Significant attenuation of macrovascular involvement by bosentan in a patient with diffuse cutaneous systemic sclerosis with multiple digital ulcers and gangrene

Abstract

Systemic sclerosis (SSc) is characterized by vascular injuries, and bosentan has recently been proved to be efficacious for the prevention of new digital ulcers in SSc. We herein report a case of SSc in a patient with refractory digital ulcers and gangrene treated with bosentan. Stenosis of the ulnar artery, evaluated by magnetic resonance angiography, was attenuated by the bosentan treatment, suggesting that bosentan exerts a reverse remodeling effect against the pathological organic changes of arteries in SSc.     

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.     

Hand function in systemic sclerosis: A clinical and ultrasonographic study

Aim of the workTo evaluate hand impairment and functional disability in scleroderma patients using clinical and ultrasonographic (US) measures.Patients and methodsFifteen scleroderma patients and 10 age and sex-matched healthy controls were studied. Patients underwent clinical examination including modified Rodnan skin score. Hand function assessment included pinch and grip strength measurement, finger range of motion (ROM) assessment, Hand Mobility in Scleroderma (HAMIS) test and Hand Functional Index (HFI). Hand disability was assessed by Health Assessment Questionnaire (HAQ), Scleroderma HAQ Visual Analogue Scale (SHAQ VAS) and Cochin scale. US hand examination included measuring hand skin thickness, screening of the finger flexor and extensor tendons, measuring cartilage thickness of the 2nd MCP joint, anteroposterior thickness of the flexor retinaculum, and surface area of the median nerve.ResultsNine patients had healed digital ulcers while only one patient had active ulcers. Seven patients had arthralgia in the hand joints. The patients had a significant decrease in grip strength and finger ROM. By US, patients showed significant increase in hand skin thickness and flexor retinaculum thickness and a significant decrease in median nerve surface area. Hand disability measures showed variable significant correlations with pinch and grip strength and hand mobility measures which were significantly correlated with US skin thickness of the 2nd inter-metacarpal web space.ConclusionsHand disability in scleroderma was mainly related to impaired hand mobility and also diminished strength. The use of US in adjunct to clinical examination refines the evaluation of hand impairment in scleroderma.     

Exploring the patient experience of digital ulcers in systemic sclerosis

Digital ulcers are common in patients with systemic sclerosis, affecting over half of patients during the course of their disease. For some patients, digital ulcers occur as isolated phenomena; whereas, for others, digital ulceration is recurrent, and often refractory to intervention. Demonstrating treatment efficacy for digital ulcer disease has typically focussed on clinician opinion of ulcer healing and new ulcer occurrence. Advances in management have improved outcomes which may have had the unfortunate effect of rendering traditional trial endpoints less effective at demonstrating treatment efficacy. Despite recent improvements in management, our work is not complete and digital ulceration remains a major cause of morbidity for many patients with systemic sclerosis. This review shall examine the patient experience of digital ulcers in systemic sclerosis. We shall consider how a detailed understanding of the severity and burden of digital ulceration, aetiopathogenesis, and their impact on emotional health, function, work and social participation might inform the development of novel clinical trial outcomes that can support future advances in the assessment and management of digital ulceration in systemic sclerosis.     

Bone mineral density in patients with systemic sclerosis and its association with hand involvement

Aim of the workThe aim of the present study is to assess bone mineral density (BMD) in systemic sclerosis (SSc) patients and to determine associated factors.Patients and methodsSixty-five female SSc patients (mean age 39.5 ± 13.5 years, disease duration 7.3 ± 5.9 years), and forty age- and sex- matched controls were included. Forty-seven patients had limited SSc and 18 had diffuse type. Patients were subjected to clinical and functional assessment. BMD was quantified at the distal radius, femoral neck and lumbar spine (L2–4) by dual energy X-ray absorptiometry.ResultsSSc patients had a higher frequency of osteoporosis at the distal radius and osteopenia at the lumbar spine (p = 0.001 and 0.002, respectively), but the BMD at the femoral neck was not significantly different from the control group. Patients with osteoporosis at the distal radius had a significantly higher frequency of hand deformities (p < 0.05) and higher functional scores reflecting more disability than patients without (p = 0.01), while patients with osteoporosis at the lumbar spine were significantly older (p < 0.001) and had a longer disease duration than those without (p = 0.001). No associations were found between menopausal status, SSc subtype, skin score, internal organ affection and osteoporosis at the three skeletal sites.ConclusionPatients with SSc have lower bone mineral density than controls at the distal radius and lumbar spine. Osteoporosis at the distal radius is associated with the presence of hand deformity and functional disability, while osteoporosis at the lumbar spine is associated with older age and longer disease duration.     

Reliability and validity of the Italian version of the hand functional disability scale in patients with systemic sclerosis

The English version of hand functional disability scale is a validated instrument for measuring hand involvement in patients with systemic sclerosis (SSc). Because validation of multiple-language versions of existing validated questionnaires plays a key role in standardizing the outcome measurement and increasing the statistical power of clinical studies, this study aims to validate a translated Italian version of hand functional disability scale which is not available at the moment. The Italian version of hand functional disability scale was tested on 50 patients with SSc. To determine test–retest reliability, 40 SSc patients were asked to complete the questionnaire a second time within 2 weeks of the initial testing session. The test–retest reliability and internal consistency were determined by intra-class correlation coefficient (ICC) and Cronbach's α. External consistency was measured by comparing with an already validated test, the Health Assessment Questionnaire (HAQ), and clinical measurements. To explore the relationships among these variables, multiple correspondence analysis (MCA) was adopted. The statistical analysis of each domain and the total score revealed a good test–retest reliability (ICCs > 0.75) and internal consistency (Cronbach's α > 0.7). Furthermore, a good external consistency was confirmed by evaluating the differences between the distributions of hand functional disability scale score for SSc patients with or without hand involvement (arthralgias, arthritis, flexion contractures, and digital ulcers) and comparing results with those obtained for HAQ. Finally, MCA demonstrates a strong correlation among functional disability scale areas and HAQ scores. The hand functional disability scale is a self-administered questionnaire and it has been specially developed to measure hand impairment in patients with hand disorders. Our data support its validity and reliability in Italian SSc patients.     

Clinical correlation of brachial artery flow-mediated dilation in patients with systemic sclerosis

Abstract

Objective To investigate the clinical significance of flow-mediated dilation (FMD) in systemic sclerosis (SSc).

Methods Thirty-three SSc patients and 12 healthy controls were studied. Ultrasound assessment of the brachial artery FMD was performed on all subjects. The results were expressed as the percentage of increase in brachial artery diameter following hyperemia.

Results Limited cutaneous SSc (lcSSc) patients had significantly lower FMD values than healthy controls (5.3 ± 2.7 versus 7.7 ± 2.0 %, p < 0.05), while the values in diffuse cutaneous SSc (dcSSc) patients (6.7 ± 4.0 %) were comparable to those in lcSSc patients and healthy controls. Although FMD values did not correlate with any clinical features in dcSSc patients, there was an inverse correlation between FMD values and disease duration in lcSSc patients (r = ?0.64, p < 0.05). Furthermore, lcSSc patients with decreased FMD values showed significantly higher prevalence of digital ulcers and elevated right ventricular systolic pressure than those with normal values (for each; 75 versus 10 %, p < 0.05).

Conclusion The FMD values represent the severity of vascular damages, which progress along with disease duration and lead to digital ulcers and pulmonary arterial hypertension, in lcSSc patients.     

Multiple sclerosis associated with systemic sclerosis

Multiple sclerosis (MS) has been increasingly reported in association with other autoimmune diseases not primary affected the nervous system. The coexistence of MS and systemic sclerosis (SSc) has been rarely described. We report here the case of a 46-year-old female patient with longstanding MS since the age of 26, who developed SSc 12 years later. Her MS was of the relapsing-remitting type, but the definite diagnosis was not made until the age of 33. MS diagnosis was based on medical history, magnetic resonance imaging (MRI) studies and positive cerebrospinal fluid analysis. One year after the diagnosis of MS, she developed Raynaud’s phenomenon, skin tightness and hypopigmented patches, suggestive of scleroderma. Further investigation with laboratory studies, including serology, hand and chest X-rays, and chest computerized tomography scan confirmed the SSc diagnosis. Our report highlights the interesting association between MS and SSc that may be due to an overlapping pathogenetic mechanism for both processes.     

Experience with azathioprine in systemic sclerosis associated with interstitial lung disease

the aim of this study was to evaluate the safety and efficacy of azathioprine in the treatment of interstitial lung disease (ILD) associated with systemic sclerosis (SSc). The records of patients with SSc with ILD who were treated with azathoprine were reviewed. Patients were treated with azathioprine and low-dose prednisone if they had progressive pulmonary symptoms (deterioration in the dyspnea score) or poor or deteriorating lung function. Response was classified as improved if the FVC increased more than 10% from baseline, and stable if it remained within 10% of baseline. Serial dyspnea scores were recorded. Eleven patients were treated with azathioprine, three of whom received treatment for 6 months or less owing to adverse effects (nausea, leukopenia and pulmonary tuberculosis in one patient each). The remaining eight patients received at least 12 months treatment and the results suggested an improvement in the mean percent predicted FVC from a baseline value of 54.25±3.53 to 63.38±6.15 after 12 months (p=0.101). Overall, five patients improved and three remained stable. The mean dyspnea score (n=8) improved from a baseline of 1.55±0.19 to 0.50±0.19 at 12 months (p=0.011). This is the first case series of patients with SSc-associated ILD treated with azathioprine. Our results suggest that azathioprine may have a role in stabilizing lung function and improving symptoms in SSc, although this needs confirmation by a randomized controlled trial.Abbreviations ILD Interstitial lung disease - SSc Systemic sclerosis     

Effect of treatment with iloprost with or without bosentan on nailfold videocapillaroscopic alterations in patients with systemic sclerosis

Introduction: Vascular involvement plays a decisive role in systemic sclerosis (SSc) pathogenesis; it is responsible for some important clinical manifestations of the disease such as Raynaud’s phenomenon and digital ulcers (DU). Bosentan, a dual receptor endothelin antagonist, and iloprost, often in combination therapy, seems to be able to interfere with the scleroderma microangiopathy.

Objectives: Aim of the study was to evaluate the effect of bosentan and iloprost on scleroderma microangiopathy, analyzed by means of capillaroscopic skin ulcer risk index (CSURI), in SSc patients treated for the prevention of DU.

Methods: Nailfold videocapillaroscopy (NVC) was performed in 95 SSc patients, treated with iloprost alone (group 1) or combination therapy with iloprost and bosentan (group 2), at baseline and after one year. In all patients CSURI was calculated according to the formula “diameter?×?number of megacapillaries/(total number of capillaries)²”: in addition, total number of capillaries, giant capillaries, micro-hemorrhages, disorganization of the vascular array, and ramified capillaries were evaluated by means of a semiquantitative score.

Results: After 12 months, we observed a reduction of the number of giant capillaries in both groups, while an increase of ramified capillaries was recorded only in group 2. CSURI improved slightly in group 2 without statistical significance; on the contrary, in group 1 a significant worsening was recorded (p?≤?0.001).

Conclusions: Our study confirms the effectiveness of bosentan, in combination with iloprost, in SSc microangiopathy observed to NVC. Moreover, the observed findings further support the role of CSURI in the evaluation and monitoring of SSc microangiopathy.     

Interstitial lung disease in systemic sclerosis

Lung involvement frequently complicates systemic sclerosis (SSc), provoking loss of quality of life and a poor expectation of survival. For this reason an early diagnosis of lung involvement is warranted: high-resolution computed tomography (HRCT), pulmonary function tests (PFT), lung scintigraphy with DTPA and bronchoalveolar lavage (BAL) are mandatory to define and follow-up pulmonary interstitium. Coughing and a sensation of breathlessness on exertion are the earliest symptoms of lung involvement. Lung involvement may be investigated with PFTs, which are non-invasive and require breathing into a tube via a mouthpiece. Forced vital capacity, which measures the total amount of air capable of being blown forcefully, and the diffusion capacity for carbon monoxide, a measure of how well oxygen diffuses into blood, are the most important functional measures. A routine chest X-ray may demonstrate fibrosis, but it is not very sensitive for detecting early or mild disease. For this reason, a HRCT scan is required. This non-invasive investigation provides images of multiple slices through the lung, from top (apex) to bottom (base), and can even detect lung involvement in early phases when no symptoms are present. ^99mT-DTPA is recommended in those patients with isolated diffusion deficits on lung function tests and in addition to HRCT in confirming the suspicion of vascular disease rather than early fibrosing alveolitis. Bronchoscopy with BAL is an invasive test that also may provide information about the inflammatory status of the affected areas of the lung detected during HRCT. In order to detect alveolitis, it should be performed as early as possible, to start prompt immunosuppressive treatment.     

Brachial plexopathy associated with systemic sclerosis

Neurological involvement is uncommon in systemic sclerosis. Most of the reported cases concern trigeminal neuropathy or peripheral nerve entrapment. We report a third case of brachial plexopathy, presumably related to vasculitis, in a patient with systemic sclerosis, which improved after cyclophosphamide therapy. Received: 7 September 2001 / Accepted: 3 April 2002     

Exon-1 polymorphism of ctla-4 gene is not associated with systemic sclerosis in Iranian patients

Although, the cytotoxic T lymphocyte antigen-4 gene polymorphism at position 49 of exon-1 has been strongly elucidated in different autoimmune diseases, but its role in predisposition to systemic sclerosis (SSc) is yet controversial. This study intends to analyze the genetic correlation of the ctla-4 gene locus with diffuse systemic sclerosis (dSSc), as well as to understand the influence of these genotypes in disease expression. Seventy known cases of SSc, and 151 age-matched healthy controls, were participated in this investigation. The frequencies of AA, GG and AG genotypes were found to be 26 (37.1%), 5 (7.2%) and 39 (55.7%) in patients, and 60 (39.7%), 19 (12.6%) and 72 (47.7%) in controls, respectively. As indicated, the differences in genotype and allele frequencies between patients and controls were insignificant (P>0.05). Moreover, the distribution of CTLA-4 polymorphism between patients did not differ significantly according to clinical and serologic features. In Iranian patients, susceptibility to SSc is not influenced by a bi-allelic ctla-4 gene (A49G) polymorphism.     

No effects of bosentan on microvasculature in patients with limited cutaneous systemic sclerosis

The endothelium-derived vasoconstrictor molecule endothelin-1 (ET-1) has been suggested to play a role in the pathogenesis of Raynaud’s phenomenon (RP) and systemic sclerosis (SSc). We studied the effect of bosentan on microvascular structure and function in patients with RP secondary to limited cutaneous SSc in a mechanistic pilot study. In this single center, open study, 15 patients with limited cutaneous SSc were treated with bosentan for 16 weeks with a follow-up period of 4 weeks. Changes in microvascular structure and function were studied with assessment of vasodilatory microvascular responses using laser Doppler fluxmetry combined with iontophoresis, capillary permeability using fluorescence videomicroscopy, nailfold capillary microscopy, and serological markers of endothelial activation. No significant changes were seen in vasodilator responses to acetylcholine and sodium nitroprusside following bosentan treatment. No effect was noted on capillary permeability during treatment. The number of nailfold capillaries remained unchanged. The endothelial activation marker vascular cell adhesion molecule did not change during treatment, but levels of thrombomodulin significantly decreased after 12 weeks of treatment. Bosentan did not induce significant changes in vasodilator responses, capillary permeability, and capillary density during treatment, so no evidence was obtained for structural improvement of microvascular structure and function in this short-time mechanistic pilot study in patients with lcSSc.     

Cyclosporine treatment of advanced interstitial pneumonitis associated with systemic sclerosis

A patient who had systemic sclerosis (SSc) with interstitial pneumonitis (IP) was being treated with prednisolone,d-penicillamine (D-P) and colchicine but developed progressive respiratory insufficiency. His ventilatory function showed the progression of restrictive disturbance without an obstructive one. We thought that this worsening was due to the developing IP but not bronchiolitis obliterans induced by D-P and started cyclosporine (CSA) therapy at 3 mg/kg/day. His symptoms improved after 3 months, and pulmonary function tests and blood gas analysis showed the best results after 1 year. There were no life-threatening side effects. CSA is an acceptable agent for advanced interstitial pneumonitis associated with SSc.     

Systemic sclerosis associated with generalized vasculitis and hypopituitarism

Systemic sclerosis (SSc) is a progressively evolving multisystemic disorder of unknown etiology. Beyond skin, several other organs can also be affected with a severity of involvement that is often heterogeneous. We describe a 53-year-old female patient who was admitted urgently to the hospital almost collapsed, because of numerous bleeding deep skin ulcers, located all over the body. Clinical findings and autoantibody screening were typical of SSc. Moreover, both histopathology and immunofluorescence findings were compatible with scleroderma and vasculitis as well. In addition, pituitary hormone investigation revealed severely damaged function of the gland. We assume that severe skin ulceration and serious hypopituitarism were both implications of underlying SSc-associated vasculitis. To the best of our knowledge, these peculiar clinical manifestations have not been described in the international literature to date.     

Cyclosporine treatment of advanced interstitial pneumonitis associated with systemic sclerosis

Abstract

A patient who had systemic sclerosis (SSc) with interstitial pneumonitis (IP) was being treated with prednisolone,d-penicillamine (D-P) and colchicine but developed progressive respiratory insufficiency. His ventilatory function showed the progression of restrictive disturbance without an obstructive one. We thought that this worsening was due to the developing IP but not bronchiolitis obliterans induced by D-P and started cyclosporine (CSA) therapy at 3 mg/kg/day. His symptoms improved after 3 months, and pulmonary function tests and blood gas analysis showed the best results after 1 year. There were no life-threatening side effects. CSA is an acceptable agent for advanced interstitial pneumonitis associated with SSc.