Etiology

RP is highly heritable, with reported estimates ranging from 55% to 64%.[5] A large genome-wide association study identified three genomic regions associated with RP, implicating three genes: ADRA2A, IRX1, and to a lesser extent MICB.[5]​ People with gene variants at these loci may have a higher risk of developing RP. In primary or secondary RP, a family history of RP or connective tissue disease may be present.[3]

Primary or idiopathic RP

The cause of primary RP is not fully understood. Vasospasm is a normal reaction to cold or temperature change, but this is exaggerated in primary RP. It has been suggested that this dysfunction in thermoregulation is due to genetic factors resulting in the overexpression and overactivity of alpha-2 adrenergic receptors, ultimately leading to extreme vasoconstriction.[2][5]​​​

The association with primary RP and other vasospastic conditions such as migraines and Prinzmetal variant coronary angina suggests a common cause.[2][3]​​​[6]

Secondary RP

Secondary RP is associated with an underlying cause such as an underlying medical condition, environmental exposure, or specific drugs.[2]

Underlying conditions:

  • Autoimmune connective tissue disease (ACTD), especially systemic sclerosis (SSc), scleroderma, or inflammatory myositis

  • Other rheumatologic diseases (e.g., rheumatoid arthritis, Sjogren syndrome, vasculitis)

  • Vascular occlusive diseases (e.g., Buerger disease)

  • Hematologic syndromes

  • Malignancy

  • Infections

  • Peripheral vascular disease.

See Systemic sclerosis (scleroderma), Rheumatoid arthritis, Sjogren syndrome, and Buerger disease.

Environmental exposures:

  • Vibration injury (from tools e.g., jackhammers)

  • Frostbite.

See Frostbite.

Drugs:[7]

  • Beta-blockers

  • Migraine therapies (e.g., clonidine, ergotamine)

  • Chemotherapy (e.g., bleomycin, cisplatin, vinblastine)

  • Cyclosporine

  • Stimulants (e.g., caffeine, cocaine, amphetamines).

Environmental exposure-related secondary RP is different from others in that there is not necessarily a fixed defect of the vascular walls of arteries/arterioles, whereas in other secondary RP there are potentially more exaggerated vascular abnormalities and endothelial dysfunction.[8][9]

Pathophysiology

Normal thermoregulation in response to cold temperatures involves a decrease in blood flow through arteriovenous (AV) anastomoses, and this is mediated by alpha-2 adrenergic receptors in these vessels. In both primary and secondary RP, the overexpression and overactivity of alpha-2 adrenergic receptors results in decreased nitrous oxide concentrations in the vascular smooth muscle, resulting in extreme vasoconstriction and consequently pallor, cyanosis, and/or rubor.[2][5]​​[10][11]​​[12]​ Thermoregulatory responses are exaggerated in acral skin, and RP therefore usually appears on the fingers and toes, and more rarely the ears, nose, tongue, nipples, or the entire hand/arm or foot/leg.[2]

One genome-wide association study (GWAS) suggests that variants in the ADRA2A gene region cause increased expression of alpha-2 adrenergic receptors in arterial tissue.[5]

Classification

The classification of RP into two clinical subtypes helps distinguish patients with dysregulation of the thermoregulatory pathway (primary RP) from those who experience altered vascular reactivity due to an underlying causative process (secondary RP).[1]

Primary or idiopathic RP[2]

RP not associated with an underlying cause. Although primary RP can be exacerbated by environmental factors (e.g., cold exposure, stress, drugs), it follows a nonprogressive course, and the clinical manifestations are reversible and usually do not result in tissue damage.

Secondary RP[2]

RP associated with an underlying cause. Secondary RP may lead to progressively severe clinical manifestations, resulting in permanent tissue damage when left untreated. Several causes have been associated with secondary RP. See Etiology.

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