormal nail fold capillaries, dilated capillaries, capillary dropouts [Figure 5], and avascular areas suggest secondary cases of Raynaud’s phenomenon.

Figure 4:
Normal nail fold capillaroscopy showing the uniform distribution of hairpin-shaped capillaries (Credits: Dr. Vishal Gaurav, Senior resident, Department of Dermatology, AIIMS, New Delhi)
Figure 5:
Nail fold capillaroscopy showing capillary dropouts at the cuticle of a finger in a case of systemic sclerosis (Credits: Dr. Vishal Gaurav, Senior resident, Department of Dermatology, AIIMS, New Delhi)


Blood investigations include complete hemogram, hepatic and renal function tests, urine routine and microscopy, urine albumin level, ESR, C-reactive protein, anti-nuclear antibody, other antibodies based on suspected underlying autoimmune disease, and serum immunoglobulin (suspected paraproteinemia). X-ray chest rules out the cervical rib as a cause in asymmetrical cases.[24] These investigations can be utilized in resource-limited settings.

Arterial doppler should be done in a suspected case of proximal vessel involvement/obstruction. Other investigations (mainly for research purposes) include thermography and laser-derived tests.[25]


European League Against Rheumatism/European Scleroderma Trials and Research group systemic sclerosis (EULAR/EUSTAR SSc) 2016 guidelines and British Society of Rheumatology 2016 guidelines recommend following treatment approach for the management of patients of primary and secondary Raynaud’s [Figure 6].[26,27]

Figure 6:
Treatment approach for the patients of primary and secondary Raynaud’s

Nonpharmacological measures are of utmost importance for the management of Raynaud’s phenomenon. They involve cessation of smoking, avoidance of causative drugs like methysergide, cyclosporine, etc., and cold protection measures. Cold protective measures include avoiding/reducing exposure to a cold environment, shifting, if possible, to a place with moderate temperature throughout the year is an option, wearing gloves and socks in cold weather, wearing footwear when walking on a cold floor, and using lukewarm/normal temperature water for bathing, washing clothes and utensils.

Pharmacological options are added if there is no response to general measures alone. Calcium channel blockers, phosphodiesterase 5 inhibitors, angiotensin receptor blockers, prostanoids, botulinum toxin, and digital sympathectomy are the available treatment modalities.

Calcium channel blockers (CCBs)

Dihydropyridines like Nifedipine are the first-line management options for the management of Raynaud’s phenomenon. Based on a meta-analysis, they have a positive effect on the disease because of a peripheral vasodilatory effect. In comparison with non-dihydropyridine CCBs, the results were more impressive with dihydropyridines. CCBs decrease the severity and frequency of the episodes of Raynaud’s phenomenon, but the effects were better in primary than secondary Raynaud’s. This might occur because of the associated vasculopathy changes in secondary cases. For patients with secondary Raynaud’s, the severity based on the visual analog scale and frequency of episodes (episodes/week) dropped by a mean difference of -0.48 and -3.15 respectively.[28]

Phosphodiesterase 5 inhibitors

These are second-line agents for Raynaud’s phenomenon. They work by increasing the availability of NO. A meta-analysis (92% cases with systemic sclerosis-associated Raynaud’s) revealed that these agents significantly decrease Raynaud’s condition score by -0.46, frequency by -0.49, and daily duration of episodes by -14.62 min. Overall, they were found to be moderately effective for Raynaud’s associated with systemic sclerosis.[29] A double-blind randomized controlled trial compared the efficacy of udenafil and amlodipine and found them to be equally effective.[30] However, due to more experience with CCBs in Raynaud’s, they are the preferred agents.

Angiotensin receptor blockers

They are the third-line option for mild Raynaud’s. The mechanism of action is peripheral vasodilation by blocking angiotensin receptors. A non-blinded randomized controlled trial comparing nifedipine (20 mg twice daily) and losartan (50 mg once daily) in primary and systemic sclerosis-related secondary Raynaud’s was done. It was found that in secondary Raynaud’s, the severity of episodes decreased to a greater extent in the losartan group (36% versus 9%) while the frequency decreased by 45% in the losartan group and increased by 56% with nifedipine.[31] The up-dosing was not done to increase the efficacy of these medications in that study. The effectiveness of Angiotensin receptor blockers has not yet been properly evaluated but they appear to be weaker agents for the management of Raynaud’s.


They induce vasodilation by stimulating prostacyclin receptors. Usually considered as a rescue option for the management of severe refractory Raynaud’s. The frequency of the attacks fell by the mean of -0.8 by intravenous iloprost, based on a meta-analysis.[32] Oral prostacyclin analogues failed to show any benefit.

Other agents

There is limited evidence of their role in the management of Raynaud’s phenomenon. Because of the inhibition of platelet activation, aspirin might play a role in Raynaud’s. Other agents like atorvastatin, fluoxetine, and pentoxifylline might have an ancillary role. A meta-analysis highlighted the statistically significant benefit of topical nitrates in secondary Raynaud’s.[33]

Some observational studies showed improvement of Raynaud’s phenomenon with endothelin receptor blockers like bosentan, and ambrisentan but a randomized placebo-controlled study failed to show any significant difference from that of placebo.[34] Hence, more controlled trials need to be performed to explore the benefits of these agents in Raynaud’s phenomenon.

Two large, controlled trials showed that Endothelin receptor blockers help prevent digital ulcers in systemic sclerosis patients.[35,36]

Invasive options

The fifth line option for severe Raynaud’s is botulinum toxin injections or digital sympathectomy. The role of botulinum toxin is controversial at present. The use of sympathectomy should be individualized and used only for refractory patients.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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