## 4 Discussion  
The present study is the first to investigate digital MVI in healthy subjects and patients with SSc. It was designed as a feasibility study without any prespecified hypotheses. Therefore, no sample size calculation was performed for this study. The main findings are that findings in peak systolic and end diastolic flow velocity differ between SSc patients and controls. It should be noted that MVI was not used and was never intended to be used as a diagnostic tool to detect SSc, as all patients had a known diagnosis of SSc. One patient was classified as \"sine scleroderma\". However, we do not  
Figure 8: Correlation matrix showing correlation coefficients for peak systolic and end diastolic flow velocity in different fingers for systemic sclerosis patients (panels **A** and **B**) and healthy controls (panels **C** and **D**). * \(p\) < 0.01, * \(p\) < 0.05. D, digit. \begin{table}
\begin{tabular}{c c c c c} \hline \hline  & **D II** & **D III** & **D IV** & **D V** \\ \hline Peak Systolic & & & & \\ \hline VIF & 1.69 & 1.18 & 1.49 & 1.09 \\ \hline End-diastolic & & & & \\ \hline VIF & 2.58 & 2.66 & 1.48 & 1.54 \\ \hline D, digit; VIF, variance inflation factor. & & & \\ \hline \hline \end{tabular}
\end{table} 
Table 3: Variance inflation factor for individual fingers in SSc patients after linear regression. believe that type of skin involvement has a great influence on the microvasculature, since microangiopathy (i.e., Raynaud's phenomenon) is almost universally present within any type of SSc patient [2]. Since our healthy control group exhibited almost no confounding comorbidities, it was well suited to define normal values of MVI and determine cut-off values to discern them from SSc patients. In addition, although HCs were significantly younger than the SSc patients, age did not have a relevant influence on the digital flow velocities based on our results. To test whether age has a strong influence on the measurements, additional patient cohorts with a more comparable age distribution will be required. In NVC, no correlation of changes with age alone has been shown. Thus, we are confident that microvascular changes are more closely related to the disease rather than age alone. One advantage of the control group is the absence of comorbidities that could have influenced the measurements. Another potential influencing factor was that about 30% of SSc patients were past or current smokers. Nevertheless, we do not think that this has an important effect in the absence of overt digital ulcers or necrosis because there were no outliers in the lower measurement ranges (Figure 6A-D) in the SSc cohort. If smoking was indeed an important influencing variable, we would expect the measurements to be even lower in this subgroup. Further, SSc patients had a higher use of vasodilating agents, potentially influencing flow measurements. Drugs used in SSc for the purpose of improving blood flow include calcium channel blockers, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and intravenous prostacyclin [12]. Based on their mechanism of action, it would be expected that the use of these drugs would artificially improve MVI (i.e., increase flow velocities). However, despite using these drugs, SSc patients had consistently and statistically significantly lower values than HCs patients. Our results further indicate that all four fingers should be assessed, since there was only a weak to moderate correlation between individual fingers. As this was also true for HCs, it seems to be an inherent characteristic of MVI measurements. There were measurements in some fingers that correlated moderately well and yielded statistically significant results. However, the regression models obtained did not provide evidence of multicollinearity, indicating that all fingers need to be examined. Nevertheless, this must be tested in a larger sample. Finally, the MVI with flow measurements performed on four fingers took less than 15 min, which is, in our view, feasible in clinical practice.