Raynaud’s phenomenon: a mirror of autoimmune disease
van Roon, Anniek Maaike
DOI:
10.33612/diss.98238042
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van Roon, A. M. (2019). Raynaud’s phenomenon: a mirror of autoimmune disease. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.98238042
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CHAPTER 7
Pulse Wave Velocity in Systemic Sclerosis: potential
benefi cial eff ects of bosentan on forearm arterial
stiff ness? An exploratory study
Anniek M. van Roon
Amaal Eman Abdulle
Saskia C. van de Zande
Arie M. van Roon
Dan Zhang
Reinhard Bos
Marc Bijl
Alja J. Stel
Hendrika Bootsma
Andries J. Smit
Douwe J. Mulder
Submitted
ABSTRACT
Objectives: The aim of this study was two-fold. First, we compared arterial stiffness
in patients with systemic sclerosis (SSc) and healthy controls (HC). Secondly, we investigated the effect of bosentan on both short-term (three months) and long-term (one year) arterial stiffness.
Methods: At baseline differences between SSc patients and age- and sex-matched HC
were studied. The follow-up of SSc patients was a randomized, prospective, 2-arm parallel group, open-label, (usual care with bosentan versus usual care only), blinded endpoint, intervention study. Pulse wave velocity (PWV), was measured to assess arterial stiffness in the aorta (carotid-femoral), upper arm (carotid-brachial), and forearm (brachial-radial), adjusted for mean arterial pressure.
Results: No significant differences were observed in PWV (at all sites) between HC and
SSc patients. No effect of bosentan on aortic and upper arm PWV was found. The change in forearm PWV was different between the groups, with a decrease (i.e. lower arterial stiffness) in the bosentan group (three months p=0.047; 1 year p=0.037).
Conclusion: This exploratory study shows that aortic, upper arm, and forearm arterial
stiffness does not appear to be increased in patients with limited cutaneous SSc, as compared to age- and sex-matched HC. Although the results demonstrate no effects on aorta and upper arm arterial stiffness, bosentan might decrease stiffness of the small-sized arteries of the forearm. Future studies are needed to further investigate the potential effect of bosentan on these arteries.
INTRODUCTION
Systemic sclerosis (SSc) is an auto-immune disease, which is characterized by progressive fibrosis of the skin and internal organs.1 The disease is hallmarked by vasculopathy, which is clinically observed as Raynaud’s phenomenon, but may also lead to digital ulcers (DU) and pulmonary arterial hypertension (PAH). Unfortunately, current treatment options are limited and there is an on-going need for new pathogenic insight into changes that occur early in the course of the disease.
Vasculopathy in SSc is generally thought to occur on a microvascular level. However, some observations suggest involvement of arterial vessels as well. For example, in patients with advanced disease, an obliteration of the ulnar artery is frequently observed.2 A potential mechanism is arterial wall fibrosis. This fibrosis, subsequently leading to narrowing of the lumen, may be detected as arterial stiffness early in the course of the disease. Arterial stiffness can be assessed by measuring pulse wave velocity (PWV). This method can easily be non-invasively applied to assess arterial stiffness of the aorta as well as the arterial stiffness of the upper extremities, with the latter being of special importance in SSc. Although several studies have assessed aortic and upper extremity PWV in SSc, results are mixed and definite conclusions cannot be drawn. Furthermore, no arterial stiffness modifying treatment has been previously investigated in SSc.
Although bosentan, a dual endothelin receptor antagonist, has been shown to improve microvascular status, its effect on arterial stiffness has never been investigated.3 Endothelin-1 has been proposed to play an important role in the pathogenesis of SSc-vasculopathy.4 Interestingly, it has been shown that endothelin-1 regulates arterial stiffness in animal models by inducing fibrosis.5,6 In chronic kidney disease, a selective endothelin-A receptor antagonist appeared to reduce arterial stiffness.7 We hypothesize that similar effects may be observed in SSc.
The aim of this exploratory study was two-fold. First, we aim to compare arterial stiffness of the aorta, the upper arm, and the forearm in patients with limited cutaneous SSc with age- and sex-matched healthy controls (HC). Secondly, we explore the effect of bosentan on arterial stiffness after 3 and 12 months of treatment in patients with SSc.
PATIENTS AND METHODS
Study population
Patients were selected from the department of vascular medicine or rheumatology of the University Medical Center Groningen (UMCG) between 2015-2018, or specifically referred for this study to the outpatient clinic. Patients were eligible to participate if they were ≥18 years of age, fulfilled the ACR/EULAR criteria for SSc,8 had a known history of RP and DU, and had an assessable PWV at screening. Patients were excluded if there were any contra-indications for the use of bosentan and/or they had significant peripheral vascular disease as consequence of macrovascular obstructive atherosclerotic disease. All patients underwent a screening visit, baseline visit and follow-up visits at three months and one year. Sex- and age-matched HC were recruited by advertisements, and only underwent a baseline visit.
Study design
Baseline differences between HC and SSc patients were studied in a case-control design. The follow-up of SSc patients was a randomized, prospective, 2-arm parallel group, open-label, (usual care only versus usual care plus bosentan), blinded endpoint, intervention study. Bosentan was prescribed within its registered indication. Both parts of the study were approved by the Medical Ethical Institutional Review Board of the UMCG (2014/337) and carried out according to the Declaration of Helsinki and Good Clinical Practice guidelines. The study was registered on clinicaltrials.gov (NCT02480335). All participants gave written informed consent. Patients were randomized in a 1:1 ratio to receive either usual care only or usual care plus bosentan (62.5 mg twice daily, titrated to 125 mg twice daily after one month if tolerated). Randomization was performed using minimization software (MinimPy 0.2, © 2010 - 2011 Mahmoud Saghaei (http:// www.saghaei.com), downloaded at: http://minimpy.sourceforge.net, date 22-10-2013).9 Allocation was stratified by age (18-29 years, 30-49 years or ≥50 years) and current treatment with iloprost/prostacyclin.
Clinical and laboratory assessments
The following patient characteristics were obtained: sex, age, smoking behaviour, comorbidities, and use of medication. In addition, height (cm), weight (kg), blood pressure (mmHg), and heart rate (bpm) were measured, and mean arterial pressure
(MAP, mmHg) and body mass index (BMI, kg/m²) were calculated. Moreover, in SSc patients disease duration was obtained at baseline. Blood was drawn from the antecubital vein during each visit prior to the vascular measurements. Safety parameters (total blood count, C-reactive protein (CRP), liver enzymes and serum creatinine), autoantibodies (antinuclear antibodies (ANA), including SSc specific topoisomerase and anti-centromere), and PAH risk assessment parameters (uric acid, and NTproBNP) were measured at the nationally accredited clinical laboratory unit of the UMCG, according to standard procedures.
Vascular measurements
Vascular measurements were carried out at our vascular laboratory, after a 15 minute stabilization period in a temperature controlled room at 23-24°C. All measurements were performed by one experienced vascular technician, who was blinded for allocation arm.
Pulse Wave Velocity
Regional PWV in meter/second, as measure of arterial stiffness, was assessed using a previously described, well validated technique.10 In short, pulse pressure waves were recorded at the carotid, femoral, brachial, and radial artery, both left and right, with the Sphygmocor EM-3 device (AtCor Medical, West Ryde, Australia, software version 8.2). PWV was calculated by dividing travelled distance by transit time, and the geometric mean of left and right was calculated.11 The aortic PWV was defined as the carotid to femoral PWV. The upper arm PWV was defined as the carotid to brachial PWV. The distance of the aortic trajectory was calculated with sternum to umbilicus plus umbilicus to femoral measurement site minus carotid to sternum. Whole arm and upper arm distance were calculated as sternum to shoulder plus shoulder to brachial/radial measurement site minus carotid to sternum. To assess the forearm PWV, the carotid to radial PWV had to be calculated first. The forearm PWV was then defined by calculating the difference in distance between carotid-brachial and carotid-radial, and the difference in transit time between the two, resulting in a brachial to radial PWV.
Ultrasound examinations were conducted with a Mylab One colour Doppler ultrasound diagnostic system (Esaote, Firenze, Italy), using a 6-13 MHz vascular probe SL3323 at 10 MHz, with built-in quality intima-media thickness (QIMT), quality arterial stiffness (QAS) software. Measurements were performed at right and left radial and brachial
artery, and repeated three times. Local PWV was calculated using the local distension curve and local pressure (calculated using brachial blood pressure).12 Unfortunately, during the study the ultrasound resolution appeared to be too low to reliably assess the brachial and radial arteries, therefore local PWV could not be calculated.
Laser Speckle Contrast Analysis
Laser Speckle Contrast Analysis (LASCA), which is a measure of peripheral blood perfusion, was performed in both hands using a PeriCam PSI System (PeriMed, Jarfalla, Sweden), and data acquisition and analysis was performed by PIMSoft (PeriMed, Jarfalla, Sweden). Perfusion was processed as numerical values in perfusion units (PU) and color-coded-images. A total of one minute was recorded at room temperature, of which a (stable) period of 10 seconds was analysed. The following three regions of interest (ROI) were selected: ROI1 entailed the index, middle and ring finger (dig 2-4) distal from the proximal interphalangeal (PIP) joint, ROI2 distal of the metacarpal joints until proximal to the PIP joint of the index, middle and ring finger, and ROI3 the hand proximal of the 2nd to 4th metacarpal joints, as described previously.13 The perfusion gradient was calculated by subtracting ROI3 from ROI1. The geometric mean of the ROIs and perfusion gradient of both hands was calculated, as the data had a Chi-squared distribution.
Nailfold Capillary Microscopy
Nailfold Capillary Microscopy (NCM) was performed using an Olympus BXFM set-up (Olympus, Tokyo, Japan), with Olympus CellSens software (Tokyo, Japan). A drop of immersion oil was placed on the nailfold to increase transparency. An image at 180x enlargement with a 3mm width in the centre of the nailfold was captured. Obtained images were assessed by one of two investigators (AR and AEA) or one of two vascular technicians (SZ and AG) after study completion. The investigators and technicians were blinded for patient characteristics, allocation arm, and study visit. In the case of SSc patients, all three visits of the same patient were assessed by the same person. The distal row of capillaries was assessed. The capillary density per 3mm, giant capillaries (apex >50µm), dilated capillaries (apex >20µm), and haemorrhages were counted. Microangiopathy evolution score (MES), Capillaroscopic Skin Ulcer Risk Index (CSURI) and Prognostic Index for Digital Lesions (PIDL) were assessed as described previously.14-17 For the CSURI a cut-off value of 2.96 was used.18
Statistical methods
Statistical analysis was performed using The Statistical Product and Service Solutions (SPSS; version 23, Released 2013, IBM Corp., Armonk, NY, USA). Binary or ordinal data were compared between groups with Chi-square, and continuous non-normal data with Mann-Whitney U test. Baseline PWV was corrected for MAP with linear regression, with PWV as the dependent variable, MAP and group as independent variables. Change in PWV within groups was tested with Wilcoxon signed Ranks test. Differences in PWV change over time (delta) between groups were calculated with log-transformed PWV-values, to correct for baseline, and corrected for change in MAP with linear regression. To explore associations between parameters, a Pearson or Spearman correlation coefficient was calculated. Data are described as median with the inter quartile range (IQR) or number (%). P-values <0.05 were considered statistically significant.
RESULTS
Study population
An overview of the inclusion procedure is depicted in figure 1. A total of 24 SSc patients were screened and 20 patients were randomized. Nineteen patients completed the baseline visit as one patient was excluded at baseline due to non-assessable PWV. In addition, 19 sex and age-matched HC completed a baseline visit. Characteristics of HC and SSc patients are shown in table 1. At baseline all patients presented with limited cutaneous skin involvement (lcSSc).
Figure 1. Overview of the inclusion procedure.
Sixteen SSc patients completed both follow-up visits, of which 9 patients received usual care plus bosentan and 7 patients received usual care only. At baseline, a difference was observed between the groups in smoking pack years, RP duration, and SSc disease duration (table 1).
Table 1. Baseline characteristics
Healthy controls (n=19)
SSc patients
(n=19) group (n=9)Bosentan group (n=7)Usual care
Female, n (%) 13 (69) 13 (69) 5 (56) 6 (86)
Age in years, median (IQR) 53 (47–63) 50 (44–54) 52 (49–66) 44 (43–54) Caucasian ethnicity, n (%) 18 (95) 17 (90) 8 (89) 6 (86) Current smoker, n (%) 2 (11) 8 (42) 4 (44) 2 (29) Smoker (ever), n (%) 7 (37) 14 (74) 8 (89) 4 (57) Pack years, median (IQR) 0 (0–7.5)a 2.5 (0–30.6)a 17.3 (0.7–34.1) 0.8 (0–2.75)
Body mass index in kg/m²,
median (IQR) 25 (23–27) 25 (21–29) 25 (22–27) 26 (20–37) Systolic blood pressure in mm
Hg, median (IQR) 130 (121–137) 127 (123–134) 126 (117–142) 127 (123–132) Diastolic blood pressure in
mm Hg, median (IQR) 81 (72–88) 85 (79–89) 84 (76–87) 83 (79–85) Mean arterial blood pressure
in mm Hg, median (IQR) 102 (92–105) 101 (95–109) 101 (93–108) 100 (98–103) Heart rate per min, median
(IQR) 63 (54–68)a 68 (59–75)a 68 (59–75) 71 (62–74) RP duration in years, median
(IQR) N/A 8.0 (4.0-13.0) 1.0 (1.0–7.0) 13.0 (6.0–16.0) SSc disease duration since
first non-RP symptom in
years, median (IQR) N/A 2.0 (1.0–7.0) 1.0 (1.0–7.5) 5.0 (2.0–14.0)
Organ involvement, n(%) Lung N/A 9 (47) 5 (56) 3 (43) ILD N/A 8 (42) 5 (56) 2 (29) PAH N/A 1 (5) 0 (0) 1 (14) Oesophageal N/A 8 (42) 4 (44) 4 (57) Comorbidity, n(%) Hypertension 0 (0) 9 (47) 4 (44) 4 (57) Hyperlipidaemia 0 (0) 4 (21) 2 (22) 1 (14)
Type 2 Diabetes Mellitus 0 (0) 1 (5) 1 (11) 0 (0)
Hypothyroidism 0 (0) 2 (10) 0 (0) 2 (29)
Essential thrombocythemia 0 (0) 1 (5) 1 (11) 0 (0) Factor V Leiden deficiency 0 (0) 1 (5) 0 (0) 0 (0)
COPD/Asthma 0 (0) 3 (16) 2 (22) 1 (14)
Healthy controls (n=19)
SSc patients
(n=19) group (n=9)Bosentan group (n=7)Usual care Medication, n(%)
Calcium channel blockers 0 (0) 8 (42) 4 (44) 3 (43)
Alfa1 blockers 0 (0) 1 (5) 0 (0) 1 (14)
Iloprost 0 (0) 3 (16) 1 (11) 2 (29)
Antihypertensive drugs (prescribed for other
indication than RP) 0 (0) 9 (47) 4 (44) 4 (57)
Antiplatelet (acetylsalicylic
acid or clopidogrel) 0 (0) 2 (10) 0 (0) 1 (14)
Statin 0 (0) 2 (10) 1 (11) 0 (0)
Immunosuppressive drugsb 0 (0) 5 (26) 3 (33) 2 (29) adifferent between healthy controls and SSc patients, p<0.05; bmethotrexate (n=2), mofetil
mycofolate (n=1), low-dose prednisone (n=1) or budesonide (oral, n=1); COPD: chronic obstructive pulmonary disease, ILD: Interstitial lung disease, PAH: pulmonary arterial hypertension, RP: Raynaud’s phenomenon, SSc: systemic sclerosis.
Baseline (patients with systemic sclerosis versus healthy controls)
Figure 2 shows the median (IQR) regional PWV measurements at the different sites. No significant differences were observed in PWV at all sites between HC and SSc patients (aortic p=0.930, upper arm p=0.486, forearm p=0.515). In SSc patients, no significant correlation of PWV (at all the different sites) with age, sex, smoking pack years, disease duration (RP and SSc), CRP, or use of antihypertensive medication was present.
The baseline LASCA did not show significant differences between HC and SSc patients in the three ROIs (table 2).
The mean capillary density was lower in SSc patients, and the number of patients with presence of giant capillaries was higher (table 2). Five SSc patients had a positive CSURI, the PIDL was higher in SSc patients, the MES showed no difference (table 2).
Intervention (usual care with bosentan versus without bosentan)
No difference was found between the groups in delta (e.g. change over time) of aortic PWV (figure 3). Upper arm PWV was significantly different between the two groups at baseline [median (IQR) for the group with bosentan 6.7 (6.3–7.4) and usual care only group 8.7 (8.5–9.3)]. The delta upper arm PWV was significantly different between the
groups, with an increase over twelve months in the bosentan group (figure 3). The change in forearm PWV was different between the groups, with a decrease in the bosentan group (figure 3).
With regard to LASCA, no difference in delta of the perfusion gradient or the different ROIs separately was found between the groups (all p>0.05; Supplementary table 1).
No differences were observed in the delta of the different NCM parameters (density, dilated capillaries, giant capillaries, haemorrhages, MES or PIDL) between groups (all p>0.05; Supplementary table 1).
Table 2. Baseline vascular measurements for the healthy controls and systemic sclerosis patients Healthy
controls (n=19) SSc patients(n=19) p-value Laser Speckle Contrast Analysis, in perfusion units, median (IQR)
ROI1 51.7 (38.7–78.9) 44.2 (29.6–74.1) 0.488
ROI2 44.9 (41.0–50.8) 43.3 (34.7–67.0) 0.977
ROI3 39.5 (37.6–49.8) 43.9 (37.3–56.8) 0.506
Perfusion gradient (ROI1–ROI3) 12.6 (-2.7–22.7) -0.1 (-5.3–14.6) 0.311
Nailfold capillary microscopy
Capillary densitya, number/3mm, median (IQR) 20.8 (18.4–24.6) 16.4 (9.4–21.1) 0.003
Dilated capillariesa, number/3mm, median (IQR) 1.6 (1.1–5.5) 3.6 (2.0–5.3) 0.539
Patients with
- Giant capillaries, n (%) 3 (16) 9 (47) 0.079
- Haemorrhages, n (%) 10 (53) 14 (74) 0.313
MES, median (IQR) 2.3 (1.9–2.6) 2.1 (1.6–4.0) 0.753
CSURI>2.96, n(%) 0 (0) 5 (26) 0.046
PIDL, median (IQR) 1.1 (0.75–1.4) 1.6 (1.0–2.3) 0.008 aMean of 8 fingers; CSURI: capillaroscopic skin ulcer risk index, MES: microangiopathy
evolution score, PIDL: prognostic index for digital lesions, ROI: region of interest, SSc: systemic sclerosis
Figure 2. Median (IQR) of the aortic (A), upper arm (B), and forearm (C) pulse wave
velocity.
Figure 3. The median (IQR) of the aortic (A), upper arm (B), and forearm (C) pulse wave
velocity over time of the bosentan and usual care group. P-values are of differences in delta (change over time) between groups.
DISCUSSION
To our knowledge, this is the first interventional study to assess the effect of the dual endothelin receptor antagonist bosentan on arterial stiffness, as measured by PWV. Although the origin of vasculopathy in SSc remains incompletely understood, our preliminary results provide several relevant additions to the current knowledge on arterial stiffness in SSc. Contrary to previous reports, we were unable to demonstrate an increased arterial stiffness in our cohort of SSc patients as compared to age- and sex-matched HC. However, our exploratory analysis may suggest potential significant effects of bosentan on forearm PWV. Given the fact that skin fibrosis is most pronounced distally, and digital ulcers frequently occur in SSc patients, these potential effects on arteries of the forearm are of special interest. However, due to the small size of these arteries (e.g. radial and ulnar arteries), reliable assessments of PWV remain challenging. Our findings may be of guidance for future studies to further investigate (improvement of) arterial stiffness of the forearm arteries.
Three different PWV regions were evaluated in the current study and compared to age- and sex-matched HC at baseline. We did not demonstrate differences in these PWV regions in SSc patients as compared to the HC. In two previous studies, a higher aortic PWV in SSc patients compared to HC was found.19,20 However, in line with our results, three more recent studies did not reproduce these differences.21-23 In patients with rheumatic diseases, such as rheumatoid arthritis and spondyloarthropathies, an increased risk of cardiovascular diseases has been found.24 It is believed that systemic inflammation and elevated CRP-levels result in accelerated atherosclerosis. In patients with SSc, however, histopathological findings of the arterial vessels are not typically atherosclerotic, and vasculopathy is believed to be more obliterative.24-26 However, it is possible that a subset of SSc patients with a more chronically elevated CRP level and systemic inflammation does have accelerated atherosclerosis. Possibly, a subset of patients could present with increased aortic arterial stiffness. This is supported by the study of Bartolini et al.,23 which found a correlation between PWV and CRP. We did not find this correlation in our study. However, these are only cross-sectional measurements of CRP, longitudinal measurements of CRP are needed to verify this hypothesis.
As atherosclerosis of the upper extremity is rare,27 changes found in arterial stiffness in the upper extremity are more likely to be SSc-related vasculopathy than atherosclerotic. Therefore PWV of the upper extremity is of special interest. In regards to the PWV of the whole arm (carotid-radial) assessed with the Sphygmocor, one study found a higher whole arm PWV in a small cohort of dcSSc patients, and three more recent studies in mainly lcSSc patients found no differences.22,23,28,29 Studies investigating the upper arm or forearm only are lacking. Only one previous study, conducted by Liu et al. (2011), investigated arterial stiffness of these two trajectories.30 They reported higher forearm PWV in SSc patients compared to HC. However, we have to stress the fact that the method used in our current study and that of Liu and colleagues (2011) do differ. Their method uses the systolic peak of the flow velocity to calculate the PWV, which is more affected by wave reflections, instead of the commonly used foot of the pressure waves. Furthermore there was a difference in the study population because they also included patients with dcSSc.
The second aim of the current study was to investigate the effect of bosentan on the different PWV measurements. This part of the manuscript should be considered exploratory as the sample size of our study was too small to draw definite conclusions. We observed a significant reduction in forearm PWV in patients receiving usual care with bosentan compared to patients receiving usual care only. This finding might indicate that bosentan has a beneficial effect on the stiffness of the small sized arteries of the forearm. Moreover, we found a difference in the change of upper arm PWV over time between the usual care with bosentan and usual care only group. However, this change is most likely a regression to mean, as the groups start with different upper arm PWV (bosentan group lower compared to the usual care group) at baseline and have comparable upper arm PWV during both follow-up visits. In addition, when analysing the change between three and twelve months, no difference was found. In addition, the current study found that bosentan did not reduce the aortic PWV. In SSc, the distal arteries are more likely to be affected by the disease, and, therefore, we hypothesize that these are the arteries that are more likely to improve with treatment. This is also supported by the only mildly abnormal vascular findings (being mainly microvascular changes) at baseline.
Local PWV measurements turned out not to be feasible with our current set-up, due to the small diameter of the radial and brachial artery. Therefore the set-up was not able to detect the small arterial wall movements in a reliable fashion. Liu et al. (2011) did perform local PWV measurements of the radial and brachial artery, with an ultrasound system, and found no increase in arterial stiffness in SSc patients compared to HC. However, they had large random variation in these measurements with high intra-observer intersession variability, and they also concluded that current local arterial stiffness indices are perhaps not applicable for assessing the stiffness of relatively small muscular arteries.30 Therefore, we believe more advanced techniques, such as higher frequency ultrasound probes, are needed to assess these local PWV measurements of the brachial, radial, and ulnar artery.
Because this was an exploratory study, statistical power was limited. The small number of patients is also due to the fact that bosentan could only be prescribed within its registered indication. Furthermore, the SSc patients, although all having lcSSc, had high heterogeneity regarding patient characteristics, resulting in a difference in disease duration between the usual care with bosentan and usual care only group. This heterogeneity is characteristic for the disease. One patient did develop diffuse cutaneous involvement during this study. However, this did not affect our results given the fact that this patient was not an outlier in the different PWV measurements. Future studies with a larger sample size and/or patients with the same subset and stage of the disease are needed. In addition, the more frequently affected ulnar artery was not assessed,31 because the used set-up is not validated to measure the ulnar artery site. Therefore, measuring techniques should be improved to assess local, as well as regional PWV of the smaller muscular arteries. For example
In conclusion, in this exploratory study the aorta, upper arm and forearm arteries do not appear to be stiffened in patients with SSc, as compared to age- and sex-matched HC. However, bosentan may potentially have a beneficial effect on the stiffness of the small-sized arteries of the forearm.
ACKNOWLEDGMENTS
The authors would like to thank A. van Gessel for her help with analysing the nailfold capillary microscopic images. Furthermore, we would like to acknowledge the helpful work of B. Najar for her analysis of the health related quality of life, and M. Habing for her help in recruiting healthy controls. Furthermore, T. Elling and C. Huisman have been of value to the study supporting with data entry. Finally, we would like to thank E. Perrels, T. Lammers and F. van der Zant for their laboratory assistance.
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