sildenafil-citrate and Scleroderma--Systemic

Systemic sclerosis (SSc)-related digital vasculopathy can progress from severe Raynaud's phenomenon to digital ulceration, is a major cause of pain and disability, and impacts negatively on quality of life. Current treatments are often ineffective and poorly tolerated. This review summarises some of the progress which has been made in the last 12 to 18 months in terms of our understanding of disease process, measurement and treatment.. The most important findings include that we can now better predict which patients with SSc are most likely to develop digital ulcers. In terms of treatment, a multicentre trial showed that the phosphodiesterase inhibitor sildenafil confers some benefit in SSc-related digital ulceration. Topical therapies are being explored: iontophoresis of vasodilators increases local blood flow, and in an avian model, VEGF121 fibrin applied in a gel matrix improved wound healing.. Progress is being made. Advances in our understanding of SSc-related vasculopathy continue to lead to exploration of new treatment approaches. Clinical trials and observational studies are challenging, but are being facilitated by developments in outcome measures and improved infrastructures and networking, allowing trials in much larger numbers of patients than have previously been possible.

Topics: Fingers; Humans; Pain; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Vascular Endothelial Growth Factor A; Vasodilator Agents

The long-term prognosis for patients with pulmonary arterial hypertension (PAH) remains poor, despite advances in treatment options that have been made in the past few decades. Recent evidence suggests that World Health Organization functional class I or II patients have significantly better long-term survival rates than patients in higher functional classes, thus providing a rationale for earlier diagnosis and treatment of PAH. However, early diagnosis is challenging and there is frequently a delay between symptom onset and diagnosis. Screening programmes play an important role in PAH detection and expert opinion favours echocardiographic screening of asymptomatic patients who may be predisposed to the development of PAH (i.e. those with systemic sclerosis or sickle cell disease), although current guidelines only recommend annual echocardiographic screening in symptomatic patients. This article reviews the currently available screening programmes, including their limitations, and describes alternative screening approaches that may identify more effectively those patients who require right heart catheterisation for a definitive PAH diagnosis.

Topics: Anemia, Sickle Cell; Antihypertensive Agents; Bosentan; Early Diagnosis; Echocardiography, Doppler; Exercise Test; Humans; Hypertension, Pulmonary; Mass Screening; Natriuretic Peptide, Brain; Peptide Fragments; Piperazines; Practice Guidelines as Topic; Purines; Respiratory Function Tests; Risk Factors; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of CTDs. In patients with SSc, PAH has a dramatic impact on prognosis and survival and is the single most common cause of disease-related death.Yearly echocardiographic screening for PAH is recommended in patients with SSc. If suspected, confirmation of PAH diagnosis by right heart catheterization is necessary. Treatment goals for patients with PAH associated with SSc (PAH-SSc) aim to slow disease progression and improve quality of life. Some measures used to gauge the effect of treatment in patients with PAH-SSc remain to be fully validated; the 6-min walk distance, for example, is a simple and reproducible means of assessing exercise capacity, but there exists a need to understand what constitutes a clinically relevant change in this specific patient population. Currently, pharmacological intervention in PAH-SSc may target one or more of three pathophysiological pathways in PAH. The prostacyclin analogue epoprostenol has been shown to improve exercise capacity and haemodynamics in PAH-SSc patients and similar data are available from smaller studies on trepostinil and iloprost. The dual endothelin receptor antagonist bosentan has been shown to improve exercise capacity and haemodynamics in PAH-SSc, and similar data have been obtained in small numbers of patients treated with the endothelin receptor A antagonists sitaxsentan and ambrisentan. Impaired production of nitric oxide may be addressed by inhibiting phosphodiesterase type-5 with sildenafil or possibly tadalafil. Combinations of multiple targeted therapies may be beneficial to this patient population.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Echocardiography; Epoprostenol; Exercise Tolerance; Humans; Hypertension, Pulmonary; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones

The therapy of systemic sclerosis (SSc) remains a challenge for dermatology, rheumatology, internal medicine, and other disciplines. Organ involvement, above all kidney and lungs, is a key therapeutic issue. The current developments in organ-specific therapy are the main topic of the article. Finally, possibilities of disease-modifying drugs and value of HSCT are discussed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Fibrosis; Fingers; Gastrointestinal Agents; Hematopoietic Stem Cell Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Kidney Transplantation; Piperazines; Purines; PUVA Therapy; Raynaud Disease; Recurrence; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfones; Ultraviolet Therapy; Vasodilator Agents

Digital ulcers (DU), defined as necrotic lesions located at distal digits or overlying bony prominences, occur in up to 50% of patients with limited or diffuse systemic sclerosis (SSc). These lesions are extremely painful and lead to substantial functional disability. The pathogenesis of DU differs depending on their location. DU located at distal aspects of digits are thought to be related to tissue ischemia from several processes, including vasospasm secondary to Raynaud's phenomenon, intimal fibro-proliferation, and thrombosis of digital arteries. DU located over bony prominences, such as the phalangeal joints and elbows, are thought to be due to repetitive microtrauma and difficulty healing due to atrophic, avascular tissue overlying the joints. Management of DU include non-pharmacologic and pharmacologic modalities. This review summarizes the current available and investigational therapies for the treatment and prevention of DU in patients with SSc.

Topics: Anticoagulants; Epoprostenol; Fingers; Humans; Piperazines; Platelet Aggregation Inhibitors; Purines; Scleroderma, Systemic; Selective Serotonin Reuptake Inhibitors; Sildenafil Citrate; Skin Ulcer; Sulfones; Therapies, Investigational; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc) and a leading cause of death in patients with it. Recent publications suggest that a prevalence of 10-15% is likely. The prognosis remains poor compared to that of idiopathic PAH. WHO recommends annual echocardiography for PAH screening of patients with SSc. Right heart catheterization is necessary to confirm the diagnosis. Nevertheless, more than half of all SSc patients have symptoms classified as WHO functional class III or IV at diagnosis. Prostacyclin therapy, delivered via continuous intravenous infusion (epoprostenol), has been demonstrated to be effective in patients with severe PAH (both idiopathic and scleroderma-related). Prostacyclin analogs (such as treprostinil and iloprost) are other options. Bosentan is the first endothelin receptor antagonist approved in the EU for the treatment of PAH, both idiopathic and related to connective tissue diseases such as scleroderma, in patients in WHO functional class III. Sildenafil by its selective inhibition of phosphodiesterase type 5 is also effective against both types of PAH. It too is now approved in the EU for this purpose in patients in WHO functional class III, but we do not yet have any information about its long-term effects in scleroderma.

Topics: Algorithms; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Cohort Studies; Echocardiography, Doppler; Epoprostenol; European Union; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Prevalence; Prognosis; Purines; Randomized Controlled Trials as Topic; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Time Factors; Vasodilator Agents; World Health Organization

DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1.. Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed.. The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone.. Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.

Topics: Adult; Aged; Bosentan; Drug Therapy, Combination; Europe; Female; Fingers; Humans; Iloprost; Male; Middle Aged; Prospective Studies; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Treatment Outcome; Vasodilator Agents; Wound Healing

A consensus on digital ulcer (DU) definition in systemic sclerosis (SSc) has been recently reached (Suliman et al., J Scleroderma Relat Disord 2:115-20, 2017), while for their evaluation, classification and categorisation, it is still missing. The aims of this study were to identify a set of essential items for digital ulcer (DU) evaluation, to assess if the existing DU classification was useful and feasible in clinical practice and to investigate if the new categorisation was preferred to the simple distinction of DU in recurrent and not recurrent, in patients with systemic sclerosis (SSc).. DeSScipher is the largest European multicentre study on SSc. It consists of five observational trials (OTs), and one of them, OT1, is focused on DU management. The DeSScipher OT1 items on DU that reached ≥ 60% of completion rate were administered to EUSTAR (European Scleroderma Trials and Research group) centres via online survey. Questions about feasibility and usefulness of the existing DU classification (DU due to digital pitting scars, to loss of tissue, derived from calcinosis and gangrene) and newly proposed categorisation (episodic, recurrent and chronic) were also asked.. A total of 84/148 (56.8%) EUSTAR centres completed the questionnaire. DeSScipher items scored by ≥ 70% of the participants as essential and feasible for DU evaluation were the number of DU defined as a loss of tissue (level of agreement 92%), recurrent DU (84%) and number of new DU (74%). For 65% of the centres, the proposed classification of DU was considered useful and feasible in clinical practice. Moreover, 80% of the centres preferred the categorisation of DU in episodic, recurrent and chronic to simple distinction in recurrent/not recurrent DU.. For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered the proposed classification and categorisation as useful and feasible. The set of items needs to be validated while further implementation of DU classification and categorisation is warranted.. Observational trial on DU (OT1) is one of the five trials of the DeSScipher project (ClinicalTrials.gov; OT1 Identifier: NCT01836263 , posted on April 19, 2013).

Topics: Adult; Bosentan; Calcium Channel Blockers; Drug Therapy, Combination; European Union; Female; Fingers; Humans; Iloprost; Male; Middle Aged; Prospective Studies; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Surveys and Questionnaires

To assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).. Randomised, placebo-controlled study in patients with SSc to assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).. Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12).. The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit.. NCT01295736.

Topics: Adult; Double-Blind Method; Female; Fingers; Humans; Intention to Treat Analysis; Ischemia; Longitudinal Studies; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Time Factors; Treatment Outcome; Vasodilator Agents

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.

Topics: Adult; Arterial Pressure; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pilot Projects; Piperazines; Prospective Studies; Pulmonary Artery; Purines; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Skin; Skin Ulcer; Sulfones; Treatment Outcome; Vasodilator Agents

In this pilot study, the effect of sildenafil on digital ulcer (DU) healing and related clinical symptoms was analysed.. A total of 19 patients with systemic sclerosis (SSc) were treated with maximally tolerated sildenafil doses up to 6 months. Primary outcome was the healing of DUs. Changes in other clinical symptoms were also evaluated.. In all, 49 DUs were present at baseline; this decreased to 17 ulcers (p<0.001) at the end of sildenafil treatment. Furthermore, the visual analogue scale (VAS) score for Raynaud's phenomenon (RP), pain and activity improved (p=0.003, p=0.002 and p=0.05, respectively). A total of 9 patients developed 12 new DUs during sildenafil treatment.. This study indicates an effect of sildenafil on DU healing in patients with SSc and an improvement of RP and associated symptoms that should be validated in controlled studies.

Topics: Adult; Aged; Dermatologic Agents; Fingers; Hand Dermatoses; Humans; Middle Aged; Phosphodiesterase Inhibitors; Pilot Projects; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfones; Treatment Outcome

Data on long-term efficacy of bosentan, an oral dual ET receptor antagonist, in SSc-associated pulmonary arterial hypertension (SSc-PAH) are lacking. We aimed to describe the long-term outcome of SSc-PAH treated with first-line monotherapy bosentan followed or not by the addition of prostanoids or sildenafil.. A prospective analysis of 49 consecutive SSc-PAH patients treated with first-line bosentan was performed. New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD) and haemodynamics were assessed at baseline and after 4 and 12 months.. At 4 months, significant improvements in NYHA functional class and haemodynamics were observed with stabilization at 1 year. There was no significant improvement in 6MWD. Overall survival estimates were 80, 56 and 51% at 1, 2 and 3 years, respectively, and were significantly worse than those in a cohort of patients with idiopathic PAH (92, 89 and 79% at 1, 2 and 3 years, respectively; P < 0.0001). Twenty-three patients (47%) died after a mean follow-up of 23 (18) months. In multivariate analysis, baseline and 4-month NYHA functional class and 4-month cardiac index were independent factors associated with overall survival.. In our cohort of consecutive SSc-PAH patients treated with first-line bosentan, improvement in NYHA functional class and haemodynamics was significant after 4 months of treatment and stabilized afterwards. One-year overall survival rate was higher than previously reported in historical series. However, long-term prognosis remains poor. Our study underlines the importance of haemodynamic evaluation 4 months after the start of treatment to provide strong parameters associated with survival-like cardiac index.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Drug Administration Schedule; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Epidemiologic Methods; Epoprostenol; Exercise Test; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Vasodilatory therapy of Raynaud's phenomenon represents a difficult clinical problem because treatment often remains inefficient and may be not tolerated because of side effects.. To investigate the effects of sildenafil on symptoms and capillary perfusion in patients with Raynaud's phenomenon, we performed a double-blinded, placebo-controlled, fixed-dose, crossover study in 16 patients with symptomatic secondary Raynaud's phenomenon resistant to vasodilatory therapy. Patients were treated with 50 mg sildenafil or placebo twice daily for 4 weeks. Symptoms were assessed by diary cards including a 10-point Raynaud's Condition Score. Capillary flow velocity was measured in digital nailfold capillaries by means of a laser Doppler anemometer. While taking sildenafil, the mean frequency of Raynaud attacks was significantly lower (35+/-14 versus 52+/-18, P=0.0064), the cumulative attack duration was significantly shorter (581+/-133 versus 1046+/-245 minutes, P=0.0038), and the mean Raynaud's Condition Score was significantly lower (2.2+/-0.4 versus 3.0+/-0.5, P=0.0386). Capillary blood flow velocity increased in each individual patient, and the mean capillary flow velocity of all patients more than quadrupled after treatment with sildenafil (0.53+/-0.09 versus 0.13+/-0.02 mm/s, P=0.0004). Two patients reported side effects leading to discontinuation of the study drug.. Sildenafil is an effective and well-tolerated treatment in patients with Raynaud's phenomenon.

Topics: Adult; Aged; Blood Flow Velocity; Connective Tissue Diseases; Cross-Over Studies; Double-Blind Method; Drug Resistance; Female; Humans; Male; Middle Aged; Patient Selection; Piperazines; Purines; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilation; Vasodilator Agents

Topics: Aged; Female; Hand; Humans; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Vasodilator Agents

Skeletal muscle damage is a common clinical manifestation of systemic sclerosis (SSc). C-X-C chemokine ligand 10 (CXCL10) is involved in myopathy and cardiomyopathy development and is associated with a more severe SSc prognosis. Interestingly, the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil reduces CXCL10 sera levels of patients with diabetic cardiomyopathy and in cardiomyocytes. Here, we analyzed the levels of CXCL10 in the sera of 116 SSc vs. 35 healthy subjects and explored differences in 17 SSc patients on stable treatment with sildenafil. CXCL10 sera levels were three-fold higher in SSc vs. healthy controls, independent of subset and antibody positivity. Sildenafil treatment was associated with lower CXCL10 sera levels. Serum CXCL10 strongly correlated with the clinical severity of muscle involvement and with creatine kinase (CK) serum concentration, suggesting a potential involvement in muscle damage in SSc.

Topics: Chemokine CXCL10; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetic Cardiomyopathies; Female; Humans; JNK Mitogen-Activated Protein Kinases; Male; Middle Aged; Muscle, Skeletal; Myocytes, Cardiac; NF-kappa B; Phosphodiesterase 5 Inhibitors; Scleroderma, Systemic; Sildenafil Citrate; STAT1 Transcription Factor

Anticentriole autoantibodies-positive systemic sclerosis (SSc) has been reported to develop pulmonary arterial hypertension (PAH) at a high rate. In this report, we describe two patients with anticentriole antibodies-positive SSc-PAH who were treated with pulmonary vasodilators. Both cases were elderly women with poor physical conditions and clinical findings of SSc. Case 1 was resistant to combination therapy with pulmonary vasodilators; in Case 2, hemodynamic improvement was obtained by upfront combination therapy at an early stage. Because anticentriole antibodies-positive SSc-PAH rapidly deteriorates, careful hemodynamic observation and timely aggressive use of pulmonary vasodilators should be considered.

Topics: Aged; Aged, 80 and over; Antibodies, Antinuclear; Autoantibodies; Bosentan; Cardiac Catheterization; Centrioles; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Female; Forced Expiratory Volume; Humans; Imatinib Mesylate; Protein Kinase Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Diffusing Capacity; Pyrimidines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Tadalafil; Tomography, X-Ray Computed; Vasodilator Agents

Topics: Cells, Cultured; Fibroblasts; Gene Expression Regulation; Humans; Hydrogen Peroxide; Interleukin-6; Interleukin-8; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Reactive Oxygen Species; Scleroderma, Systemic; Sildenafil Citrate; Transcription, Genetic

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

Ischaemic digital ulcers (DUs) are an indicator of the severity of the microangiopathy in patients with systemic sclerosis (SSc). DUs are a frequent complication, affecting about 50% of patients with SSc, and are often recurrent. In cross-sectional studies involving patients with SSc, the frequency of ischaemic DUs was 12-16% with a major impact on hand function and quality of life. Effective therapy for DUs remains elusive. Intravenous iloprost has been demonstrated to have a positive effect on healing of active DUs. Bosentan, an oral endothelin receptor antagonist, only showed a benefit in preventing the occurrence of new DUs. Despite limited evidence, recent guidelines have recommended phosphodiesterase type 5 inhibitors as an option. Injection of botulinum toxin and digital sympathectomy have been increasingly used for ischaemic DUs. Here we present the complex case of a SSc patient already treated with sildenafil and bosentan in whom an active DU was successfully treated with botulinum toxin A. Despite the lack of a randomised controlled trial, results are encouraging for the use of botulinum toxin in the treatment of DUs and could perhaps help to avoid some amputations, as in the present case.

Topics: Administration, Intravenous; Administration, Oral; Bosentan; Botulinum Toxins, Type A; Cross-Sectional Studies; Female; Fingers; Humans; Iloprost; Middle Aged; Phosphodiesterase 5 Inhibitors; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfonamides; Treatment Outcome; Wound Healing

The aim of this study was to evaluate in systemic sclerosis (SSc) retrospectively the effect of Bosentan and Sildenafil and their combination on Raynaud's phenomenon (RP), function, and capillaroscopic patterns. One hundred and twenty-three SSc patients (mean age ± sd, 57.69 ± 14.07 years) were retrospectively evaluated and divided into two groups according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification score: group 1 score < 10, group 2 score > 10. Each group was divided into three subgroups according to treatment: Bosentan, Sildenafil, and Bosentan + Sildenafil. Nailfold videocapillaroscopy (NVC), Scleroderma Health Assessment Questionnaire (SHAQ) and Raynaud Condition Score (RCS) were performed at baseline and after 3 and 6 months. In Bosentan (29 patients: 12, group 1; 17, group 2), NVC changed significantly in both groups, after 3 and 6 months (p = 0.00439, group 1; p = 0.00035, group 2). In group 1, the "active" and the "late" patterns reduced, and the "aspecific" increased. In group 2, there was a reduction of late patterns, a worsening of SHAQ (p < 0.005) and an improvement of RCS (p = 0.00014). In Sildenafil (63 patients: 35, group 1; 28, group 2), after 3 months, NVC patterns changed significantly in both groups(p = 0.042 group 1, p = 0.00089 group 2). In group 1, the late and early patterns increased, and the aspecific decreased. In group 2, a significant change of NVC pattern was observed also after 6 months (p = 0.00089): the late pattern increased while the active one reduced. After 6 months, SHAQ was significantly reduced in group 1 (p = 0.00027) and in group 2 (p = 0.0043). RCS improved in both groups (p = 0.0042, group 1; p = 0.0016, group 2). Combination therapy (Bosentan + Sildenafil) (31 patients: 14, group 1; 17, group 2) induced significant changes on NVC only in group 1 after 3 (p = 0.00256) and 6 months (p = 0.000349) with a reduction of the late and active patterns and an increase of the early pattern. In both groups, after 6 months, SHAQ (p < 0.05, group 1; p = 0.00049, group 2) and RCS significantly reduced (group 1, p = 0.00024; group 2, p = 0.0021). Patients treated with Bosentan + Sildenafil show a significant improvement of RCS and NVC. This combination therapy may exert a vascular activity achieving an amelioration of the structure of microvasculature in SSc.

Topics: Adult; Aged; Bosentan; Capillaries; Drug Therapy, Combination; Female; Humans; Male; Microscopic Angioscopy; Microvessels; Middle Aged; Nails; Raynaud Disease; Retrospective Studies; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vasodilator Agents

Systemic sclerosis (SSc) is a connective tissue disease frequently associated with Raynaud's Phenomenon (RP). Among possible pharmacological treatments, phosphodiesterase 5 inhibitors are considered in cases of severe non -responsive RP. We present the case of a male SSc patient wh presented with critical finger ischemia and concomitant appearance of myocardial fibrosis after sudden interruption of sildenafil treatment.

Topics: Antirheumatic Agents; Cardiomyopathies; Fingers; Humans; Ischemia; Male; Middle Aged; Myocardium; Raynaud Disease; Risk Factors; Scleroderma, Systemic; Sildenafil Citrate; Substance Withdrawal Syndrome; Time Factors

Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-β signalling. Here, we aimed to demonstrate that riociguat, the drug candidate for clinical trials in systemic sclerosis (SSc), is effective in experimental fibrosis and to compare its efficacy to that of phosphodiesterase V inhibitors that also increase the intracellular levels of cyclic guanosine monophosphate.. The antifibrotic effects of riociguat and sildenafil were compared in the tight-skin 1 model, in bleomycin-induced fibrosis and in a model of sclerodermatous chronic graft-versus-host-disease (cGvHD). Doses of 0.1-3 mg/kg twice a day for riociguat and of 3-10 mg/kg twice a day for sildenafil were used.. Riociguat dose-dependently reduced skin thickening, myofibroblast differentiation and accumulation of collagen with potent antifibrotic effects at 1 and 3 mg/kg. Riociguat also ameliorated fibrosis of the gastrointestinal tract in the cGvHD model. The antifibrotic effects were associated with reduced phosphorylation of extracellular signal-regulated kinases. Sildenafil at doses of 3 and 10 mg/kg exerted mild antifibrotic effects that were significantly less pronounced compared with 1 and 3 mg/kg riociguat.. These data demonstrated potent antifibrotic effects of riociguat on experimental skin and organ fibrosis. These findings suggest a role for riociguat for the treatment of fibrotic diseases, especially for the treatment of SSc. A phase II study with riociguat in patients with SSc is currently starting.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrosis; Guanylate Cyclase; Mice; Mice, Inbred Strains; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyrimidines; Scleroderma, Systemic; Sildenafil Citrate; Skin

Systemic sclerosis (SSc) is a multi-organ fibrotic disease that affects the skin and various internal organs. Therapeutic strategies for tissue fibrosis have not been established; however, aberrantly activated fibroblasts in affected lesions are key targets for modulating fibrosis. Recently, increased intracellular cyclic GMP (cGMP) levels were demonstrated to improve fibrosis levels in various diseases. The purpose of this study was to assess the anti-fibrotic properties of cGMP in cultured fibroblasts from patients with SSc. The phosphodiesterase (PDE) 5 inhibitor sildenafil increased the intracellular cGMP levels in skin fibroblasts in a dose-dependent manner. Sildenafil treatment also significantly decreased the expression of several pro-fibrotic factors that were upregulated by TGF-β1 treatment in SSc skin fibroblasts. These inhibitory effects occurred via non-canonical TGF-β signaling. Our findings revealed that sildenafil might be a novel strategy to treat tissue fibrosis and vasculopathy in SSc.

Topics: Adult; Aged; Blotting, Western; Cells, Cultured; Collagen Type I; Collagen Type I, alpha 1 Chain; Connective Tissue Growth Factor; Cyclic GMP; Dose-Response Relationship, Drug; Female; Fibroblasts; Fibrosis; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Scleroderma, Systemic; Sildenafil Citrate; Skin; Transforming Growth Factor beta1

Pulmonary arterial hypertension (PAH) in scleroderma (SSc) patients is a devastating complication with high mortality if untreated. Early recognition and specific treatment of PAH may improve outcome. Regular interval screening for PAH is generally recommended in scleroderma patients especially with the availability of emerging new therapies. The aim of this study is to determine the self-reported screening and treatment practices for SSc-PAH amongst rheumatologists in New Zealand (NZ).. An anonymous online questionnaire survey was emailed to all rheumatologists in New Zealand.. Responses were received from 65% (39/60) of rheumatologists. The majority of patients had limited SSc (lcSSc) (57%) versus diffuse SSc (dcSSc) (34%). Twelve percent of patients had PAH. Eighty-two percent of rheumatologists screened for PAH in all SSc patients regardless of symptoms. The most commonly used screening modalities were pulmonary function tests (PFT) (97%) followed by clinical examination (95%) and echocardiogram (TTE) (92%). The majority of rheumatologists performed screening tests on a yearly basis (80% used PFT and 64% used TTE). A right heart catheter was used to confirm PAH in 70% of patients. Sixty-four percent of rheumatologists extend screening interval time if their patients were clinically stable. The most common PAH-specific therapy used was sildenafil (57%) followed by bosentan (19%). Sixty-four percent of rheumatologists supported a national PAH-SSc screening guideline.. This study has shown a wide variability of how NZ rheumatologists screen for PAH in scleroderma patients. The development of a PAH-SSc guideline for screening and diagnosis may help standardise treatment practices in NZ.

Topics: Anticoagulants; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Echocardiography; Electrocardiography; Exercise Test; Humans; Hypertension, Pulmonary; Mass Screening; New Zealand; Physical Examination; Piperazines; Practice Patterns, Physicians'; Purines; Respiratory Function Tests; Rheumatology; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Surveys and Questionnaires; Vasodilator Agents

To retrospectively analyze the efficacy and safety of sildenafil (Sf) in patients with systemic sclerosis (SS).. Sf was used in 16 patients (including 14 women) aged 20-66 years (mean 48.6 +/- 14.6 years; median 51.5 years) with SS of a duration of 2 months to 27 years (mean 8.8 +/- 7.3 years; median 6.5 years). The indications for Sf treatment were significant Raynaud's phenomenon (RP) in 3 patients, digital ulcers (DU) and/or necroses (N) in 9, pulmonary hypertension (PH) in 5 (2 patients had PH concurrent with DU/N), and critical ischemia of the left fingers in 1 patient. RP was seen in all the patients and so the effect of Sf on the course of RP was evaluated in the whole patient group.. There was a significant decrease in the frequency and intensity of Raynaud's attacks in 11 (73%) of the 15 patients treated with Sf. This effect was obvious just in the first days of Sf treatment and remained stable throughout the treatment. No RP changes were seen in 3 patients. All 7 patients with DUs showed a decrease in their sizes just within the first two weeks of treatment. Complete DU healing was observed within 4-12 weeks of treatment. During a month, the necrotic area reduced and the signs of reparation appeared in 4 of the 6 patients. Pain ceased just within the first 5-7 days of treatment. Sf resulted in a rapid reduction in systolic pulmonary artery pressure (sPAP); in one case the latter diminished from 60 to 40 mm Hg just 90 min after the first intake of Sf 50 mg and remained unchanged during all 6 months during which the female patient was taking the drug. Doppler echocardiography showed that sPAP decreased from 103 to 85 mm Hg in another female taking Sf 100 mg for a month. The two cases showed clinical improvement as alleviated dyspnea and increased physical activity. In another case, Sf was discontinued because of dizziness after its first intake in a dose of 12.5 mg. The initial drug intake of the drug was not followed by adverse reactions in 12 (75%) of the 16 patients. Four patients had Sf-induced complaints, including headache (1), dizziness (2), and more severe angina pectoris (1). In different periods after treatment initiation, four more patients developed complications, such as fatal myocardial infarction after 6-week treatment, atrial fibrillation at 8 weeks, more severe angina at 6 months, and congestive heart failure after 5-year treatment. These complications were observed in patients with severe ECG changes, such as myocardial focal fibrosis or blood supply impairment.. Sf is an effective drug to treat the manifestations of scleroderma vasculopathy, such as RP, DU/N, and PH. Sf is well tolerated in most cases. The SS patients with pronounced ECG changes have an increased risk of severe cardiac events and they need careful ECG monitoring.

Topics: Adult; Aged; Drug Monitoring; Echocardiography, Doppler; Electrocardiography; Female; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Retrospective Studies; Scleroderma, Systemic; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vascular Diseases; Young Adult

Systemic sclerosis is an inflammatory disease of the connective tissue characterized by vasculopathy and accumulation of collagen and other components of the connective matrix, affecting the skin and internal organs. The appearance of skin ulcers as a result of vascular damage is very common in the history of the disease. Skin ulcers, painful and slow healing due to atrophy and local ischemia, get worse the quality of life of patients. Often, the use of conventional therapies (such as calcium channel blockers and prostanoids) does not cause the complete healing of the lesions. We report the case of a patient in whom therapeutic association between endothelin antagonist (bosentan) and phosphodiesterase-V inhibitor (sildenafil) resulted in complete healing of old ulcers both to upper and lower limbs and allowed the interruption of intravenous therapies.

Topics: Bosentan; Endothelin Receptor Antagonists; Female; Humans; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Remission Induction; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfonamides; Sulfones

Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known.. This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively.. Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients.. Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed.

Topics: Adult; Databases, Factual; Erectile Dysfunction; Humans; Kidney Diseases; Male; Middle Aged; Muscular Diseases; Piperazines; Prospective Studies; Purines; Scleroderma, Systemic; Severity of Illness Index; Sildenafil Citrate; Skin Diseases; Sulfones; Surveys and Questionnaires; Treatment Outcome; Vasodilator Agents

A patient with pulmonary arterial hypertension secondary to systemic sclerosis was successfully treated with sitaxentan prior to its worldwide withdrawal (because of hepatotoxicity concerns), but then ironically experienced acute hepatic dysfunction during substitute bosentan therapy, and was eventually stabilised on a phosphodiesterase-5 inhibitor.

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Liver; Liver Function Tests; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Safety-Based Drug Withdrawals; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes

Topics: Administration, Oral; Adult; Aged; Dose-Response Relationship, Drug; Female; Fingers; Humans; Male; Middle Aged; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Bosentan; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Fingers; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfonamides; Sulfones

A 54-year-old woman with a 20-year history of Raynaud phenomenon was admitted to our hospital complaining of progressive dyspnea on exertion since 5 years previously. Interstitial lung disease was diagnosed, accompanied by pulmonary arterial hypertension (PAH) associated with systemic sclerosis. After oxygen therapy and treatment with sildenafil, her clinical condition and PAH gradually improved. However, she was readmitted due to deterioration of Raynaud phenomenon and progressive dyspnea in March 2009. Right heart catheterization findings demonstrated that her mean pulmonary arterial pressure (PAP) was elevated, at 48 mmHg. Bosentan was therefore added to an increased dose of sildenafil. Consequently, her dyspnea, 6-min walking distance, serum brain natriuretic peptide level, and PAP improved. Combination therapy with bosentan and sildenafil was effective for this case of refractory PAH associated with fibrotic lung in systemic sclerosis.

Topics: Antihypertensive Agents; Bosentan; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Middle Aged; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Pulmonary hypertension (PH) is an important cause of mortality in systemic sclerosis (SSc), where it can be isolated (pulmonary arterial hypertension [PAH]) or associated with interstitial lung disease (ILD). This study was undertaken to characterize determinants of survival among SSc patients with either type of PH who received PAH-specific therapy.. Consecutive SSc patients with PAH or ILD-associated PH confirmed by right heart catheterization were included in the study. Kaplan-Meier and Cox proportional hazards models were used to compare survival between SSc patients with PAH and those with ILD-associated PH and to identify predictors of survival.. Fifty-nine patients (39 with PAH and 20 with ILD-associated PH) were identified. The majority (15 of 20 with ILD-associated PH and 27 of 39 with PAH) received an endothelin receptor antagonist as initial therapy. Median followup time was 4.4 years (range 2.7-7.4 years). Survival was significantly worse in SSc patients with ILD-associated PH than in those with PAH (1-, 2-, and 3-year survival rates 82%, 46%, and 39% versus 87%, 79%, and 64%, respectively; P < 0.01 by log rank test). In a multivariable analysis, ILD-associated PH was associated with a 5-fold increase in risk of death compared with PAH. Pulmonary vascular resistance index was also an independent predictor of mortality in the overall cohort (hazard ratio 1.05, P < 0.01) and was a significant univariable risk factor in each group separately. Type of initial PAH therapy and the use of warfarin were not related to survival.. Survival in SSc complicated by PH remains poor despite currently available treatment options. While therapy may be associated with improved survival in PAH compared with historical controls, the prognosis for patients with ILD-associated PH is particularly grim. Early diagnosis and treatment may improve outcomes since worsening hemodynamic factors were associated with reduced survival.

Topics: Bosentan; Cohort Studies; Comorbidity; Endothelin Receptor Antagonists; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Isoxazoles; Lung Diseases, Interstitial; Male; Maryland; Middle Aged; Piperazines; Prognosis; Proportional Hazards Models; Purines; Receptors, Endothelin; Scleroderma, Diffuse; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; Thiophenes; Vasodilator Agents

Topics: Amputation, Surgical; Female; Fingers; Hand Dermatoses; Humans; Ischemia; Microcirculation; Middle Aged; Piperazines; Postoperative Complications; Purines; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfones; Vasodilator Agents

Acral ulcers in patients with progressive systemic sclerosis (PSS) are often recalcitrant to therapy. Sildenafil, an inhibitor of phosphodiesterase-5, dilates small arteries by increasing endothelial cGMP. Oral administration of sildenafil to a 35-year-old white male patient suffering from incapacitating PSS with severe pulmonary arterial hypertension and acral ulcers induced a clinically significant reduction in dyspnea and increase in walking distance within one week as well as complete and long-lasting healing of all ulcers within five weeks. This case demonstrates the efficacy of sildenafil in the treatment of scleroderma-associated refractory acral ulcers.

Topics: Adult; Extremities; Humans; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfones; Treatment Outcome; Wound Healing

We present a case of scleroderma complicated by severe pulmonary hypertension. The use of a three-drug (bosentan, iloprost, and sildenafil) approach contributed to significant improvement of both the clinical conditions and the pulmonary hemodynamics. Combining three pulmonary vasodilators with different mechanisms of action could benefit patients with severe pulmonary hypertension resistant to conventional therapy.

Topics: Bosentan; Drug Therapy, Combination; Electrocardiography; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Combination therapy has been recommended for the treatment of pulmonary arterial hypertension (PAH). However, there is scant information on combination therapy after failure of monotherapy, particularly in patients with scleroderma-associated PAH (PAH-SSD). From a group of 82 consecutive patients with PAH who received initial bosentan monotherapy, a total of 13 idiopathic PAH (IPAH) and 12 PAH-SSD patients requiring additional therapy with sildenafil were studied. Sildenafil was added for clinical deterioration based upon symptoms, New York Heart Association (NYHA) classification or 6-min walk distance (6MWD). Clinical data and haemodynamics were collected at baseline. Assessments were made at 1-3-month intervals. At baseline, there were no differences in demographics, NYHA classification, haemodynamics or 6MWD between the two groups. After initiation of bosentan, both groups experienced clinical improvement but ultimately deteriorated (median time to monotherapy failure 792 versus 458 days for IPAH and PAH-SSD patients, respectively). After addition of sildenafil, more IPAH patients tended to improve in NYHA class (five out of 13 versus two out of 12) and walked further (mean difference in 6MWD 47+/-77 m versus -7+/-40 m) compared with PAH-SSD patients. In conclusion, addition of sildenafil after bosentan monotherapy failure improved New York Heart Association class and 6-min walk distance in idiopathic pulmonary arterial hypertension patients but failed to improve either parameter in scleroderma-associated pulmonary arterial hypertension patients. Additional studies are needed to assess the tolerability and efficacy of this combination in patients with scleroderma-associated pulmonary arterial hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Exercise Test; Female; Humans; Hypertension, Pulmonary; Lung Volume Measurements; Male; Middle Aged; Piperazines; Pulmonary Wedge Pressure; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antihypertensive Agents; Bosentan; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Phosphodiesterase Inhibitors; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

We describe two systemic sclerosis (SSc) patients with isolated pulmonary arterial hypertension (PAH) who were given treatment with 50 mg oral sildenafil per day. We evaluated the efficacy of oral sildenafil for isolated PAH in SSc patients by direct assessment with cardiac catheterization before and 6 months after the initiation of sildenafil. Right-heart catheterization demonstrated decreased mean pulmonary artery pressure, decreased pulmonary vascular resistance, and increased cardiac output after treatment with sildenafil. Brain natriuretic peptide levels were gradually decreased. The 6-min walking distance was greatly extended. Moreover, the physical conditions of both patients were much improved. We recognized no adverse events. We propose that oral sildenafil may be beneficial as a selective pulmonary vasodilator and as long-term treatment in SSc patients with isolated PAH.

Topics: Female; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged; Natriuretic Peptide, Brain; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Adult; Dose-Response Relationship, Drug; Feasibility Studies; Female; Humans; Male; Middle Aged; Piperazines; Purines; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Skin Temperature; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Endothelin Receptor Antagonists; Forecasting; Humans; Phosphodiesterase Inhibitors; Piperazines; Prognosis; Prostaglandins I; Purines; Quality of Life; Research; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Topics: Aged; Alprostadil; Female; Humans; Phosphodiesterase Inhibitors; Piperazines; Purines; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Administration, Oral; Aged; Dose-Response Relationship, Drug; Finger Joint; Follow-Up Studies; Humans; Male; Piperazines; Purines; Range of Motion, Articular; Recovery of Function; Scleroderma, Systemic; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome

Topics: Adult; Female; Fingers; Humans; Male; Middle Aged; Piperazines; Purines; Raynaud Disease; Retrospective Studies; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfones; Vasodilator Agents

Systemic sclerosis (scleroderma) is a multisystem fibrotic disease that commonly manifests with severe Raynaud's phenomenon and slow-healing cutaneous ulcerations. Reduced nitric oxide levels have been proposed to play a role in the pathogenesis of vascular disease in scleroderma, and therefore sildenafil (which increases nitric oxide levels) is an attractive therapeutic prospect. We describe a patient with limited cutaneous systemic sclerosis who presented with severe nonhealing finger ulcerations despite conventional management, who showed marked improvement with oral sildenafil.

Topics: Administration, Oral; Adult; Fingers; Humans; Male; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfones; Treatment Outcome; Vasodilator Agents

A 65-year-old woman was admitted because of dyspnea at rest and peripheral edema due to scleroderma-associated pulmonary fibrosis and hypertension, as well as Raynaud's phenomenon.. She had a marked restrictive ventilatory disorder with severe impairment of diffusion capacity. Right heart catheterization demonstrated a mean pulmonary artery pressure of 50 mmHg. She was able to walk only 220 m. All usual methods of treatment failed to give satisfactory results so that sildenafil (phospherodiesterase type-5 |PDE-5| inhibitor; Viagra ((R)) was given, even though it is not licensed for this indications ("off-label", as a therapeutic attempt. This achieved definite reduction in pulmonary arterial pressure and significantly improved the clinical symptoms. In particular, it drastically reduced the level of atrial natriuretic peptide, an important prognostic marker in right heart failure. Sildenafil also significantly raised peripheral perfusion and the signs of Raynaud's syndrome.. PDE-5 inhibitors are efficacious in scleroderma-associated pulmonary hypertension and may also provide a new option in the treatment of Raynaud's disease.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Atrial Natriuretic Factor; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Fingers; Humans; Hypertension, Pulmonary; Laser-Doppler Flowmetry; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Prognosis; Pulmonary Wedge Pressure; Purines; Raynaud Disease; Regional Blood Flow; Scleroderma, Systemic; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Aged; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Piperazines; Pulmonary Fibrosis; Purines; Raynaud Disease; Scleroderma, Systemic; Sildenafil Citrate; Sulfones