cardiovascular-agents and Scleroderma--Systemic

The purpose of this article is to highlight novel therapies that are being used in scleroderma (SSc). Therapeutic interventions in SSc generally target at least one of three ongoing biological processes characteristic of the disease: vasculopathy, autoimmunity and tissue fibrosis. Treatment decisions in SSc are determined by the level of disease activity and the degree of specific organ involvement. Traditional therapy has primarily focused on organ-specific management without clear evidence of overall disease modification.. The authors provide a review of a variety of agents, which are already used for other autoimmune diseases, that are now being used to treat active SSc skin or lung disease, including rituximab, tocilizumab and IVIG. Several agents studied in vitro and in animal models of fibrosis have shown promise, including bortezomib, LPA-1 antagonists, anti-CCN2 therapy, anti-IL-13 and thrombin antagonists. The authors also provide details on targeting intracellular molecular pathways and matricellular proteins, which is another novel area of investigation.. Combination therapy may be necessary to control the complex biological network active in SSc. Most of the current evidence that suggest benefit of these agents is based on small population studies. Ultimately well-designed clinical trials are required to define the role of these agents in treating SSc.

Topics: Animals; Cardiovascular Agents; Cytokines; Drugs, Investigational; Humans; Immunologic Factors; Intercellular Signaling Peptides and Proteins; Scleroderma, Systemic

Raynaud's phenomenon (RP) and digital ulcers (DU) are the clinical manifestations of vasculopathy in systemic sclerosis. Both interfere with hand function and hold the possibility of severe complications, thus adversely influencing patients' quality of life. Managing RP and DU is often a challenge for the treating physician, who has to establish a treatment plan based upon knowledge of the current therapeutic options. The first step is to differentiate primary from secondary RP, where combining history and physical examination with diagnostic modalities, such as nailfold capillaroscopy, aids in reaching the correct diagnosis. Next a wide range of treatment options is offered nowadays, starting from first-line agents, as calcium channel blockers, to the more targeted-ones, like endothelin receptor antagonists. Research and clinical experience with each agent are reviewed in the text, as well as the combinations that more recently gain field in the treatment of DU.

Topics: Bosentan; Calcium Channel Blockers; Cardiovascular Agents; Endothelin Receptor Antagonists; Enzyme Inhibitors; Fingers; Humans; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Raynaud Disease; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Vasodilator Agents

Here we give an overview over treatment recommendations propagated by the European League Against Rheumatism (EULAR), EULAR Scleroderma Trials and Research Group, the German Network for Systemic Sclerosis, the European Respiratory Society, and the International Society of Heart and Lung Transplantation. As response to immunosuppressant (IS) therapy is usually weaker in systematic sclerosis (SSc) compared to other connective tissue disorders IS should be considered with caution. To prevent scleroderma renal crisis steroid doses should not exceed 15 mg/d. The definitive role of a number of new immunosuppressant drugs and the effects of autologous stem cell transplantation in systemic clerosis (SSc) have to be elucidated. Prostanoids, especially iloprost, are widely used as intravenous formulas for the treatment of severe Raynaud's phenomenon (RP) and digital ulcers (DU). Calcium antagonists are of limited therapeutic value. Bosentan, an oral endothelin receptor antagonists (ETRA), was shown to prevent new DU, but failed to heal existing DU, while the oral phopshodiesterase inhibitor (PDI) Sildenafil reduces the occurrence of RP and might be effective in ulcer healing. Combination therapies of PDI with ETRA are currently evaluated. Therapy of pulmonary arterial hypertension (PAH) is usually started as oral monotherapy, frequently using an ETRA. When this first-line therapy is not tolerated ETRA is substituted by PDI. If treatment goals are not reached with monotherapy combinationtherapy is started, for example by adding a PDI to an existing ETRA. In general, treatment of PAH in patients with connective tissue disease follows the same algorithms as in idiopathic PAH.

Topics: Antihypertensive Agents; Cardiovascular Agents; Drug Therapy, Combination; Europe; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Practice Guidelines as Topic; Raynaud Disease; Scleroderma, Systemic; Societies, Medical; Stem Cell Transplantation; Treatment Outcome; Ulcer

Systemic sclerosis (SSc) is a complex and heterogeneous chronic illness characterized by substantial patient to patient variability in clinical manifestations, internal organ involvement, and outcome. Genetic factors contribute to disease susceptibility, but environmental influences also play a significant role. The pathogenesis of SSc encompasses vascular, immunological, and fibrotic processes, which contribute to clinical manifestations and morbidity and must be addressed in the treatment plan. Although vascular interventions appear to reduce the frequency and severity of complications, such as scleroderma renal crisis and pulmonary hypertension, current therapies generally target the immune component of SSc in a non-selective fashion and have largely failed as diseases-modifying interventions. Newer insights into the mechanisms underlying autoimmunity, vascular injury and destruction, and particularly tissue fibrosis provide novel potential targets for therapy. Transforming growth factor-ss is a ubiquitous cytokine that appears to contribute to fibroblast activation, collagen overproduction, and pathological tissue fibrosis. Neutralizing antibodies and small molecules that block TGF-beta activation or function are effective in shutting down TGF-beta signaling and selectively inhibit the progression of fibrosis and may be entering clinical trials for the treatment of SSc.

Topics: Blood Vessels; Cardiovascular Agents; Fibrosis; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Inflammation; Kidney Diseases; Lung Diseases, Interstitial; Raynaud Disease; Scleroderma, Systemic; Skin; Transforming Growth Factor beta; Treatment Outcome

Microvascular abnormalities and fibrosis are important targets of therapy in systemic sclerosis (scleroderma). Calcium channel blockers, ACE inhibitors, sartans, phosphodiesterase-5 inhibitors and serotonin re-uptake blockers are used for Raynaud's phenomenon. Intravenous prostanoids (alprostadil, iloprost, epoprostenol, treprostinil) and endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan) show efficacy in treatment of pulmonary hypertension and distal ischemia. Successful treatment of digital ulcers secondary to systemic sclerosis was possible with sildenafil and bosentan. A platelet gel is currently in clinical trials for scleroderma-related digital ulcers. Several drugs, which directly reduce excessive production of collagens and other connective tissue proteins have been applied in systemic sclerosis. These include interferon gamma, d-penicillamine, kolchichicine, calcitriol, and imanitib. However, so far, strategies to control fibrosis by directly reducing excessive connective tissue production have been disappointing in controlled studies.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antifibrinolytic Agents; Calcium Channel Blockers; Cardiovascular Agents; Hematologic Agents; Humans; Scleroderma, Systemic

Systemic scleroderma is a generalized disease of connective tissue involving mainly the skin, the gastrointestinal tract, the lungs, the heart, and the kidneys. It can be present in different forms, of which acroscleroderma, with limited cutaneous and extracutaneous involvement, and diffuse scleroderma within a more rapid progression are most characteristic. Circulating antibodies against antinucleolar antigens are present in most patients with systemic scleroderma. They are helpful for establishing a classification and for determining the prognosis of the disease; their involvement in the pathogenesis, however, is still unclear. Alterations of the blood vessels and induction of fibroblasts by potent mediators are thought to play an important role in the early phase of scleroderma. Therefore early diagnosis is required, which then can initiate vasoactive therapy. In patients with systemic scleroderma, who also suffer from additional myositis, interstitial lung diseases, or arthritis, anti-inflammatory treatment with prednisolone and azathioprine is suggested. Development and progression of fibrosis cannot yet be influenced sufficiently. Only D-penicillamine affecting cross-linking of collagen has been widely used in scleroderma and has some beneficial effect.

Topics: Anti-Inflammatory Agents; Autoantibodies; Cardiovascular Agents; Connective Tissue; Extracellular Matrix; Female; Humans; Immune System; Male; Scleroderma, Systemic

Systemic sclerosis (SSc) is characterized by endothelial dysfunction and widespread microangiopathy. However, a macrovascular damage could be also associated. Aortic pulse wave velocity (aPWV) is known to be a reliable indicator of arterial stiffness and a useful prognostic predictor of cardiovascular events. Moreover, aPWV may be easily measured by non-invasive, user-friendly tool. Aim of our study was to evaluate aPWV alterations in a series of SSc patients.. The aPWV was evaluated in 35 consecutive female SSc patients and 26 sex- and age-matched healthy controls. aPWV alterations were correlated with cardiopulmonary involvement.. A significant increase of aPWV was observed in SSc patients compared to controls (9.4 ± 3.2 m/s vs 7.3 ± 1 m/s; P = 0.002). In particular, 14/35 (40%) SSc patients and only 1/26 (4%) controls (P=0.0009) showed increased aPWV (>9 m/s cut-off value). Moreover, echocardiography evaluation showed an increased prevalence of right atrial and ventricular dilatation (atrial volume: 23.6 ± 6.2 mL vs 20.3 ± 4.3 mL, P=0.026; ventricular diameter 19.5 ± 4.9 mm vs 15.9 ± 1.6 mm; P=0.001) associated to higher values of pulmonary arterial systolic pressure (PAPs) in SSc patients (31.5 ± 10.4 mmHg vs 21.6 ± 2.9 mmHg; P<0.0001; 40% of SSc patients showed an abnormal PAPs). Clinically, SSc patients presented a reduction of six-minute walking test (413 ± 96 m vs 491 ± 49 m; P=0.001), not correlated with pulmonary function tests. Increased aPWV values were evidenced only in SSc patients >50 years old. Furthermore, altered aPWV was more frequently associated with limited cutaneous pattern, longer disease duration (≥ 5 years), and/or presence of anticentromere antibody (ACA).. A significantly higher prevalence of abnormally increased aPWV was evidenced in SSc patients compared to healthy controls. The possibility of more pronounced and diffuse vascular damage in a particular SSc subset (ACA-positive subjects with limited cutaneous scleroderma and longer disease duration) might be raised.

Topics: Adult; Aged; Aorta; Cardiovascular Agents; Comorbidity; Endothelium, Vascular; Female; Heart Function Tests; Humans; Middle Aged; Phenotype; Prevalence; Pulse Wave Analysis; Respiratory Function Tests; Risk Factors; Scleroderma, Systemic; Vascular Stiffness

Sildenafil, a phosphodiesterase-5-inhibitor and Bosentan, an endothelin-1-receptor antagonist combined therapy could have beneficial effect in systemic sclerosis (SSc) patients with peripheral artery disease.. We report a case of a 48-year-old Black woman, who developed severe left limb claudication and walking limitation following a left femoropopliteal bypass occlusion in 2014. She was a heavy smoker and had a history of right middle cerebral artery ischemic stroke and bilateral Raynaud phenomenon.. According to the American College of Rheumatology/European League Against Rheumatism-2013 criteria, diagnosis of limited cutaneous SSc was retained with macrovascular lesions. She was referred for investigation of left limb claudication on treadmill using transcutaneous oxygen pressure measurement during exercise to argue for the vascular origin of the walking impairment. She had a severe left limb ischemia and the maximum walking distance (MWD) she reached was 118 m in March 2015 despite the medical optimal treatment and walking rehabilitation.. Sildenafil, 20 mg tid, was introduced due to active digital ulcers. In July 2015, the MWD increased to 288 m, then to 452 m in December 2015. Adding Bosentan to Sildenafil to prevent recurrent digital ulcers resulted in an MWD of 1576 m.. Recently, the patient is treated with the combined therapy. She has no more pain during walking and his quality of life has improved.. Sildenafil and Bosentan combined therapy was associated in our case with an improvement of MWD without adverse effect. Further clinical trials are necessary to confirm our original observation.

Topics: Bosentan; Cardiovascular Agents; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Middle Aged; Peripheral Arterial Disease; Phosphodiesterase 5 Inhibitors; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides

Cardiac disease in SSc can manifest in various ways and is associated with a poor prognosis. There is little evidence on how best to detect and manage cardiac disease in SSc. Our objective was to produce an expert consensus best practice pathway for the management of cardiac disease in SSc.. The UK Systemic Sclerosis Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including cardiac disease. A multidisciplinary task force was convened. The guidelines were partly informed by a comprehensive literature review.. A best practice pathway for cardiac disease (with a focus on primary cardiac disease) in SSc is presented, including approaches for early detection and standard pharmacological and device therapies. Due to the benefits, shared care and a multidisciplinary approach are recommended. A future research agenda has been formulated in response to the relative lack of understanding of the natural history of primary cardiac disease that was highlighted by the initiative.. The physician should be alert to the possibility of cardiac disease in SSc; it is best managed within a multidisciplinary team including both rheumatologists and cardiologists. This pathway provides a reference for all physicians managing patients with SSc.

Topics: Arrhythmias, Cardiac; Biomarkers; Cardiomyopathies; Cardiovascular Agents; Electrocardiography; Evidence-Based Medicine; Heart Failure; Humans; Magnetic Resonance Angiography; Medical History Taking; Monitoring, Ambulatory; Patient Care Team; Pericarditis; Physical Examination; Risk Factors; Scleroderma, Systemic

Topics: Bosentan; Cardiovascular Agents; Dose-Response Relationship, Drug; Familial Primary Pulmonary Hypertension; Fingers; Humans; Hypertension, Pulmonary; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Treatment Outcome

Topics: Cardiovascular Agents; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Predictive Value of Tests; Raynaud Disease; Scleroderma, Systemic; Treatment Outcome; Ulcer

The increased incidence of pulmonary hypertension and its association with decreased survival is well-recognised in patients with systemic sclerosis. This association is not widely appreciated in patients with polymyositis-dermatomyositis. We report clinical and hemodynamic characteristics and response to vasoactive therapy in three patients with polymyositis-dermatomyositis and pulmonary hypertension and discuss them in light of the available literature.

Topics: Adult; Cardiovascular Agents; Dermatomyositis; Fatal Outcome; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged; Scleroderma, Systemic; Vasodilator Agents

To examine left ventricular (LV) myocardial perfusion and function, in systemic sclerosis. Myocardial perfusion was assessed at rest, during cold exposure, and at peak exercise in 10 patients with systemic sclerosis. Seven of the 10 patients were examined with Doppler echocardiography; before and after long-term diltiazem treatment. Compared with average resting values, isotope uptake was increased by 48% after exercise, compared with cold exposure the exercise value was increased by 35%. After 11 months of diltiazem treatment there was no change in myocardial uptake, compared with respective values before treatment. Doppler echocardiography showed an increase in LV end-diastolic diameter, fractional shortening, and left ventricular outflow tract velocity, after treatment. This indicates that long-term diltiazem treatment does not increase myocardial perfusion at rest, post-exercise, or during cold exposure. On the other hand diltiazem treatment may improve left ventricular performance.

Topics: Aged; Cardiovascular Agents; Cold Temperature; Coronary Circulation; Diltiazem; Echocardiography, Doppler; Female; Heart; Humans; Male; Middle Aged; Radionuclide Imaging; Scleroderma, Systemic; Ventricular Function, Left

Thirteen patients with Raynaud's phenomenon secondary to systemic sclerosis received three 8-hour infusions of a synthetic prostacyclin analogue (Iloprost) on consecutive days and were followed-up over a period of 10 weeks during the winter of 1985/86. Six weeks after infusion, digital peripheral vascular resistance had fallen (P less than 0.05) and dicrotic notch proportion of pulse amplitude increased (P less than 0.05). Digital blood flow and pulse amplitude (measured by photoplethymography) were also increased but did not reach statistical significance. The trend of improvement in these blood flow parameters was still evident after 10 weeks. The number of cutaneous lesions (digital ulcers, etc) fell from 26 lesions before infusion to only 7 lesions by the end of the study, confirming the subjective improvement reported by the patients.

Topics: Adult; Cardiovascular Agents; Epoprostenol; Female; Fingers; Humans; Iloprost; Infusions, Intravenous; Male; Microcirculation; Middle Aged; Raynaud Disease; Regional Blood Flow; Scleroderma, Systemic; Vascular Resistance

Sera from 101 patients with progressive systemic scleroderma were analyzed for circulating aminopropeptides of type III collagen using a radioimmunoassay which measures the intact and degraded forms (Fab assay). About 41% of the patients were found to have values above the normal range. A good correlation was observed between elevated levels of aminopropeptides and the degree of involvement of the skin and internal organs in the patients. Most patients (89%) with an active progression of the disease but not those in a stationary phase showed increased serum levels of aminopropeptides. Treatment with corticosteroids apparently normalized the levels of aminopropeptides. Only minor changes were observed with an antibody-based radioimmunoassay which measures primarily the intact form of the aminopropeptide.

Topics: Adult; Aged; Calcitonin; Cardiovascular Agents; Humans; Middle Aged; Peptide Fragments; Procollagen; Prognosis; Radioimmunoassay; Scleroderma, Systemic

Topics: Adenosine Diphosphate; Arterial Occlusive Diseases; Blood Platelets; Cardiovascular Agents; Collagen; Epoprostenol; Fingers; Humans; Iloprost; Ischemia; Male; Middle Aged; Platelet Aggregation; Scleroderma, Systemic; Time Factors

Topics: Arteriosclerosis; Cardiovascular Agents; Muscle Relaxants, Central; Peripheral Vascular Diseases; Scleroderma, Systemic; Vascular Diseases; Vasodilator Agents