Objective: A key unanswered question in systemic sclerosis (SSc) is how microvascular
abnormality and fibrosis inter-relate. Our aim was to use state-of-the-art non-invasive
imaging methods to gain new insights into pathophysiology, comparing patients with
different subtypes of SSc, including early dcSSc, not only to healthy controls but also to
patients with causes of Raynaud's phenomenon not progressing to fibrosis.
Methods: Laser Doppler imaging, nailfold capillaroscopy, spectroscopy, and ultrasound
measured (respectively) perfusion, microvascular structure, oxygenation/oxidative stress,
and skin thickening in the hands of 265 subjects: 31 patients with primary Raynaud’s
phenomenon (PRP), 35 with undifferentiated connective tissue disease (UCTD), 93 with
limited cutaneous SSc (lcSSc), 46 with diffuse cutaneous SSc (dcSSc, including 27 ‘early’) and
60 healthy controls.
Results: Mean perfusion was reduced in SSc groups compared to controls (lcSSc 172 perfusion
units [standard deviation 157], late-dcSSc 90 , early-dcSSc 68  vs. controls 211
; p=0.0002) as was finger-oxygenation (lcSSc 12.1 [13.6] arbitrary units [AU], late-dcSSc
12.2 [8.4], early-dcSSc 11.1 [11.3] vs controls 14.9 [10.5]; p=0.0049). Oxidative stress was
increased at the hand-dorsum in SSc groups (p=0.0007). Perfusion positively correlated with
oxygenation (r=0.23, p<0.001), and capillary density negatively with skin thickness (r=-0.26,
Conclusion: Our findings lend support to the hypothesis that in SSc, particularly early dcSSc,
(but not in PRP or UCTD), reduced perfusion (together with structural microvascular
abnormality) associates with reduced oxygenation, with oxidative stress and with skin
thickening/fibrosis, most likely driving a vicious cycle which ultimately results in irreversible
tissue injury. Findings in skin may mirror alterations in internal organs.