Results are expressed as the ratio of the sum of the number of telangiectasia for each body area for all patients to the sum of the total number of telangiectasia for all patients.
Results are expressed as Spearman rank correlation coefficients. The gray X indicates that the coefficient is not significant. TA indicates telangiectasia.
eMethods. Further Methodology
eFigure. ROC Curves Assessing the Ability to Discriminate the Presence of PH
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Jouvray M, Launay D, Dubucquoi S, et al. Whole-Body Distribution and Clinical Association of Telangiectases in Systemic Sclerosis. JAMA Dermatol. 2018;154(7):796–805. doi:10.1001/jamadermatol.2018.0916
What is the association between whole-body distribution and number of whole-body telangiectases with characteristics of patients with systemic sclerosis?
In this cross-sectional study of 106 patients, telangiectases were predominantly located on the face (37.2%), hands (26.4%), and the upper part of the trunk (17.1%). Independent associations were observed between the number of telangiectases and male sex, pulmonary hypertension, history of pulmonary embolism, microvascular abnormalities, renal involvement, and soluble endoglin level.
Telangiectases are associated with the severity of vasculopathy in systemic sclerosis.
In systemic sclerosis (SSc), to date, no study has precisely described the total number and fine distribution of telangiectases (TAs), their clinical association with the disease, and the biological mechanisms causing their development.
To describe the whole-body distribution of TAs and assess the association between the whole-body TA number and the characteristics of patients with SSc.
Design, Setting, and Participants
A single-center, cross-sectional study was conducted between July 11, 2016, and March 15, 2017, at the National Referral Centre for Rare Systemic and Autoimmune Diseases in France. A population-based sample of 106 adults who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria for SSc were included; 8 patients who had previously received laser treatment for TAs were excluded.
Main Outcomes and Measures
The number of TAs on the whole body (total and those >5 mm) and TA distribution in different areas were recorded. The association with clinical and biological data was studied using univariate and multivariate linear regression.
A total of 106 patients (83 [78.3%] women) were enrolled, including 12 with precapillary pulmonary hypertension (PH). Mean (SD) age was 60.6 (13.5) years. Telangiectasia distribution was 37.2% on the face, 33.2% on the upper limbs, including 26.4% on the hands, 28.1% on the trunk, including 17.1% for the upper part of the trunk, and 1.5% on the lower limbs. In analysis using the multivariate linear regression model, the whole-body TA number was independently associated with male sex (percentage change, 144.4%; 95% CI, 7.5% to 455.9%; P = .03), PH (162.8%; 95% CI, 5.6% to 553.8%; P = .04), history of pulmonary embolism (336.4%; 95% CI, 39.0% to 1270.1%; P = .01), glomerular filtration rate (−1.6%; 95% CI, −3.2% to −0.1% per 1-mL/min/1.73 m2 increase; P = .04), and soluble endoglin level (28.2%; 95% CI, 1.2% to 62.5% per 1-ng/mL increase; P = .04). Receiver operating characteristic analyses assessing the ability of TAs to identify the presence of PH revealed that the area under the curve was significant for the TA number on the whole body (0.77; 95% CI, 0.57 to 0.88), on the hands and face (0.81; 95% CI, 0.57 to 0.91), and on the hands (95% CI, 0.77; 95% CI, 0.57 to 0.89).
Conclusions and Relevance
In the patients in this study with SSc, TAs were predominantly located on the face, hands, and the upper part of the trunk. Telangiectases appeared to be associated with vasculopathy features of SSc, particularly with PH and soluble endoglin levels.
Systemic sclerosis (SSc) is a rare, severe connective tissue disease characterized by microvascular damage, speciﬁc immunologic abnormalities, and sclerosis of the skin and internal organs.1 In SSc, vasculopathy is caused by major endothelial dysfunction, defective angiogenesis, and activation of coagulation and platelets.2 Clinical symptoms of vascular involvement are mainly Raynaud phenomenon, digital ulcers, scleroderma renal crisis, and precapillary pulmonary hypertension (PH).2 Some studies suggested that telangiectases (TAs) could also be 1 of the vascular manifestation of SSc by reflecting an aberrant neoangiogenesis.3-8 Telangiectases are formed by a dilatation of the postcapillary venules in the upper horizontal plexus of the skin.9 They are common in SSc and are included in the 2013 American College of Rheumatology/European League Against Rheumatism guidelines for SSc.1 Moreover, TAs could be associated with the presence of PH in SSc and the Detection of Pulmonary Arterial Hypertension in SSc (DETECT) algorithm has included TAs (absence or presence) as a risk factor for this complication.5,6,10
While some studies have addressed the association between TAs and clinical manifestations of SSc, many questions remain unanswered. Although TAs are most commonly observed on the hands and face, they can be present on the whole body.3-8 However, to our knowledge, no study has precisely described the total number and fine distribution of TAs in SSc. Moreover, the clinical association of SSc with TAs observed on the whole body is unknown, as are the biological mechanisms causing the development of TAs in SSc. The role of angiogenic factors, such as the vascular endothelial growth factor (VEGF) and transforming growth factor β pathways, especially endoglin (CD105), have been suggested.11-13
To address these issues, we designed a cross-sectional study to describe the total number, whole-body distribution, and association with clinical manifestations of TAs in SSc. Because we hypothesized that TAs could reflect vasculopathy in SSc, we focused on severe vascular manifestations, including PH and measured VEGF and soluble endoglin levels.
We designed a cross-sectional study and recruited patients (n = 106) older than 18 years followed up in our National Referral Centre for Rare Systemic and Autoimmune Diseases from July 11, 2016, to March 15, 2017. Patients were included if they fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc.1 Patients with a history of laser therapy to reduce the number of TAs were excluded.
This study was authorized by the French Ministry of Research. To issue such authorization, the Ministry of Research sought the advice of an independent ethics committee, the Comité de Protection des Personnes, which voted positively. French legislation on noninterventional studies requires collecting nonopposition of patients but does not require written consent. As such, nonopposition was obtained from each patient included in the study for the use of their deidentified medical records data. Participants did not receive financial compensation.
The number of TAs on the whole body (total and those >5 mm, measured using a template) and their distribution in different areas, including the face (centrofacial area, temporofrontal area, cheeks, lips, and tongue), trunk (neck, thorax, abdomen, back, and lower back), upper limbs (arms, forearms, and hands), and lower limbs (thighs, legs, and feet), were recorded at inclusion. In addition to the total number of TAs, we calculated a TA score from a method previously applied: for each area, TAs were scored as 0 if none were present, 1 if there were less than 10, and 2 if 10 or more were counted.5
A global clinical evaluation of the patients was performed using a standardized case report form completed by a trained physician (including M.J., D.L., V.S., M.L., S.M.-D., H.M., and E.H.) (eMethods in the Supplement). These data were collected, at most, 1 year before and after TA were counted, usually on the same month and day for each patient (77 of 106 [72.6%]), with a mean (SD) duration between TA counting and clinical data collection of 18 (80) days.
The serum (and plasma for VEGF-165b) samples for measurement of VEGF, VEGF-165b, and soluble endoglin levels were collected at the day of inclusion and then stored at −80°C. They were measured, respectively, by Human VEGF Quantikine enzyme-linked immunoassay (ELISA) kit, Human VEGF-165b DuoSet ELISA kit, and Human Endoglin/CD105 Quantikine ELISA Kit (all from R&D Systems), according to the supplier's recommendations. However, the level of VEGF-165b was below the threshold of the kit used and therefore could not be analyzed. The presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipine, or anti-β2 glycoprotein antibodies) was detected according to the supplier's recommendations (eMethods in the Supplement).
Characteristics of the population were described using mean (SD), or median (interquartile range [IQR]) in case of nonnormality, for quantitative variables and number (percentage) for qualitative variables. Characteristics of patients with and without PH were compared using t tests, or Wilcoxon rank sum tests in case of nonnormality, for quantitative variables and Fisher exact tests for qualitative variables.
The mean distribution of TAs for each body area was calculated and graphically represented by the ratio of the sum of the TA number for each body area for all patients to the sum of the total TA number for all patients. Correlations between the TA number for each body area and the total number were calculated using Spearman rank correlation coefficients and graphically represented using a correlogram.
To study the associations between the total TA number as the dependent variable and the characteristics of patients as the explanatory variables, we first log-transformed the total TA number (natural logarithms of the TA number +1) to normalize the distribution of the dependent variable. Then we studied the associations using (1) univariate linear regressions and (2) adjusted linear regressions for age at inclusion, sex, smoking history, disease duration since inclusion, scleroderma classification, and autoantibody status (anticentromere, antitopoisomerase I, and anti-RNA polymerase III antibodies). Finally, 2 multiple linear regression models were built to study the associations between the log-transformed total number of TAs and (1) clinical (PH, digital ulcers, glomerular filtration rate [GFR], deep vein thrombosis, pulmonary embolism, and arterial thrombosis) vasculopathy variables and (2) clinical and biological (VEGF and soluble endoglin levels) vasculopathy variables. These models were also adjusted for age at inclusion, sex, smoking history, disease duration since inclusion, SSc classification, and autoantibody status (anticentromere, antitopoisomerase I, and anti-RNA polymerase III). The regression coefficients were expressed as the percentage change in TA number (95% CI) per unit change in the explanatory variable. For this determination, they were back-transformed and converted to percentage change by multiplying by 100 and subtracting 100%. Regression diagnostics were performed.
Finally, receiver-operating characteristic (ROC) curves were plotted and the areas under the curve were calculated to assess the ability to discriminate between patients with and without PH of (1) the total TA number, (2) the TA score, (3) the TA number on the hands and face, and (4) the TA number on the hands.
All statistical analyses were performed with R software, version 3.2.5,14 using Hmisc, corrplot, and ROCR packages. The threshold for statistical significance was set at P < .05.
The study population comprised 106 patients (Table 1); most were women (83 [78.3%]) and had limited cutaneous SSc (77 [72.6%]). There were 12 (11.3%) patients with PH, 51 (50.0%) with interstitial lung disease (ILD), 51 (48.6%) with digital ulcers, 16 (15.1%) with a history of deep vein thrombosis, 8 (7.5%) with a history of pulmonary embolism, and 12 (11.3%) with a history of arterial thrombosis. No patient had a history of scleroderma renal crisis.
Compared with patients without PH, those with PH presented with a higher Medsger severity scale score (median, 7 [IQR, 4] vs 4 [IQR, 3]; P = .007). In addition, there were higher proportions of patients with dyspnea (New York Heart Association) stages III to IV (83.3% vs 24.5%; P < .001), less than 60% predicted diffusing capacity of the lung for carbon monoxide (DLCO) (100.0% vs 32.2%; P < .001), and N-terminal probrain natriuretic peptide (Nt-proBNP) levels greater than 300 ng/L (58.3% vs 16.3%; P = .003) (Table 1).
Ninety-eight patients (92.5%) had at least 1 TA, including 55 (51.9%) with at least 1 TA larger than 5 mm. The median numbers of TAs and TAs larger than 5 mm, as well as TA score per patient, were 30 (IQR, 82.7), 1 (IQR, 5), and 5 (IQR, 6), respectively (Table 1). The distribution of TAs was as follows: 37.2% on the face; 33.2% on the upper limbs, including 26.4% on the hands; 28.1% on the trunk, including 17.1% on the upper part of the trunk; and 1.5% on the lower limbs (Figure 1). We found a positive, significant correlation between the total TA number on the whole body and TAs on the face (r = 0.89; P < .001), on the upper limbs (r = 0.87; P < .001), and on the hands (r = 0.77; P < .001) (Figure 2).
In adjusted analyses, the total TA number was positively, significantly associated with the disease duration since the date of the First Non Raynaud’s Phenomenon symptom, European Scleroderma Trials and Research activity score, Medsger severity scale score, PH, DLCO less than 60% of the predicted value, increase in estimated systolic pulmonary artery pressure, active and late nailfold videocapillaroscopy patterns, pulmonary embolism, increased C-reactive protein level, and increased soluble endoglin level. We also found an association with dyspnea stages III to IV, 6-minute walk distance of 433 m or more, and Nt-proBNP level greater than 300 ng/L, but only in nonadjusted analyses. Conversely, there was no association between the total TA number and the serum level of VEGF (Table 2).
The multivariable model including clinical and biological markers of vasculopathy revealed that the total TA number was independently associated with male sex (percentage change, 144.4%; 95% CI, 7.5% to 455.9%; P = .03), PH (162.8%; 95% CI, 5.6% to 553.8%; P = .04), history of pulmonary embolism (336.4%; 95% CI, 39.0% to 1270.1%; P = .01), GFR (−1.6%; 95% CI, −3.2% to −0.1%) per 1 mL/min/1.73 m2 increase, P = .04) and soluble endoglin level (28.2%; 95% CI, 1.2% to 62.5%; P = .04) per 1-ng/mL increase (Table 3).
The ROC analyses assessing the ability of TAs to indicate the presence of PH revealed that the area under the curve was significant for the TA number on the whole body (0.77; 95% CI, 0.57-0.88), the hands (0.77; 95% CI, 0.57 to 0.89), and the hands and face (0.81; 95% CI, 0.57-0.91). The analyses also showed significance for the TA score (0.73; 95% CI, 0.56-0.83) (eFigure 1 in the Supplement).
This study aimed to describe the whole-body distribution of TAs in patients with SSc and assess the associations with clinical and biological manifestations with a focus on vascular characteristics. The main results are (1) the median TA number was 30 (IQR, 82.7) and TAs were mostly distributed on the face, hands, and upper part of the trunk; (2) male sex, PH, history of pulmonary embolism, decreased GFR, and soluble endoglin levels were independently associated with the total TA number; (3) TA number on the hands and/or face was well correlated with the total TA number and could be useful to identify patients with SSc who require closer monitoring for PH.
In our study, 92.5% of patients with SSc had at least 1 TA. The TAs were mostly distributed on the face, hands, and upper part of the trunk (Figure 1). To our knowledge, these results have not been previously and precisely described for SSc. Some studies have suggested that TAs were primarily distributed on the ventral surface of the digits.3,4,15 We showed that the total TA number was well correlated with the number on the hands and/or face. This finding is meaningful because, since a thorough assessment of TAs on the whole body is time consuming, our study suggests that a simple count on the hands and/or face could sufficiently represent the total TA number. There is no clear explanation why TAs are preferentially found in these areas. In hereditary hemorrhagic TA, TA distribution is similar to what we observed in SSc,16,17 and 1 hypothesis to explain this distribution could be environmental factors (eg, microtrauma, sun exposure) and a variation in the endothelium between the different areas.16,17
In this study, we observed associations between the TA number and several vasculopathy features (active/late nailfold videocapillaroscopy patterns, PH, history of pulmonary embolism, decreased GFR, and soluble endoglin level), but not with others (digital ulcers, calcinosis, and VEGF levels). We also found a significant association with male sex.
The most severe vascular complication of SSc (ie, PH) was independently associated with the TA number (but not with TA >5 mm). In the literature, this association has been described using different methods of TA collection and PH definitions.4,5,7 One study found an association between the prevalence of TAs larger than 5 mm on the hands and face and PH.6 In addition, we and others have shown an association between the number of TAs and higher levels of dyspnea, Nt-proBNP, and systolic pulmonary artery pressure, and with a lower 6-minute walk distance and DLCO less than 60% of the predicted value.5,7,18 These findings can be explained by the association between PH and these variables. To further assess the association between the number of TAs and PH, we evaluated the potential for the use of the TA number on the hands and/or face in clinical practice to identify patients with current PH. Using ROC curves, we found that the total TA number, TA number on the hands and/or face, as well as the TA score significantly but moderately identify patients with PH. Together, these results suggest that the TA number rather than only the presence or absence of TAs (as used in the DETECT score10) could be useful to identify patients with SSc who have PH and that counting TAs on the patients’ hands could be sufficient. No causative role can be determined from a cross-sectional study; further prospective studies are necessary to determine whether the TA number may serve as an early clinical biomarker or improve the sensitivity and specificity of DETECT for an early diagnosis of PH in SSc.
The severity of the vasculopathy can also be reflected by some capillaroscopy patterns and a decreased GFR. In line with many studies, we found a positive association between TAs and active and late nailfold videocapillaroscopy patterns.6,18,19 The TA number was also independently associated with decreased GFR in patients without a history of scleroderma renal crisis. To our knowledge, this finding has not been previously reported. Only 1 study has assessed an association between TAs and GFR, but the results were negative.5 We found that male sex was independently associated with TAs. This association is consistent with other studies that found that vascular disease in SSc is more severe in men.20,21
In our study, the total TA number was also independently associated with a history of pulmonary embolism, but not with other venous or arterial thromboses. Several studies have shown an increased risk of venous thrombosis in patients with SSc compared with healthy controls, but none of them described a subpopulation with a higher risk.22-25 There is no clear explanation for this association. We could suggest that TAs, as a marker of vasculopathy, could reflect the widespread endothelial dysfunction in SSc. Endothelial dysfunction could be a trigger to thrombotic deposition by causing the loss of endothelial antithrombotic properties.2,26 The association found only with pulmonary embolism suggests that the endothelial dysfunction could be more important in pulmonary vessels in patients with SSc. Thrombotic events in individuals with hereditary hemorrhagic TA have also been reported. The events could be secondary to elevated activity of factor VIII and von Willebrand factor, which are also found to be increased in SSc.27,28
In our study, the TA number was independently associated with the soluble endoglin level, which was consistent with 2 other studies.5,29 Soluble endoglin is a biomarker of various vascular pathologies, including SSc, related to endothelial dysfunction and membrane endoglin expression.13,30 Increased soluble endoglin levels have been reported in patients with SSc with vasculopathy features, especially in those with elevated systolic pulmonary artery pressure, whereas decreased soluble endoglin levels have been reported in hereditary hemorrhagic TA.29,31,32 Soluble endoglin could act as an antagonist by interacting with transforming growth factor β pathway, which might result in endothelial function impairment.33 This antagonistic effect could mimic the clinical phenotype of hereditary hemorrhagic TA 1.12 Some polymorphisms of the endoglin gene have also been reported in patients with SSc.13,34 Finally, TAs have been described in patients with cancer treated using an antiendoglin monoclonal antibody.35 At present, it is not known whether antiendoglin antibodies are present in patients with SSc. These data suggest that dysregulation of endoglin expression or function may be related to the development of vasculopathy in SSc.
We found no association between the TA number and VEGF. A proangiogenic factor, VEGF can increase the vascular permeability, stimulate the migration and proliferation of endothelial cells, and induce tube formation.11 Several studies have shown an overexpression of VEGF in the skin and serum of patients with SSc, but none of the studies evaluated the association with TAs.11,36,37 The absence of differences found in our study can be partially explained by the existence of an antiangiogenic splicing variant (ie, VEGF-165b), which is detected by the kits usually used to measure levels of VEGF.38,39 An interesting strategy for studying VEGF might be to analyze the VEGF-165b/VEGF ratio to better differentiate the proangiogenic or antiangiogenic effect of these factors. However, in our study, the plasma level of VEGF-165b was under the threshold of the kit used and therefore could not be analyzed.
To our knowledge, this study is the first to precisely describe the total number and distribution of TAs on the whole body in a well-phenotyped SSc population. The main limitation of our study is the cross-sectional design, which does not allow establishment of a temporal association between the presence of TAs and the subsequent development of vascular complications. Further prospective studies are mandatory to determine whether the TA number may serve as a clinical biomarker for the development of severe vascular disease, including PH. Furthermore, some authors consider that TAs are associated with gastric antral vascular ectasia.40 However, we did not collect data on the presence of gastric antral vascular ectasia or perform a systematic esophagogastroduodenoscopy. Finally, owing to the small number of patients with PH (n = 12) for ROC analysis, the optimal threshold for the number of TAs to discriminate PH and the associated sensitivity and specificity was not estimated, and 95% CIs for areas under the curve were wide.
We showed that TAs were predominantly located on the face, hands, and upper part of the trunk in SSc and that there was a good correlation between the TA number on the face and/or hands and the total TA number. We also demonstrated an association between the TA number and several vasculopathy features, including PH, history of pulmonary embolism, microvascular abnormalities, renal involvement, and male sex. A positive association with soluble endoglin levels was also noted, suggesting the involvement of this angiogenic factor in the development of TAs. Finally, we suggest that the TA number on the hands and/or face could be useful in clinical practice to identify patients with SSc who require closer monitoring for PH.
Accepted for Publication: March 9, 2018.
Corresonding Author: David Launay, MD, PhD, Département De Médecine Interne et Immunologie Clinique, CHRU Lille, 2 rue Oscar Lambret, F-59000, Lille 59037, France (firstname.lastname@example.org).
Published Online: May 16, 2018. doi:10.1001/jamadermatol.2018.0916
Author Contributions: Drs Launay and Dubucquoi contributed equally to this work, and Drs Hachulla and Giovannelli contributed equally to this work. Drs Jouvray and Giovannelli had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Jouvray, Launay, Sobanski, Giovannelli.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Jouvray, Launay, Dubucquoi.
Critical revision of the manuscript for important intellectual content: Jouvray, Launay, Sobanski, Podevin, Lambert, Morell-Dubois, Maillard-Lefebvre, Hatron, Hachulla, Giovannelli.
Statistical analysis: Giovannelli.
Administrative, technical, or material support: Sobanski, Podevin, Lambert, Morell-Dubois.
Study supervision: Hatron, Giovannelli.
Conflict of Interest Disclosures: Dr Launay reports receiving grants from Shire, CSL Behring, and Roche outside the submitted work. Dr Sobanski reports receiving personal fees from Grifols and grants from Grifols, Pfizer, Actelion, Octapharma, Shire, and GlaxoSmithKline, outside the submitted work. There were no other disclosures.
Additional Contributions: Sandrine Poizot and Maité Balden (CHU Lille, Institut d'Immunologie) provided technical help. There was no financial compensation.