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Pathogenesis of RP
The pathogenesis of RP involves a complex interplay between
genetic, neural, vascular and intravascular factors. Although a
detailed review of the pathogenesis of RP is beyond the scope of this
review, an overview of the key pathogenetic mechanisms informs
a systematic approach to both the assessment and management
of RP. We will highlight the main pathogenic mechanisms that have
been implicated in PRP and/or SSc-RP to date.
Genetic
Genetic factors appear to play an important role in the
development of RP as demonstrated in familial and twin studies.13
Indeed, previous work has demonstrated half of patients with PRP
have positive family history with first degree relatives having RP.
Of mechanistic and therapeutic interest, Munir et al reported that
RP is associated with a polymorphism in the NOS1 gene.14
Vascular
Increased vascular tone including vasospasm including the digital
arteries is central to the pathogenesis of RP.15,16 In SSc, there is
endothelial dysfunction and overproduction of vasoconstrictors
(eg endothelin-1 and angiotensin II) and impaired vasodilation
with reduced production or reduced efficacy of vasodilators (eg
nitric oxide and prostacyclin).17,18
Neural
The primary deficit in PRP is considered to be a ‘local fault’ in
vascular function of thermoregulation.19 Central autonomous
involvement has also been suggested to be important in the
pathogenesis of connective tissue disease-associated RP.20 Cold
stimuli causes relocation of alpha 2c-adrenergic receptors from the
Golgi apparatus to the cell surface, through activation of the rho
kinase, which then increases the sensitivity of contractile proteins
and subsequent vasoconstriction.21 Increased alpha 2c-adrenergic
expression in vascular smooth muscle cells has been reported in
RP.22 Vasoconstriction compromises arteriovenous anastomoses
and nutritional blood flow, which is further compounded in
patients with SSc by vascular damage and occlusion.18,19
Abnormalities in vasoactive peptides (eg of calcitonin gene-
related peptide vascular biology) have also been implicated in the
pathogenesis of RP.23
Intravascular factors
Intravascular factors are also likely to play an important part in
the pathogenesis of RP through increased viscosity (for example in
certain haematological disorders). Contributory mechanisms which
have been implicated in the pathogenesis of RP include (but are
not limited to) platelet and white cell activation, red cell structural
deformity and defective fibrinolysis.2