Ulcers In Systemic Sclerosis Patients Research Articles

The association between CONUT score, mRSS, and development of digital ulcers in SSc patients

Objective: Digital ulcers (DUs) are a common manifestation of digital vascular damage in patients with Systemic Sclerosis (SSc), with more than half of SSc patients experiencing DUs at some point in their lives. Currently, there is a need for biomarkers related to inflammation or vascular damage that can predict the development of DUs. Methods: In this cross-sectional study, we included 42 patients with diffuse (n=26) and limited cutaneous (n=16) SSc. All patients were followed for one year to monitor the occurrence of DUs. DUs occurred at least once in 20 patients, while 22 patients never developed DUs. Patient characteristics and baseline CONUT scores were compared between SSc patients with and without DUs. Data were analyzed using the SPSS 25.0 software (IBM SPSS Statistics 25, Armonk, NY: IBM Corp.). Continuous variables were presented as mean ± standard deviation, and the Independent samples t-test was used for parametric test assumptions, while the Mann-Whitney U test was used for non-parametric test assumptions to compare independent groups. The difference between categorical variables was analyzed using Chi-Square analysis. Statistical significance was set at P<0.05. Results: The average age of the study group was 50.29 ± 13.9 years, and the disease duration was 9.31 ± 7.11 years. There were no significant differences in terms of age, disease duration, body mass index, serum levels of albumin and vitamin D, lipid panels, and inflammatory indexes (NLR, PLR) between SSc patients with and without digital ulcers (p>0.05 for all). The CONUT score was 0.86 ± 1.49 in patients without DUs and 1.2 ± 1.01 in patients with DUs (p: 0.092). The baseline modified Rodnan skin score (mRSS) was significantly higher in SSc patients with DUs. Conclusion: The baseline CONUT score was not significantly different in SSc patients with and without DUs. However, a higher mRSS was positively correlated with an increased risk of developing DUs in SSc patients.

Raynaud's Phenomenon: A Brush Up!

Raynaud's Phenomenon: A Brush Up!

Maresin1 is a predictive marker of new digital ulcers in systemic sclerosis patients.

Digital ulcers (DUs) are one of the main causes of disability among systemic sclerosis (SSc) patients. The inflammation plays a crucial role in mediating the pathophysiological process underlying SSc. Objective of this study was to evaluate Maresin1 (MaR1) serum levels in SSc patients and in healthy controls (HC). Secondary aims were to evaluate the relationship between MaR and diseases variables and to assess the predictive role of MaR1 in the development of new digital ulcers (DUs) during 18weeks follow-up. MaR1 serum level was evaluated in 55 SSc patients and 24 HC. In SSc patients, clinical assessment was performed at baseline and after 18week follow-up by the same-blinded observer on serum MaR1 levels. MaR1 was significantly lower in SSc patients than in HC [367pg/ml (IQR 304-468.3pg/ml) vs 467.7pg/ml (IQR 422-522pg/ml), p<0.001]. During follow-up, six patients (10.9%) developed DUs. MaR1 was higher in SSc patients with new DUs than in patients without new DUs [518.2pg/ml (IQR 468.2-596.5pg/ml) vs 355pg/ml (IQR 299.8-444.7pg/ml), p<0.01]. Free survival from new DUs is significantly lower in SSc patients with increased MaR1 serum level than in SSc patient with normal MaR1 serum level. In multivariate analysis, serum level of MaR1>393.2pg/ml is a predictive marker for new DUs. In SSc patients, MaR1 is reduced compared to HC and it is a predictive marker of new DUs.

CD21low B cells are predictive markers of new digital ulcers in systemic sclerosis

SummaryThe objective of this study was to evaluate the predictive role of CD21low B cells as markers of new digital ulcers in systemic sclerosis patients. Peripheral blood B cell subpopulations and clinical assessments have been evaluated in 74 systemic sclerosis patients at baseline and after a 12‐month follow‐up. After a 12‐month follow‐up, 23 (31.1%) systemic sclerosis patients developed new digital ulcers. The median percentage of CD21low B cells was significantly higher in patients with than without new digital ulcers [10.1 (4.3–13.6) versus 4.8 (3.5–7.4); p < 0.01]. The 10% cut‐off shows good diagnostic accuracy [area under the curve (AUC) = 0.732, confidence interval (CI) = 0.587–0.878; P = 0.01]. Kaplan–Meier curves show a significantly reduced free survival from new digital ulcers in systemic sclerosis patients with CD21low B cells ≥ 10% (p < 0.0001). In multivariate analysis, CD21low B cells ≥ 10%, modified Rodnan skin score (mRSS) and systolic pulmonary arterial pressure (sPAP) are associated with the development of new digital ulcers. We hypothesize that CD21low B cells are a predictive marker of new digital ulcers in systemic sclerosis patients.

The first composite score predicting Digital Ulcers in systemic sclerosis patients using Clinical data, Imaging and Patient history\u2014CIP-DUS

BackgroundDigital ulcers (DU) present a challenging complication in systemic sclerosis (SSc). The aim of this study was to combine clinical characteristics and imaging methods to a composite score for the prediction of DU in SSc patients.MethodsSeventy-nine SSc patients received clinical examination, their patient history was taken and nailfold capillaroscopy (NC), colour Doppler ultrasonography (CDUS) and fluorescence optical imaging (FOI) of the hands were performed at baseline. Newly developed DU over a period of approximately 12 months were registered. We used criteria with area under the curve (AUC) of at least 0.6 in regard to the development of these new DU to create the score (CIP-DUS, clinical features, imaging, patient history—digital ulcer score).ResultsTwenty-nine percent of all SSc patients developed new DU during follow-up (48.1% diffuse, 18.4% limited SSc). Based on the cross-validated (cv) AUC, a weight (cvAUC > 0.6 and ≤ 0.65: 1; cvAUC > 0.65 and ≤ 0.7: 2; cvAUC > 0.7: 3) was assigned to each selected parameter. The performance of the final CIP-DUS was assessed with and without the CDUS/FOI component. For the scleroderma patterns in NC, three points were appointed to late, two to active and one point to early capillaroscopy pattern according to Cutolo et al. The CIP-DUS including the CDUS and FOI parameters resulted in a good diagnostic performance (AUC after cross-validation: 0.83, 95%CI 0.74 to 0.92) and was well calibrated (chi-square = 12.3, p = 0.58). The cut-off associated with the maximum of sensitivity and specificity was estimated at ≥ 10 points resulting in a sensitivity of 100% and specificity of 74% for new DU during follow-up. Excluding CDUS and FOI parameters leads to a non-statistically significant lower performance (AUC after cross-validation: 0.81, 95%CI 0.72 to 0.91). However, including CDUS and FOI resulted in a better classification of patients in respect to the outcome new DU in follow-up due to significantly better reclassification performance (NRI = 62.1, p = 0.001) and discrimination improvement (IDI = 9.7, p = 0.01).ConclusionA new score was introduced with the aim to predict digital ulcers. If applied correctly and with the new imaging techniques proposed, all patients at risk of digital ulcers throughout 12 months could be identified.

Reduction of fat free mass index and phase angle is a risk factor for development digital ulcers in systemic sclerosis patients.

This study aims to evaluate the role of fat free mass index (FFMI) and phase angle (PhA) as markers to predict occurrence of new digital ulcers in systemic sclerosis (SSc) patients. Body composition evaluation from bioelectrical impedance and clinical assessment were performed in SSc patients at enrollment and after 12months follow-up. Seventy-nine SSc patients (67 female) with a mean age of 53 ± 13years were enrolled. In SSc patients with a digital ulcers history, FFMI value is lower (p < 0.05) and phase angle (PhA) value is higher (p < 0.01) than SSc patients without a digital ulcers history. After 12months of follow-up, 30 patients (38%) presented at least one new episode of digital ulcers. Patients with reduced FFMI had a relative risk of 6.7 for new digital ulcers (CI 2.1-21.8, p < 0.001). Patients with reduced PhA had a relative risk of 10.1 for new digital ulcers (CI 3.5-29.5, p < 0.0001). In multivariate analysis, FFMI and PhA were associated with major vascular complication (digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis). FFMI loss, assessed as delta between follow-up and baseline, is higher in SSc with short duration (≤ 3years) than SSc patients with long duration [0.4 (0-0.50) vs - 0.10 (- 0.2-0)]. In SSc patients, reduction of the FFMI and PhA represents after 12months a risk factor for development of new digital ulcers and major vascular complication. Key Points • Fat free mass index represents a risk factor for development of digital ulcers • Phase angle represents a risk factor for development of digital ulcers • Body compositions in systemic sclerosis are a marker of activity disease.

Serum level of endostatin and digital ulcers in systemic sclerosis patients.

Patients with systemic sclerosis (SSc) are at a high risk of the development of ischaemic digital ulcers (DUs) that can be complicated with infections, gangrene, and osteomyelitis. The aim of this study is to evaluate the role of endostatin in scleroderma DUs.In total, 90 SSc patients were enrolled in this study. Serum endostatin levels and DU assessment were determined in all SSc patients. The serum levels of endostatin significantly increased with progression of capillaroscopic damage (P < .01). The serum levels of endostatin are significantly (P < .05) higher in SSc patients with new DUs than in SSc patients without new DUs (127 ± 31.1 ng/mL vs 116.3 ± 39.7 ng/mL). The Receiver Operating Characteristic (ROC) curves demonstrated good accuracy of new DU prediction for the serum level of endostatin (0.70, P < .01 [95% confidence interval (CI) 0.59-0.81]). Using a cut-off value of 116 ng/mL, the odds ratio was 2.609 (CI 1.075-6.330, P < .05). The serum levels of endostatin are significantly (P < .01) higher in SSc patients with infected DUs than in SSc patients without infected DUs (139.2 [114.6-340.91] ng/mL vs 117.5 [64.3-163.9] ng/mL). Serum levels of endostatin are higher in patients with DUs, especially in those with infected DUs.

Lower-limb Ulcers in Systemic Sclerosis: A Multicentre Retrospective Case-control Study.

Lower-limb ulcers in systemic sclerosis patients are rarely reported. The aim of this study was to describe the main causes and outcomes of lower-limb ulcers in systemic sclerosis patients and to assess factors associated with ischaemic causes (arterial disease and/or microvascular impairment). A retrospective, multicentre, case-control study was conducted in 2013 and 2014, including 45 systemic sclerosis patients presenting lower-limb ulcers between 2008 and 2013. The estimated prevalence of lower-limb ulcers among systemic sclerosis patients was 12.8%. Ulcers were related to venous insufficiency in 22 cases (49%), ischaemic causes in 21 (47%) and other causes in 2 (4%). Complete healing was observed in 60% of cases in a mean time of 10.3 months; 59% relapsed during a mean follow-up of 22 months. Ischaemic lower-limb ulcer outcomes were poor, with a 28.6% amputation rate. Logistic-regression multivariate analyses between ischaemic lower-limb ulcer cases and matched systemic sclerosis-controls identified past or concomitant digital ulcer and cutaneous sclerosis of the feet as independent risk factors associated with ischaemic lower-limb ulcers.

Macrocirculation versus microcirculation and digital ulcers in systemic sclerosis patients.

Macrocirculation versus microcirculation and digital ulcers in systemic sclerosis patients.

Geographic variation as a risk factor for digital ulcers in systemic sclerosis patients: a multicentre registry

Objective: To evaluate the influence of geographic variation on the risk of digital ulcer (DU) development in systemic sclerosis (SSc) patients.Methods: This cross-sectional, multicentre study evaluated patients with SSc from centres located in different geographic regions of Brazil (subtropical and tropical climate zones). Demographic and clinical data were collected.Results: The study included 141 patients with SSc (26 from the subtropical and 115 from the tropical zone). In total, 43 DUs were observed in 23 (16%) of the patients. By a simple logistic regression model, the presence of DUs was associated with a higher modified Rodnan skin score, previous necrosis or amputation of the extremities, flexion contracture of the fingers, active smoking, higher avascular score on capillaroscopy, higher severity of Raynaud’s phenomenon, a higher Health Assessment Questionnaire Disability Index (HAQ-DI) score, a higher visual analogue scale score for Raynaud’s phenomenon and overall disease, and the subtropical climate zone. Using multiple logistic regression, the presence of DUs was significantly associated with patients living in the subtropical climate zone [odds ratio (OR) = 5.4, p = 0.002], necrosis or amputation (OR = 5.2, p = 0.011), and a higher HAQ-DI score (OR = 2.6, p = 0.021).Conclusion: In this multicentre study in a continental country with different climates, patients with SSc living in a subtropical climate region had a 5.4 times higher risk of developing DUs than patients living in a warmer region (tropical climate), suggesting a more severe course of peripheral vasculopathy among patients living in geographic regions with relatively cold weather.

The skin in autoimmune diseases-Unmet needs.

Treatment of skin manifestations in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and dermatomyositis (DM) is based on the results of only few randomized controlled trials. The first-line treatment for disfiguring and widespread cutaneous involvement in SLE is antimalarials, but some patients are therapy resistant. Recently, the monoclonal antibody belimumab was approved for SLE as an adjunct therapy for patients with autoantibody-positive disease who despite standard therapy show high disease activity, intolerance of other treatments, or an unacceptably high need for corticosteroids. However, a validated skin score has not been used to confirm the efficacy of belimumab on mucocutaneous manifestations. In SSc, another multi-systemic progressive disease, involvement of the lung, kidney, and the heart is frequently treated with corticosteroids and immunosuppressives, but therapeutic modalities for cutaneous lesions, such as skin sclerosis and digital ulcers, are limited. In the past years, treatment with the endothelin-receptor antagonist bosentan has been proven to reduce the occurrence of new digital ulcers in SSc patients but has no or limited effect on healing of digital ulcers. DM is an idiopathic autoimmune disease characterized by inflammation of the muscles and skin, which is treated with immunosuppressives. Corticosteroids are the first-line treatment for muscle involvement in DM, but skin lesions often flare by reduction or discontinuation. In summary, there is a high unmet need for new therapeutic strategies focusing on skin involvement in systemic autoimmune diseases. Therefore, innovative designs of randomized controlled trials with validated skin scores are warranted to develop new therapeutic strategies for patients with cutaneous manifestations.

Serum heparanase levels: A protective marker against digital ulcers in patients with systemic sclerosis.

Heparanase is an endo-β-D-glucuronidase cleaving heparan sulfate side-chains of heparin sulfate proteoglycans, which is involved in wound healing, inflammation, neovascularization and tumor progression through the degradation and remodeling of the extracellular matrix and the release of sequestered pro-angiogenic factors. Because heparanase-mediated biological processes seem to be involved in the development of systemic sclerosis (SSc), we investigated the clinical correlation of serum heparanase levels in patients with this disease. Serum heparanase levels were significantly higher in SSc patients than in healthy individuals, while comparable between diffuse cutaneous SSc and limited cutaneous SSc subgroups. On the other hand, SSc patients with digital ulcers had serum heparanase levels significantly lower than those without. These results suggest that serum heparanase levels may be elevated in SSc patients reflecting the contribution of heparanase-dependent biological processes to the development of SSc. SSc patients with high serum heparanase levels may be protected from the development of digital ulcers due to the increased release of sequestered pro-angiogenic factors such as vascular endothelial growth factor. Therefore, serum heparanase levels may serve as a protective marker against digital ulcers in SSc patients.

A possible contribution of endothelial CCN1 downregulation due to Fli1 deficiency to the development of digital ulcers in systemic sclerosis.

CCN1 is a pleiotropic molecule involved in angiogenesis and postnatal vasculogenesis, both of which are impaired in systemic sclerosis (SSc). To elucidate the potential role of CCN1 in the development of SSc, we investigated CCN1 expression in the lesional skin of SSc patients and SSc animal models and the clinical correlation of serum CCN1 levels. CCN1 expression was markedly decreased in dermal small blood vessels of SSc patients compared with those of healthy controls, while comparable between normal and SSc dermal fibroblasts. Transcription factor Fli1, whose deficiency due to epigenetic suppression is implicated in the pathogenesis of SSc, occupied the CCN1 promoter and gene silencing of Fli1 resulted in the reduction of CCN1 expression in human dermal microvascular endothelial cells. Consistently, CCN1 expression was suppressed uniformly and remarkably in dermal blood vessels of Fli1(+/-) mice and partially in those of endothelial cell-specific Fli1 knockout mice. Furthermore, serum CCN1 levels were significantly decreased in SSc patients with previous and current history of digital ulcers as compared to those without. Collectively, these results suggest that endothelial CCN1 downregulation at least partially due to Fli1 deficiency may contribute to the development of digital ulcers in SSc patients. This study further supports the idea that epigenetic downregulation of Fli1 is a potential predisposing factor in the pathogenesis of SSc.

FRI0373 Decreased flow mediated dilatation and nailfold capillaroscopic findings can be predictors of digital ulcers in systemic sclerosis patients

BackgroundRaynaud Phenomenon (RP) is a clinical marker for microangiopathy. Systemic sclerosis is a chronic autoimmune disease characterized by widespread vasculophaty and tissue fibrosis. Vasculopathy includes vascular remodelling with progressive narrowing...

High serum sCD163/sTWEAK ratio is associated with lower risk of digital ulcers but more severe skin disease in patients with systemic sclerosis

IntroductionSystemic sclerosis (SSc) is an autoimmune disease characterized by chronic inflammation, vascular injury and excessive fibrosis. CD163 is a scavenger receptor which affects inflammatory response and may contribute to connective tissue remodelling. It has recently been demonstrated that CD163 can bind and neutralize the TNF-like weak inducer of apoptosis (TWEAK), a multifunctional cytokine which regulates inflammation, angiogenesis and tissue remodelling. We aimed to investigate the relationships between serum levels of soluble CD163 (sCD163) and soluble TWEAK (sTWEAK) in relation to disease manifestations in SSc patients.MethodsThis study included 89 patients with SSc who had not received immunosuppressive drugs or steroids for at least 6 months and 48 age- and sex-matched healthy controls (HC) from four European centres. Serum concentrations of sTWEAK and sCD163 were measured using commercially available ELISA kits.ResultsThe mean serum concentrations of sTWEAK were comparable between SSc patients (mean +/- SD: 270 +/- 171 pg/mL) and HC (294 +/- 147pg/mL, P >0.05). Concentration of sCD163 and sCD163/sTWEAK ratio were significantly greater in SSc patients (984 +/- 420 ng/mL and 4837 +/- 3103, respectively) as compared to HC (823 +/- 331 ng/mL and 3115 +/- 1346 respectively, P <0.05 for both). High sCD163 levels and a high sCD163/sTWEAK ratio (defined as > mean +2SD of HC) were both associated with a lower risk of digital ulcers in SSc patients (OR, 95%CI: 0.09; 0.01, 0.71, and 0.17; 0.06, 0.51, respectively). Accordingly, patients without digital ulcers had a significantly higher sCD163 concentration and sCD163/sTWEAK ratio as compared to SSc patients with digital ulcers (P <0.01 for both) and HC (P <0.05 for both). A high sCD163/sTWEAK ratio, but not high sCD163 levels, was associated with greater skin involvement.ConclusionsThe results of our study indicate that CD163-TWEAK interactions might play a role in the pathogenesis of SSc and that CD163 may protect against the development of digital ulcers in SSc. Further studies are required to reveal whether targeting of the CD163-TWEAK pathway might be a potential strategy for treating vascular disease and/or skin fibrosis in SSc.

Successful Treatment with Bosentan of Lower Extremity Ulcers in a Scleroderma Patient

Digital ulcers are a well-known problem in patients with systemic sclerosis. Lower extremity ulcers are less prevalent but are also a challenging and underestimated complication of the disease causing important pain and morbidity. Bosentan, an oral dual endothelin receptor antagonist, has been shown to be effective in preventing digital ulcers in patients with systemic sclerosis. A few recent observations showed the efficacy of bosentan for accelerating the healing of nondigital ulcers in scleroderma patients. This report deals with a 48-year-old patient with systemic sclerosis who developed painful ulcers on the left ankle and hallux. The ulcers were refractory to a combination of vasodilator therapy with a calcium antagonist and several courses of intravenous prostanoids, low molecular weight heparin, aspirin, simvastatin, and intensive local treatment. Bosentan treatment showed spectacular healing of the ulcers already after 4 months of therapy. This case supports the previous few observations of accelerating wound healing of lower extremity ulcers in systemic sclerosis patients with bosentan treatment.

Prospective, open-label, uncontrolled pilot study to study safety and efficacy of sildenafil in systemic sclerosis–related pulmonary artery hypertension and cutaneous vascular complications

Pulmonary artery hypertension (PAH) remains the leading cause of morbidity and mortality in systemic sclerosis, while Raynaud's phenomenon and digital ulcers significantly add to the morbidity in systemic sclerosis (SSc). This study was undertaken to evaluate the role of sildenafil in PAH, Raynaud's phenomenon, and digital ulcers in systemic sclerosis patients. A prospective, open-label, uncontrolled pilot study was done at a tertiary care centre in India to study the safety and efficacy of oral sildenafil in PAH, Raynaud's phenomenon, digital infarcts, and ulcers in SSc. Seventeen patients fulfilling ACR classification criteria for scleroderma and having PAH were recruited. Six-minute walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and 2D ECHO were performed in all the study subjects at baseline and at 3 months post-treatment. All patients were treated with oral sildenafil 25 mg three times a day for a period of 3 months. The pre- and post-treatment values of mean pulmonary artery pressure (PAP), 6-min walk test, WHO class of dyspnoea, and severity of Raynaud's phenomenon were compared to look for any significant change. Sixteen patients who completed 3-month follow-up had shown statistically significant improvement in 6-min walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and mPAP. Also, there was no occurrence of new digital infarcts or ulcers, and existing ulcers showed signs of healing. Sildenafil is highly efficacious cheaper and safe alternative to other available therapies for SSc-associated PAH, Raynaud's phenomenon, and digital infarcts/ulcers.

Modelling epistasis in genetic disease using Petri nets, evolutionary computation and frequent itemset mining

Petri nets are useful for mathematically modelling disease-causing genetic epistasis. A Petri net model of an interaction has the potential to lead to biological insight into the cause of a genetic disease. However, defining a Petri net by hand for a particular interaction is extremely difficult because of the sheer complexity of the problem and degrees of freedom inherent in a Petri net’s architecture. We propose therefore a novel method, based on evolutionary computation and data mining, for automatically constructing Petri net models of non-linear gene interactions. The method comprises two main steps. Firstly, an initial partial Petri net is set up with several repeated sub-nets that model individual genes and a set of constraints, comprising relevant common sense and biological knowledge, is also defined. These constraints characterise the class of Petri nets that are desired. Secondly, this initial Petri net structure and the constraints are used as the input to a genetic algorithm. The genetic algorithm searches for a Petri net architecture that is both a superset of the initial net, and also conforms to all of the given constraints. The genetic algorithm evaluation function that we employ gives equal weighting to both the accuracy of the net and also its parsimony. We demonstrate our method using an epistatic model related to the presence of digital ulcers in systemic sclerosis patients that was recently reported in the literature. Our results show that although individual “perfect” Petri nets can frequently be discovered for this interaction, the true value of this approach lies in generating many different perfect nets, and applying data mining techniques to them in order to elucidate common and statistically significant patterns of interaction.

Efficacy of the endothelin receptor blocker bosentan for refractory sickle cell leg ulcers

In February 2007, a 46-year-old woman with sickle cell anaemia (SCA) was hospitalized for dyspnea of progressive onset. She had suffered from bilateral leg ulcers since 1979, which had been complicated with episodes of wound infections and ankle stiffness. They were very disabling, leading to frequent loss of work, intense pain and depression. The following treatments were either unsuccessful or resulted in partial improvement: classical tulles, hydrocellular dressings, hydrogels, skin grafts, topical dripping of granulocyte-macrophage colony-stimulating factor and regular transfusions. True remission exceeding more than a few weeks had never occurred during the last 18 years. A glomerulopathy was diagnosed in 2004, and treatment with ramipril was begun. At admission, the cutaneous ulcers were covered with adherent fibrinous layer and were located on the internal aspect of the right leg, and on the external ankle of the right foot, with an involved area of 29 cm2. They were painful with a score of 7 on a 1–10 visual analogue scale. Peripheral pulses were palpated and the right femoral head showed osteonecrosis. Pulmonary hypertension, characterized by an increased resting tricuspid regurgitation jet velocity of 3·5 m/s, was confirmed by right heart catheterization that disclosed a mean pulmonary artery pressure of 37 mmHg and pulmonary vascular resistance of 216 dyn.s/cm5. The pre-transfusion haemoglobin level was 85 g/l (unchanged), the lactate dehydrogenase level was 536 U/l (normal <250), and serum creatinine was 99 μmol/l. The proteinuria was 1·8 g/d. Because of pulmonary hypertension, bosentan was started at 125 mg/d for 1 month, followed by 250 mg/d. Similar programmed transfusions were continued. Progressive improvement of the ulcers was thereafter observed, with total healing at 3 weeks. No recurrence occurred in the following 10-month period. We report here a patient with refractory sickle cell leg ulcers that resolved totally and durably under bosentan therapy given for treatment of pulmonary hypertension. Of note, the course of her ulcers was the worst of our recently published series, with resistance to all classical modalities (Halabi-Tawil et al, 2008). There was no concomitant change of therapy including other oral drugs, types of dressings and frequency of transfusions. Moreover, the complete remission of ulcers under bosentan therapy lasted up to 10 months. All these points strongly suggest that in this patient, bosentan therapy was responsible for ulcer healing. Leg ulcers are one of the most common and disabling complications of SCA, whose treatment is very discouraging, especially in the prolonged ‘malignant’ form (Halabi-Tawil et al, 2008). Recently, sickle cell ulcers have been recognized to be associated with other complications, such as priapism and pulmonary hypertension, constituting a subphenotype of SCA, in which intravascular haemolysis and endothelial lesions play a key role (Kato et al, 2006). Indeed, in SCA, high levels of endothelin-1 (Hebbel & Vercelloti, 1997; Tharaux et al, 2005) and impaired bioavailability of nitric oxide (Reiter et al, 2002) exist, and lead to vasoconstriction and vasculopathy. Therefore, it is logical to hypothesize that an endothelin receptor blocker would be beneficial, by inactivating one of these two factors. Of note, the efficacy of bosentan for the prevention and, to a lesser extent, treatment of ulcers in systemic sclerosis patients has been reported (Garcia de la Peña-Lefebvre et al, 2008). A recent study evaluated that 37% of SCA patients suffering from pulmonary hypertension have also leg ulcers (De Castro et al, 2008). So, it would be interesting to monitor the evolution of ulcers in patients treated with bosentan for pulmonary hypertension, before starting a prospective trial testing this drug in the most prolonged and resistant forms of leg ulcers in SCA. This case could lead to novel endothelial directed therapy for leg ulcers, which remain one of the most difficult therapeutic problems of SCA. No financial or other potential conflicts of interest exist.

Long-term experience of bosentan for treating ulcers and healed ulcers in systemic sclerosis patients

Our objective was to evaluate the efficacy and tolerability of bosentan in patients with systemic sclerosis (SSc) who develop ulcers and healed ulcers. We also wanted to analyse the effect of bosentan on other skin and general outcome measurements. In the present prospective, observational, non-controlled study, we followed all patients with SSc who started treatment with bosentan for ischaemic ulcers and healed ulcers from January 2003 to June 2006 in our centre. We recorded skin and general outcome measurements at baseline and at 6 months. Fifteen patients were included. After a median follow-up of 24.7 months (range: 4-36), there was a significant decrease in the number of ulcers. A trend towards efficacy was seen in the number of healed ulcers and in the severity of ulcers. No significant effect was seen in other skin and general outcome measurements. Toxicity related to bosentan included mild transitory events and one toxic hepatitis. Bosentan may be a safe long-term alternative for treating the recurrence of skin ulcers and healed ulcers in SSc patients.