Ischemic Digital Ulcers Research Articles

Use of bosentan for digital ulcers related to systemic sclerosis: a real-life retrospective French study of 89 patients treated since specific approval

Objectives: Ischaemic digital ulcers (DUs) are a common complication of systemic sclerosis (SSc). This study aimed to characterize patients with SSc and ongoing DUs treated with the endothelin receptor antagonist bosentan in clinical practice in France.Method: An observational, retrospective, longitudinal study was conducted in 10 French expert centres. Medical records from randomly selected adult SSc patients who received treatment with bosentan for DU prevention from March 2007 to December 2010 were analysed. The primary objective was to determine the profile of patients at treatment initiation. Secondary objectives were to monitor bosentan dosing, treatment schedule, and reasons for treatment termination.Results: The study included 89 patients (mean age 52 years, 69% female, 44% diffuse cutaneous SSc). At bosentan treatment initiation, the mean duration of Raynaud’s phenomenon was 15 ± 12 years, and the mean time since first episode with DU was 6.5 ± 7 years. Most patients had a history of at least two episodes with DUs, separated by < 12 months (61%), and had received intravenous iloprost (63%). Previous DU complications included auto-amputation (8%), surgical amputation (6%), osteitis (6%), and gangrene (4.5%). Active smokers (25%) had a history of significantly more surgical amputation (p = 0.004) and osteitis (p = 0.004) than non-smokers. At least one active DU at bosentan initiation was detected in 82% of patients. Bosentan was used according to prescription guidelines and was well tolerated; six patients (7%) withdrew from treatment because of raised liver enzymes.Conclusions: Patients treated with bosentan for DU prevention in France have severe, refractory, ongoing ulcerative disease. Active smoking was correlated to a history of DU complications. Tolerance of bosentan was comparable to previous studies.

Digital Ulcers in Systemic Sclerosis – How to Manage in 2013?

Digital ulcers (DUs) are among the most frequent and disabling vascular complications in patients with systemic sclerosis (SSc). The etiology and pathogenesis of DUs differs depending on the lesion localization. For this reason the underlying etiologic and pathogenetic factors will guide the therapeutic decision. The main pathogenic mechanism that contributes to the development of fingertip DUs is ischemia owing to SSc-related vasculopathy. DUs over bony prominences are mainly a result of skin fibrosis, epidermal thinning and mechanical friction. At the areas of subcutaneous calcinosis DUs can develop as a result of mechanical friction and inflammation. Thus, in cases of DUs over bony prominences and calcinosis, avoidance of trauma and skin care are main measures of primary prophylaxis. In pure ischemic DUs, a combination of vasodilators (calcium channel blockers (CCBs), intravenous prostanoid, phosphodiesterase inhibitors) and antiplatelet drugs should be applied. Despite the lack of controlled trials addressing the administration of antiplatelet agents and anticoagulants in DUs in the context of SSc, the current knowledge about the platelet and coagulation dysfunction leads to their frequent administration from the leading experts in the field of SSc. In our opinion, as more powerful agents, anticoagulants should be considered in severe cases of development of digital gangrenes. Analgetics and antibiotics may be indicated and local treatment is a mandatory care. Currently, the EUSTAR recommendations for the treatment of RP and DUs in SSc include CCBs, intravenous prostanoids and endothelin receptor antagonists. Although for the inclusion of other options in the official recommendations, their efficacy should be confirmed by controlled clinical trials, they are routinely used in the leading scleroderma-centers based on the current knowledge about the pathogenesis of development of DUs in SSc.

Macitentan: First Global Approval

Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) with sustained receptor binding properties developed by Actelion Pharmaceuticals Ltd. In October 2013, oral macitentan 10 mg once daily received its first global approval in the US, followed closely by Canada, for the treatment of pulmonary arterial hypertension (PAH). The drug has also received a positive opinion in the EU from the Committee for Medicinal Products for Human Use for the treatment of PAH, and is under regulatory review in several other countries for the same indication. Endothelin (ET)-1 influences pathological changes via two ET receptor subtypes (ETA and ETB), to which it binds with high affinity. ET-1 is implicated in several forms of vascular disease making it a valid target for the treatment of pulmonary vascular diseases such as PAH. Clinical development is underway for other indications, including Eisenmenger syndrome, ischaemic digital ulcers secondary to systemic sclerosis, and glioblastoma. Macitentan was also evaluated in idiopathic pulmonary fibrosis; however, a phase 2 trial did not meet its primary endpoint and further investigation in this indication was discontinued. Macitentan was developed by modifying the structure of bosentan in the search for an optimal dual ERA with improved efficacy and tolerability compared with other ERAs. This article summarizes the milestones in the development of macitentan leading to this first approval for PAH.

Initial Evidence in Thromboangiitis Obliterans (Buerger’s Disease) Treatment with Bosentan

Thromboangiitis obliterans (TAO) is a vascular disease that affects small and medium-sized arteries and veins of both upper and lower extremities. Distal ischaemic lesions and digital necrotic ulcers, as well as major amputation rates, among these patients are not negligible. So far, no treatment option has been demonstrated to be completely effective for this disease. Endothelin-1 (ET-1) has been increasingly associated to vascular damage. Furthermore, elevated levels of ET-1 have been proved in TAO patients. Thus, ET-1 receptor antagonists may be considered as a treatment option in this disease. Consistently, initial results from open-label studies or case reports show promising efficacy of bosentan for treatment and prevention of digital ulcers in TAO with a favourable safety profile. In any case, bosentan should be further investigated in TAO patient management. To confirm initial promising findings, larger controlled randomised trials with a control group are needed. In the meantime, bosentan should be considered as a hopeful investigational agent for treating these patients.

AB0829 Usefulness of cochin hand function score in spanish patients with systemic sclerosis

BackgroundCochin Hand Function Score(CHFS) is a questionnaire proposed and validated by Poole JL et al(Arthritis Rheum 2004; 51:805-9), to measure the disability due to hand involvement in Systemic Sclerosis(SSc) patients....

FRI0378 Interleukin 6 and vascular disease in patients with systemic sclerosis

BackgroundInterleukin 6 (IL6) has been associated with modified Rodnan Skin Score (mRSS), interstitial lung disease (ILD), anti-Scl70 and anti-RNA polymerase III antibodies, as well as with ischemic digital ulcers (IDU)...

FRI0370 Joint and tendon involvement predict severe disease progression in systemic sclerosis: a eustar prospective study

BackgroundJoint involvement is frequent and strongly contributes to impaired quality of life in systemic sclerosis (SSc). In a previous cross-sectional study, synovitis and tendon friction rubs were associated with systemic...

AB0785 Incidence and treatments of digital and non-digital ulcers in 86 systemic sclerosis patients

BackgroundDigital ulcers (DU) occur in nearly more than half of the patients with systemic sclerosis (SSc). Non-digital ulcers (legs) have also been described in SSc patients. DU are usually multiple,...

THU0237 Impact of recurrent ischemic digital ulcers on hand disability in systemic sclerosis –

BackgroundIschemic digital ulcers (DU) are a common complication of systemic sclerosis (SSc).ObjectivesTo evaluate the impact of recurrent DU on hand disability in a prospective, longitudinal, observational study of 24 months.MethodsPatients...

Long-term cyclic intravenous iloprost in systemic sclerosis: clinical experience from a single center

The aim of the present study was to retrospectively evaluate response to therapy in 73 patients affected by systemic sclerosis (SSc) who underwent long-term cyclic treatment with intravenous iloprost for peripheral vascular involvement (average duration of treatment 54.12±41.04 months). Seventy-three SSc patients were enrolled. Data were collected by reviewing clinical records and by phone or direct interview. Patients underwent a thorough physical examination at the end of follow up. The incidence of severe vascular manifestations was also assessed. Statistical analysis was performed by Wilcoxon's signed rank test and descriptive statistics using Statview software. In this study cohort, 55 of 73 (75.2%) patients had a history of ischemic digital ulcers (DUs); 28 patients (38.4%) had active DUs at the beginning of treatment. Skin ulcers healed completely in 25 of 28 patients (89.3%) at the end of the first treatment. However, 40 of 55 patients (72.6%) relapsed after an average of 24 months. There was a significant correlation between relapse rate and/or number of ulcers and clinical factors (diffuse subset, changes in results of Allen's test, NT-pro BNP levels). The annual incidence of pulmonary arterial hypertension (PAH) was 2.34 (95%CI: 0.94-4.83) per 100 person years, the rate of gangrene was 2.7%, and no cases of scleroderma renal crisis were recorded. The incidence of PAH and of digital gangrene was higher than that observed in unselected SSc case series. These data suggest that our patients treated with iloprost have a higher vascular involvement than large case series of unselected SSc patients. A number of clinical factors are correlated to the severity of vascular involvement and could have an impact on the response to therapy. The clinical significance of these findings requires clarification and further investigation is needed.

Angiogenic biomarkers predict the occurrence of digital ulcers in systemic sclerosis

ObjectiveTo evaluate the possible merit of endothelial markers for the prediction of ischaemic digital ulcers in patients with systemic sclerosis (SSc).MethodsCirculating endothelial progenitor cells (EPC), circulating endothelial cells and serum...

Efecto del bosentan en pacientes con úlceras digitales de etiología isquémica

Introduction Tissue ischaemia is the end result of a process involving a large number of molecules that mediate the endothelium-vascular smooth muscle interaction, among which is found endothelin-1 (ET-1), a molecule synthesized by the vascular endothelium and induces vasoconstriction, is proinflammatory, and has mitogenic action. Objective To evaluate the use of bosentan, a dual endothelin receptor antagonist in the treatment of ischaemic digital ulcers. Patients and method A total of 18 patients were treated with bosentan for digital ulcers secondary to scleroderma or other cause (outside indication guidelines), with severe involvement of distal vessels and non-revascularisable. Results The aetiology was atherosclerosis in 11 patients, Buerguer disease in 5, embolism in 1, and scleroderma in 1 patient. The median length of treatment was 90 days. Three (16.7 %) patients required minor amputation and 1 case (5.5 %) below-knee amputation. There was no increase in transaminases in any case. There was an improvement of pain in 16 patients (88.9 %) and 11 (61.1 %) had decreased the size of the lesions. Conclusions This is the first study to show that treatment with bosentan may be useful in non-revascularisable patients, improving pain and lesion size, with a low incidence of major amputations in the short term.

Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial

ObjectivesIschaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor...

Efficacy of Bosentan in Digital Ischemic Ulcers

Thromboangiitis obliterans (also known as Buerger's disease) is an inflammatory vascular disorder that affects small and medium-sized arteries and veins in the extremities. There is no specific treatment and the only effective intervention is absolute cessation of tobacco use. Endothelial dysfunction appears to be of relevance to this condition and a report has even found that high serum levels of endothelin correlate with the presence of necrosis. We report two cases of digital necrosis showing a very satisfactory response to treatment with bosentan, a dual endothelin receptor antagonist.

A score of risk factors associated with ischemic digital ulcers in patients affected by systemic sclerosis treated with iloprost

A single series of patients affected by systemic sclerosis (SSc) and cyclically treated with iloprost was reviewed in order to evaluate the incidence of digital ulcers (DUs) and to compare the characteristics between the patients with and without this painful and disabling vascular complication. The record charts of 85 SSc patients were revised. Ischemic DUs and scleroderma contracture ulcers were separately considered. Twenty-nine subjects developed ischemic DUs during the course of the disease; whereas, scleroderma contracture ulcers occurred in six subjects. Ischemic DUs were associated with younger age at scleroderma onset, a longer disease duration, a longer time delay from scleroderma diagnosis to iloprost therapy, a bigger skin involvement, the presence of joint contractures, a videocapillaroscopic late pattern, a history of smoking, and of corticosteroids therapy. After the exclusion of four subjects with concomitant peripheral arterial disease, a forward-stepwise logistic regression analysis showed that only four variables, i.e., age at scleroderma onset, delay in beginning iloprost therapy, history of smoking, and presence of joint contractures remained significantly associated with ischemic DUs. In a score reflecting the sum of these four risk factors, the prevalence of ischemic DUs increased progressively from the lowest to the highest value of the score. The predictivity of this model was evaluated by the receiver-operating characteristics curve, with an estimated area under the curve of 0.836 with 95% confidence interval from 0.736 to 0.937. All the patients with scleroderma contracture ulcers were characterized by both diffuse pattern of disease and positivity for anti-Scl70 antibody. In this retrospective study, scleroderma patients with ischemic DUs are characterized by early disease onset, delay in beginning iloprost therapy, smoking habit, and presence of joint contraction. A score reflecting the sum of these factors may be useful to predict the risk of developing ischemic DUs.

Upregulation of Myxovirus-resistance Protein A: A Possible Marker of Type I Interferon Induction in Systemic Sclerosis

.To examine whether myxovirus-resistance protein A (MxA) mRNA expression, commonly considered a reliable marker of Type I interferon (IFN) bioactivity, is modified in patients with systemic sclerosis (SSc); if it is associated to specific clinical features; and if its modulation is accompanied by modulation of mRNA for the Type I IFN receptor (IFNAR). Quantification of mRNA for MxA and the subunit IFNAR1 and isoforms of IFNAR2 was performed by real-time polymerase chain reaction in 50 patients with SSc. Results were compared with those obtained from healthy controls and patients with another autoimmune disease such as multiple sclerosis. . Levels of MxA mRNA above the 99th percentile of values found in healthy controls were observed in 9 out of 50 patients with SSc (p < 0.001). Induced MxA expression was significantly associated with some features of more severe disease, such as lower forced vital capacity and the presence of ischemic digital ulcers. No differences in the levels of IFNAR were found within MxA-induced and MxA-non-induced patients, but there was a direct correlation between levels of MxA and the soluble isoform of IFNAR2. . Our results show induction of MxA expression in some patients with SSc, which correlates with the presence of ischemic ulcers and other signs of worse disease, suggesting a potential role of Type I IFN in the pathogenesis of this disease and/or its complications.

Lack of efficacy of quinapril on vascular damage in limited cutaneous systemic sclerosis

Gliddon et al. conducted a randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy of the angiotensin-converting enzyme inhibitor quinapril for the management of vascular damage in systemic sclerosis (SSc). The trial comprised 213 patients with limited cutaneous SSc or Raynaud's phenomenon (mean age 54 years, 182 females) who were randomly assigned to receive 80 mg/day, or the maximum tolerated dose, of quinapril (n = 105) or placebo (n = 108) for 2-3 years. Patients were assessed every 3 months. The number of new ischemic digital ulcers was recorded as the primary end point, while the frequency of Raynaud's phenomenon episodes, skin score, health status, pulmonary artery pressure and treatments for ischemia were also monitored as secondary end points. There were no detectable differences between patients treated with quinapril and those receiving placebo; however, although no severe adverse effects were observed, patients taking quinapril experienced significantly more adverse effects.

Bosentan dans la sclérodermie: Perspectives

Systemic sclerosis (SSc) is a complex, immune-mediated disease. The etiology and pathogenesis of SSc remain incompletely understood. Vascular injury, excessive fibrosis, autoimmunity and inflammation are permanent features of the disease process leading to irreversible organ damage and significant morbidity and mortality in SSc patients. One hypothesis suggests that endothelial damage and vascular dysfunction may be some of earliest pathogenic alterations. Despite significant efforts developed in the past twenty years, no single therapy has been proven to increase survival in SSc patients in a prospective randomised trial. Endothelin-1 is considered to be a central pathogenic factor in systemic sclerosis (SSc), leading to vasoconstriction and fibrosis. Bosentan is a specific, orally active, dual endothelin receptor antagonist that has recently been approved for the treatment of primary pulmonary arterial hypertension (PAH) orPAH associated with systemic sclerosis. Furthermore, bosentan is a useful option for the prevention of ischemic digital ulcers in the setting of systemic sclerosis. These findings suggest that bosentan could have therapeutic benefits on others vascular injuries. Recent data in many experimental animal models demonstrated the fundamental role of endothelin in the pathogenesis of fibrosis, and the anti-fibrotic potential of bosentan. Nonetheless, its exact place in the management of fibrosis in patients with SSc will be clarified by results of furthers studies. Several new therapeutic approaches are currently under evaluation in ScS. An attractive therapeutic approach is the combination of drugs with different mechanisms of action, with the objective to maximize their clinical benefit.

Therapeutisches Management akraler Manifestationen der systemischen Sklerose

□ Acral manifestations of systemic sclerosis include Raynaud's phenomenon, calcinosis cutis, and sclerodactyly. In the later stages of the disease, contractures of the skin and joints as well as obliterative vasculopathy leading to digital ulcers and necrotic lesions may occur. Patients with acral manifestations of systemic sclerosis are ideally treated by a team that includes a rheumatologist, dermatologist, hand surgeon, physiotherapist, and, eventually, a psychologist. □ Calcium channel antagonists, α 1 -adrenergic blockade with prazosin, and prostacyclin analogs were proven to be effective in the treatment of scleroderma-related Raynaud's phenomenon. Losartan, an angiotensin II receptor inhibitor, and fluoxetine, a selective serotonin reuptake inhibitor, have been beneficial for systemic sclerosis-associated Raynaud's phenomenon in pilot studies. Parenteral prostacyclin analogs, e.g., iloprost, can be recommended as first-line treatment of ischemic digital ulcers. When prostacyclin analogs fail, the phosphodiesterase type 5 inhibitor sildenafil can be tried to improve ulcer healing. Bosentan, an endothelin receptor antagonist, may prevent new digital ulcers. At present, there are no medical agents agreed to be generally effective in the reduction of calcinotic deposits or cutaneous fibrosis, although some drugs have been identified as potentially beneficial. □ Surgical treatment of acral manifestations consists of excision or curettage of symptomatic calcific deposits, digital sympathectomy, arterial reconstruction, and amputation in rare cases. Flexion contractures of the proximal interphalangeal joints, with secondary hyperextension of the metacarpophalangeal joints, can be treated by arthrodesis of the proximal interphalangeal joints and resection arthroplasty or prostheses at the metacarpophalangeal joints to improve hand function.

Autoimmune disorders: nail signs and therapeutic approaches

Systemic sclerosis (scleroderma, SSc) is an autoimmune disease that targets small and medium-sized arteries and arterioles in the involved tissues, resulting in a fibrotic vasculopathy and tissue fibrosis. Several prominent nail and periungual changes are apparent in scleroderma. Examination of the nail fold capillaries can reveal the nature and extent of microvascular pathology in patients with collagen vascular disease and Raynaud's phenomenon. Among the complications stemming from Raynaud's phenomenon can be painful ischemic digital ulcers. This can be managed, and potentially prevented, through pharmacologic and nonpharmacologic means. Whereas oral calcium channel blockers remain the most convenient therapy, oral endothelin receptor antagonists and intravenous prostaglandins may be important therapeutic advances for ischemic digital vascular lesions.