Institut für Röntgendiagnostik, University of Würzburg, Würzburg,
1 Medizinische Poliklinik, University of Würzburg, Würzburg and
2 Siemens AG, Medical Engineering Group, Erlangen, Germany
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Abstract |
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Methods. Vascularity in the nailbeds of 15 healthy controls and 35 patients with CTD (systemic sclerosis or systemic lupus erythematosus) was quantified using a multi-D array transducer before and after cold and warm challenge, respectively. The results were compared with the clinically evaluated initial skin lesions. Vascularity was compared similarly between 10 pRP and 22 sRP patients.
Results. Vascularity at ambient temperature differed between healthy subjects and sRP patients as well as between healthy subjects and CTD patients without initial skin lesions. Patients with pRP had normal vascularity at ambient temperature but differed from healthy controls in response to a dynamic temperature challenge. CDU confirmed the clinical evaluation in 89.4% of the patients with RP and in 78.0% of the skin lesions.
Conclusion. The novel CDU technique presented here makes it possible to discriminate between pRP and sRP and to quantify vascular changes in CTD patients.
KEY WORDS: Connective tissue disease, Raynaud's phenomenon, Ultrasound, Doppler studies.
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Introduction |
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Various methods, including nailfold microscopy, laser Doppler flow monitoring, thermography and plethysmography, have been used to evaluate distal digital vascularity and to assess the microvascular damage that has accumulated [3]. However, due to lack of availability, feasibility and reproducibility, none of the above methods has been generally accepted in clinical routine [3]. In our search for a convenient method to evaluate peripheral vascularity, we used colour Doppler ultrasound (CDU) together with novel ultrasound array technology in order to visualize the smallest vessels in the nailbed, which have an extremely low blood flow. We checked whether this method would be useful in differentiating pRP from sRP, as a possible clinical application. In addition, we evaluated the method in the assessment of both the presence and the severity of digital vascular damage in CTD by comparing the digital skin lesions found on initial clinical evaluation with the vascular changes determined by CDU. Our results hold promise as the basis for a means of identifying those patients with or without RP who have underlying CTD at an early stage in the course of the disease. A standardized examination, including functional tests, was established and the results were categorized for clinical use.
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Patients and methods |
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Ultrasound examination
All CDU examinations were performed by the same person (MJ), who was not aware of the patients' diagnoses. In control subjects and patients, both the second and third right finger were examined. In patients with disease-related digital skin damage, at least one of the two fingers examined had initial lesions. The examinations were performed according to the following protocol. After 20 min of acclimatization at ambient temperature (1921°C, baseline vascularity) the hand to be studied was positioned stably on a soft pillow. Dorsovolar scans of the nailbed (sagittal and transverse; Fig. 1A and B
, respectively) and of the fingertip (transverse; Fig. 1C
) were obtained in a standardized manner and stored digitally on a picture archiving and communication system. To avoid misinterpretation of colour signals caused by motion artefacts, in some cases pulsed Doppler was used for clarification. In addition, the distal radial and ulnar arteries and the digital arteries were analysed in all patients in order to exclude a haemodynamically relevant stenosis of these vessels. Patients with such stenoses were not included.
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Dynamic challenge
To induce hyperaemia, control subjects and patients placed their right hand into warm water (40°C) for 5 min before CDU was repeated. After at least 15 min of re-equilibration to baseline conditions at ambient temperature, the subjects placed their right hand into cold water (10°C) for 5 min to induce vasoconstriction before CDU was repeated. In all cases the dynamic challenges were well tolerated.
Technical aspects of the ultrasound examination
The studies were performed with a Sonoline Elegra Advanced ultrasound machine equipped with a newly developed multi-D linear array transducer (MDA) (VFX 135; Siemens Medical Systems, Ultrasound Group, Issaquah, Washington, USA). The VFX 135 covers a high frequency range (up to 13 MHz) and is designed for the high-resolution imaging of superficial structures. This broadband transducer is capable of transmitting very short ultrasound pulses and has the advantage of high axial resolution. MDA transducers comprise multiple rows of transducer elements. Conventional linear arrays have a single row of elements and generate non-homogeneous elevation beam profiles, i.e. profiles that are perpendicular to the scanning plane. The elevation beam profile is typically wider in the near depth range as well as in the far depth range, and is focused only in the mid range. Using multi-D technology, the elevation beam profile is depth-controlled. For echoes from near the surface, only the inner row of elements is activated, whereas for echoes from deeper structures multiple rows of elements are employed. This results in a reduced slice thickness, particularly in the near range. Consequently, lateral resolution in the elevation direction is increased, partial volume artefacts are reduced, and contrast resolution in the image is improved. The VFX 135 transducer is therefore particularly suited to tissue and colour flow imaging of structures close to the skin surface. Multi-D technology is widely available and the costs are similar to those associated with the use of other high-frequency transducers.
We used standard frequencies of 12.0 MHz for B-mode and 9.0 MHz for colour-mode scanning with the focus at 5 mm. The ultrasound system was optimized to detect the lowest signal possible by selecting a low pulse-repetition frequency (551 Hz), a low wall filter, and a high priority (14). Colour gain was adjusted at the beginning of each examination by selecting the highest value at which the colour image was still unaffected by artefacts.
Quantification of colour signals and anatomical definition of the region of interest
To determine vascularity on the three scans obtained from each of the fingers examined, we defined a region of interest (ROI), which was located between the fingernail and the bony surface of the distal phalanx between the nailfold proximally and the end of the fingertip distally (sagittal scan of the nailbed), which did not include the lateral digital arteries in the transverse plane (transverse scan of the nailbed just distal to the nailfold), and which was surrounded by the skin surface (transverse scan of the fingertip just distal to the end of the phalanx) (Fig. 1AC
). Vascularity was obtained by computer-aided ROI analysis using specialized software (Quanticon, version 3.08; EchoTech, Hallbergmoos, Germany). After positioning the ROIs on the three scans, the absolute number of colour signals detected was assumed to represent the vascularity within the region analysed (colour signals per ROI). Because the vasculature of the nailbed was situated mainly in the centre of the ROI, we did not express our measurements as relative values, to avoid falsification by different finger sizes.
Statistics
Separate analyses were carried out for the results obtained for the second and third fingers (Wilcoxon test), and for the results obtained for female and male control individuals (U-test). Each baseline examination was performed twice to determine intra-observer variability. Moreover, within a 3-month period all persons included in the study were examined for a second time by another person (MK) to determine inter-observer variability. For each of the groups (healthy controls vs patients with pRP or patients with sRP, and controls vs CTD patients with or without initial digital skin lesions), the mean vascularity was determined (± S.D.) at baseline, after cold challenge and after warm challenge (descriptive statistics). Data for control subjects obtained before and after a cold or a warm challenge were analysed by simple analysis of variance (ANOVA). In the same manner, two-factor ANOVA was used to analyse the data obtained for controls and CTD patients with or without initial digital skin lesions, and also the data obtained for controls and patients with pRP and sRP (before and after the challenges). Because of the clinically important aim of differentiating pRP from sRP in patients who do not present with typical symptoms of CTD, only data for patients without obvious digital skin lesions were analysed; therefore, five patients with concomitant digital skin lesions out of 22 patients with sRP were excluded from the statistical analysis.
To compare the ultrasound results with the clinical diagnoses (healthy controls, pRP and sRP patients; controls, CTD patients with and without initial digital skin lesions), we performed discriminant analysis using the predictors before and after both the cold and the warm challenge.
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Results |
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Raynaud's phenomenon
At ambient temperature, healthy controls and patients with pRP showed similar vascularities, which were clearly distinguishable from the lower vascularities determined in patients suffering from sRP associated with CTD (Fig. 2). The cold challenge induced decreases in all three groups (healthy controls and patients with pRP and sRP); however, this decrease in vascularity was more pronounced in pRP and sRP patients.
In patients with pRP, the mean baseline vascularity was 25 467 ± 3063 colour signals per ROI; after the cold challenge the mean vascularity decreased to 2302 ± 2175 colour signals per ROI (P < 0.001) (Fig. 4), and after the warm challenge it increased to 30 090 ± 8448 colour signals per ROI (P < 0.01). Compared with healthy control subjects starting from a similar baseline vascularity, the decrease in vascularity induced by the cold challenge was significantly different (P < 0.001) (Fig. 2
).
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Connective tissue disorders with and without initial digital skin lesions
At ambient temperature, all patients who suffered from CTD with initial disease-related digital skin lesions had an extremely low vascularity. Interestingly, the subgroup of CTD patients who had no obvious digital skin lesions also had reduced vascularity that was intermediate between those of healthy subjects and CTD patients with digital skin lesions (Fig. 3). After the warm challenge, vascularity increased in healthy controls but also in both patient subgroups; this increase was clearly more pronounced in healthy controls than in CTD patients. Especially CTD patients with digital skin lesions had only a limited elevation of vascularity after the warm challenge.
The mean baseline vascularity of CTD patients without digital skin lesions was 6260 ± 7531 colour signals per ROI (Fig. 5); after the warm challenge it increased to 18 510 ± 8640 colour signals per ROI (P < 0.001), and after the cold challenge it decreased to 1517 ± 2290 colour signals per ROI (P < 0.001). When comparing this patient subgroup with the healthy controls, the vascularities at baseline and after the dynamic challenges both differed significantly (P < 0.001) (Fig. 3
).
In CTD patients presenting with initial digital skin lesions, the mean baseline vascularity was 711 ± 1311 colour signals per ROI. After the warm challenge it increased to 10 343 ± 3623 colour signals per ROI (P < 0.001) (Fig. 6), and after the cold challenge it decreased significantly to 446 ± 401 colour signals per ROI (P < 0.01). Upon comparison of patients with or without digital skin lesions, the vascularities at baseline and after the dynamic challenges both differed significantly (P < 0.001) (Fig. 3
).
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Further analyses
Intra-observer variability was negligible (r = 0.97; baseline examinations only). Equally, inter-observer variability was low and yielded excellent coefficients of r = 0.93 (baseline), r = 0.72 (cold challenge) and r = 0.82 (warm challenge). Vascularities of the second and the third right fingers of the same hand did not differ significantly either between controls and patients or between baseline or dynamic conditions.
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Discussion |
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Connective tissue disorders
Hyperplastic intimal changes in the peripheral digital arteries may result in substantially reduced vascularity in SSc and SLE, although the pathophysiological mechanism may be different [1, 810]. We obtained extremely low vascularities in CTD patients, a pathological finding that was even more pronounced in patients with initial digital skin lesions. It is important to note that CTD patients without any disease-related skin lesions also had a significantly lower vascularity than healthy controls. This suggests that structural changes in the vasculature occur at an early stage of the disease that might be easily quantified by ultrasound. Because most SSc patients had initial digital skin changes, we did not perform an additional subgroup analysis of SSc vs SLE patients in this preliminary study. In 22% of the patients, CDU analysis of nailfold vascularity was unable to predict the clinical classification of the study subgroups (controls, CTD patients with and without initial digital skin lesions) (Table 3). This may be expected, as the progression of (early) vascular damage to clinically evident digital skin lesions is a continuous process in CTD.
It has been reported that a warm stimulus can significantly increase peripheral vascularity in patients with SSc [3]. We also observed this phenomenon in all of our patients with CTD after a warm challenge. However, the inducible increase in vascularity was significantly lower in CTD patients than in healthy controls, suggesting a restricted vessel response after the dynamic challenge. This was probably a result of irreversible structural changes in the vasculature.
The assessment of disease status in SSc or SLE is important in prognosis and in guiding risk-adapted treatment. Several approaches, such as a modified health assessment questionnaire and an index of accumulated damage in SLE, have been presented [11, 12]. The method described here might be useful in quantifying the degree of digital vascular damage. It could be evaluated as a useful way of determining the progression of the underlying disease and could help in the assessment of responses to treatment over time in SSc and SLE.
Methodological aspects
Constant adjustment of the ultrasound parameters is essential. Pressure on digital vessels caused by the ultrasound transducer can be circumvented by ensuring that a thin layer of gel is maintained between the patient's nail and the transducer. Results can be falsified by changes in ambient temperature, acclimatization time, the severity and duration of the dynamic challenges, and delay in image acquisition after the challenge. Even the patient's sympathetic tone at the time of the test may remain poorly controllable in the assessment of digital vascularity. However, our standardized examination protocol resulted in a high level of reproducibility of the method, with low inter-observer variability. The ultrasound examination of two fingers [excluding the acclimatization time (20 min), the re-equilibration time (15 min) and the dynamic challenges (5 min each)] followed by the computer-aided determination of the vascularities takes about 15 min per subject and is easy to learn. High-resolution and CDU techniques are used increasingly. They are easy to perform and are no burden on the patient.
In conclusion, the novel CDU technique presented here appears to be able to detect and quantify early vascular damage in CTD patients, to unmask RP, and even to differentiate between pRP and sRP. In an ongoing study of patients suffering from CTD we are monitoring responses to treatment and the progression and/or regression of disease activity with the CDU method presented here. Further studies will be needed to assess the clinical value of CDU compared with the other diagnostic tools that are available.
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Notes |
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References |
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