Early sign of microangiopathy in systemic sclerosis: The significance of cold stress test in dynamic laser Doppler flowmetry

1 Introduction

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by the vascular dysfunction and excessive fibrosis in the skin and other organs [1]. Raynaud’s phenomenon and digital ulcers are common clinical manifestations of the vascular dysfunction. The vascular dysfunction may result from endothelial injury and abnormal vasoconstrictions induced by autoantibodies [2].

Microcirculatory abnormalities in SSc are revealed by nailfold capillaroscopy as well as laser Doppler flowmetry (LDF). In fact, abnormal patterns and functions of nailfold capillaries revealed by nailfold capillaroscopy has been included in the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc [3, 4]. Abnormal nailfold capillary pattern in SSc included enlarged capillaries and capillary loss with or without pericapillary hemorrhages [3]. Alternatively, LDF could be used to assess local microvascular blood flow [5–8]. Currently, LDF is widely used in scientific research but its role in clinical use is constrained due to low diagnostic significance [9, 10]. Although previous literature showed baseline fingertip blood perfusion is lower in patients with SSc compared to controls, the difference was negated by heating probing at body temperature [8]. In other words, subtle microcirculatory abnormalities in SSc may not be detected by LDF using probes at body temperature. In patients with SSc, the value of LDF lies in measuring improvement of microcirculation before and after intervention [11–13].

Although microvascular disease is a hallmark of SSc, macrovascular abnormalities in SSc have also been well documented in the literature [14–19]. While microvascular and macrovascular abnormalities frequently coexist in disease such as diabetes mellitus and peripheral vascular disease, [20] the association between microvascular abnormalities and macrovasculopathy in SSc remains to be elucidated [21].

2 Hypothesis

Baseline microcirculatory blood flow measured by LDF may be normal in patients with SSc, even when macrovascular vasculopathy is obvious. LDF combined with cold stress test is required to detect the subtle microcirculatory abnormalities in SSc.

3 Supporting evidence

In this study, LDF and peripheral angiography were performed and compared to examine the microvascular and macrovascular abnormalities, respectively, in a patient with SSc. A 67-year-old non-smoking Taiwanese male came with multiple ulcerations on his fingers for one year. He has no history of diabetes mellitus or other underlying systemic diseases. Physical examination showed ulcers on the fingertips, sclerodactyly of the fingers, and Raynaud’s phenomenon. Laboratory survey showed positive antinuclear antibody titer [1:80], anti-centromere type. After excluding other causes contributed to vasculopathy such as Buerger’s disease and diabetes mellitus-related peripheral arterial occlusive disease, the diagnosis of SSc was made according to the 2013 ACR/EULAR criteria. For macrocirculation, the angiography revealed occlusions of bilateral ulnar arteries and proper palmar digital arteries on 2–5th fingers (Fig. 1A, B). For microcirculation, while the significance of nailfold capillaroscopy in SSc is well recognized, the role of LDF in SSc is less clear. We then measured LDF by a LDF machine (PeriFlux System 5000; Perimed, Stockholm, Sweden) [22–25] for the fingers and compared the results with angiographic findings. Although the occlusions of bilateral ulnar and digital arteries were obvious in angiography, the baseline skin temperature and perfusion unit on right fingers remained within normal limits (Table 1). In other words, there is discordance between macrovasculopathy and baseline microcirculatory blood flow. To further identify microcirculatory abnormalities, we performed cold stress test, which revealed a significant slow recovery of skin blood flow 40 minutes after cold stress (Fig. 2). Oral prednisolone and methotrexate were administered for diseases control. Low level laser therapy was also arranged for poor healing wounds on fingers. However, the treatments had limited effects. Fingers ulcers and sclerodactyly persisted despite treatments. Follow-up lab data still showed similar ANA titer.

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Fig. 1

Angiographic findings of systemic sclerosis. Total occlusion of bilateral ulnar arteries were obvious. Occlusion of proper palmar digital arteries on bilateral 2–5th fingers were also observed.

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Fig. 2

Dynamic blood flow detected by laser Doppler flowmetry (LDF) 40 minutes after cold immersion. Bilateral hands were immersed in cold water (4°C for 10 minutes) and then exposed to room temperature. At room temperature, blood flow of ring finger of each hand was measured and expressed as perfusion unit (PU). PU was measured every minute in the first 10 minutes and every other minute in following 30 minutes. The blood flow of the patient showed slow recovery after cold immersion in contrast to dramatic rebound of the normal control.

The macro- and microcirculatory abnormalities as measured by angiography and LDF may be discordant. Cold stressor/immersion test with LDF might be required to demonstrate the subtle abnormalities of microcirculatory blood flow in SSc. This might be explained by the cutaneous microvasculature anatomy.

Cutaneous microcirculation is classified into two horizontal plexuses, which are located in the papillary dermis and the dermal-subcutaneous junction, respectively. While arteriovenous anastomoses are located in the two plexuses and are responsible for thermoregulation, the superficial plexus is also the source of capillary loops, which offer nutritional support to the skin and consist only a small proportion of cutaneous blood flow [26]. In nailfold, capillary loops are characterized by horizontal parallel pattern so that a large part of the loops can be observed using dynamic capillaroscopy [27]. In SSc, the structure and the function of capillary loops in nail folds is abnormal. While capillaroscopy measures only the superficial nutritional plexus, LDF measures gross cutaneous blood flow, including blood flow in the two plexuses. Because of compensation within thermoregulatory flow, the baseline finding of LDF may be normal even if the gross occlusion of arteries is obvious [28]. In that case, cold stress test is essential to measure the dynamic and slow recovery of blood flow as induced by sympathetic dysfunction, [22, 29–31] which may result from the endothelial injury induced by autoantibodies in SSc [32, 33]. A recent study showed that, in patients with metabolic syndrome, a disease with endothelial dysfunction, vasoconstriction and vasodilatation indices correlate with metabolic parameters and VEGF levels [34]. Since endothelial dysfunction in SSc is likely related to autoantibodies, a comparison study performed in SSc patients would help further address which mediators are involved in autoantibodies-mediated endothelial dysfunction.

5 Conclusion

Microcirculatory abnormalities in SSc are revealed by nailfold capillaroscopy and LDF. The dynamic changes of LDF flow induced by cold stress test are required to demonstrate the subtle microcirculatory abnormalities in SSc.

Funding sources

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Conflicts of interest

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