iloprost and Scleroderma--Systemic

Iloprost is recommend worldwide for the treatment of RP and the healing of DUs. The aim of this study is to report the regimens of Iloprost administered in different rheumatological centers within the same regional Health System Methods: A questionnaire exploring different items related to the use of Iloprost was developed and reviewed by three expert rheumatologists. The questionnaire was distributed as an online survey to all local SSc referral centers in Emilia-Romagna (Italy). Data are reported as percentage or median with interquartile range (IQR), as appropriate. An updated review of world literature on this topic was also carried out.. All the invited centers completed the survey. There were both local (8) and university hospitals (4). The majority (58%) had a rheumatologist as head physician. All centers used Iloprost: a single monthly administration was the most common treatment (75%). The cycle lasted 1 [IQR 1-2] days with a 0.5-2.0 ng/Kg/min dose according to the drug tolerance of the patients. There were overall 68 spots (beds, reclining armchair, or simple armchair); 2.0 [1.5-4.0] patients were able to receive Iloprost at the same time. University Hospitals had more physicians at their disposal than local hospitals but less paramedic personnel (respectively: 1.8 vs 1.2 physicians, 1.5 vs 2.1 nurses).. These observations were in line with the majority of previous studies reporting different regimens, comparing similar (but not identical) dose and schedule administration, however, despite differences being at times substantial, no standard infusion method is yet available.

Topics: Epoprostenol; Humans; Iloprost; Prostaglandins I; Scleroderma, Systemic; Surveys and Questionnaires; Wound Healing

Systemic sclerosis (SSc) is an autoimmune chronic disease characterized by vascular impairment, immune dysfunction and collagen deposition. Raynaud's phenomenon (RP) and digital ulcers (DU) are prominent features of SSc. Intravenous (IV) iloprost (ILO), according to the recently updated EULAR recommendations, is indicated for RP after failure of oral therapy. Moreover, IV ILO could be useful in DU healing. IV ILO is currently available mainly on the European market approved for RP secondary to SSc with 3-5 days infusion cycle. Unfortunately, data published varies regarding regimen (dosage, duration and frequency). Up to now, ILO has been studied in small cohorts of patients and in few randomized controlled trials.. A systematic review of studies on IV ILO in patients with SSc complicated by DU and RP was performed. Insufficient data were available to perform a meta-analysis according to the GRADE system. We performed a three-stage internet-based Delphi consensus exercise.. Three major indications were identified for IV ILO usage in SSc: RP non-responsive to oral therapy, DU healing, and DU prevention. IV ILO should be administered between 0.5 and 2.0ng/kg/min according to patient tolerability with a frequency depending on the indication.. Although these suggestions are supported by this expert group to be used in clinical setting, it will be necessary to formally validate the present suggestions in future clinical trials.

Topics: Consensus; Fingers; Humans; Iloprost; Injections, Intravenous; Raynaud Disease; Scleroderma, Systemic; Skin Ulcer; Vasodilator Agents

Digital ulcers (DUs) are a common visible manifestation of the progressive vascular disease that characterizes the SSc disease process. DUs not only impact significantly on patients' quality of life and hand function, but are also a biomarker of internal organ involvement and of disease severity. The aetiology of (digital) vascular disease in SSc is multifactorial, and many of these factors are potentially amenable to therapeutic intervention. The management of DU disease in SSc is multifaceted. Patient education and non-pharmacological interventions (e.g. smoking cessation) should not be neglected. There are a number of drug therapies available to prevent (e.g. phosphodiesterase type-5 inhibitors and ET receptor-1 antagonists) and treat (e.g. i.v. iloprost) DUs. DUs are also important for two other reasons: firstly, as a primary end point in SSc-related clinical trials; and secondly, DUs are included in the ACR/EULAR SSc classification criteria. However, the reliability of rheumatologists to grade DUs is poor to moderate at best, and this poses challenges in both clinical practice and research. The purpose of this review is to provide the reader with a description of the spectrum of DU disease in SSc including pathophysiology, epidemiology and clinical burden, all of which inform the multifaceted approach to management.

Topics: Blood Coagulation Disorders; Endothelin Receptor Antagonists; Endothelium, Vascular; Fingers; Humans; Iloprost; Patient Education as Topic; Phosphodiesterase 5 Inhibitors; Reperfusion Injury; Scleroderma, Systemic; Skin Ulcer; Smoking Cessation; Vasodilator Agents

Raynaud phenomenon (RP) is the hallmark of Systemic Sclerosis (SSc). Visceral RP has also been proposed in SSc patients. Cardiac Raynaud's phenomenon (C-RP) was evaluated in a few clinical studies both as cold-induced transient myocardial ischaemia and as presence of advanced myocardial fibrosis and contraction band necrosis in autopsied patients. Until today numerous techniques, such as scintigraphy and myocardial contrast echocardiography, have been used to evaluate C-RP. In this case report for the first time we have used Cardiac Magnetic Resonance (CMR) after cold test to demonstrate the presence of the C-RP. In addition we have shown that therapy with Iloprost can be used to reduce episodes of C-RP.

Topics: Antibodies, Antinuclear; Female; Fibrosis; Heart; Humans; Iloprost; Ischemic Attack, Transient; Magnetic Resonance Imaging; Middle Aged; Myocardium; Platelet Aggregation Inhibitors; Raynaud Disease; Recovery of Function; Scleroderma, Systemic

Patients with systemic sclerosis frequently have Raynaud's phenomenon and digital ischemic ulcers. Iloprost, a synthetic prostacyclin analogue, may be effective in these cases. Searching in Epistemonikos database, which is maintained by screening 20 databases, we identified three systematic reviews including seven randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded iloprost may lead to little or no difference in the frequency or severity of secondary Raynaud, and it is associated to adverse effects and important costs.. Los pacientes con esclerodermia presentan con frecuencia fenómeno de Raynaud asociado y úlceras digitales isquémicas. El iloprost, un análogo sintético de prostaciclina, podría ser efectivo en estos casos. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 20 bases de datos, identificamos tres revisiones sistemáticas que en conjunto incluyen siete estudios aleatorizados. Realizamos un metanálisis y tablas de resumen de los resultados utilizando el método GRADE. Concluimos que iloprost podría disminuir poco o nada la frecuencia y gravedad de los episodios de Raynaud secundario, y se asocia a efectos adversos y costos importantes.

Topics: Databases, Factual; Humans; Iloprost; Randomized Controlled Trials as Topic; Raynaud Disease; Scleroderma, Systemic; Vasodilator Agents

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Female; Fingers; Humans; Iloprost; Ischemia; Male; Raynaud Disease; Risk Factors; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Vasodilator Agents

Ischaemic ulcerations of the fingertips are common in SSc and a source of pain and disability. Healing has been demonstrated with intravenous iloprost and two studies with bosentan have demonstrated reduction in the occurrence of new digital ulcers (DUs) over 4-6 months of treatment. Both bosentan studies showed no benefit in healing DU and because of this, net DU burden is no different between drug and placebo and accordingly secondary measures of outcome including pain and hand functionality are inconsistently affected. While it is likely an artefact, it remains unclear that current outcome measures including the Scleroderma Health Assessment Questionnaire (SHAQ), the UK Functional Score and the Michigan Hand Questionnaire are sensitive to change in the domain of digital ischaemia. Major events including amputation and hospitalization occur too infrequently to serve as practical measures of outcome in trials. Future studies of DU therapies will benefit from development of an ulcer-specific measure of outcome.

Topics: Bosentan; Fingers; Hand Dermatoses; Humans; Iloprost; Ischemia; Scleroderma, Systemic; Severity of Illness Index; Skin Ulcer; Sulfonamides; Treatment Outcome; Vasodilator Agents

An imbalance between prostacyclin (PGI2) and thromboxane A2 is observed in patients with scleroderma. Iloprost is a stable analogue of PGI2 with a plasma half-life of 20-30 min. Intravenous iloprost is effective in the treatment of Raynaud's phenomenon related to scleroderma, decreasing the frequency and severity of attacks. It also appears useful for the treatment of digital ulcers. Inhaled iloprost is an effective treatment for NYHA class III pulmonary arterial hypertension, either idiopathic primary or associated with a particular condition, such as scleroderma. Intravenous iloprost improves kidney vasospasm in patients with scleroderma. The possible benefits of sequential intravenous iloprost on the natural course of scleroderma require further investigation.

Topics: Humans; Hypertension; Iloprost; Raynaud Disease; Renal Circulation; Scleroderma, Systemic; Vasodilator Agents

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

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

Pulmonary arterial hypertension (PAH) is one of the main causes of death in patients with systemic sclerosis (SSc), particularly in its limited forms.. Survival with conventional treatment associated with Epoprostenol is two times less in SSc patients than in idiopathic PAH. WHO recommendations (annually heart echoscreening) must be applied in all patients with SSc. Conventional therapy associates anticoagulation, to avoid excessive exertion, pregnancy, warm baths, no pressurised flights. Calcium-channel blockers give long term survival in patients with positive acute vasodilatator test with nitric oxide (NO) but these patients are very rare in SSc. Diuretics are very useful in treating right heart insufficiency. Randomized control trials in PAH have demonstrated the short term efficacy of i.v. epoprostenol, nebulized iloprost, oral beraprost and oral bosentan, a dual endothelin-1 receptor antagonist. Results in SSc are very limited except for i.v. epoprostenol. Long-term efficacy in terms of survival has been demonstrated in non randomized studies for i.v. epoprostenol and oral bosentan in patients with idiopathic and familial PAH. Atrial septostomy and lung transplantation could be an alternative to treatment, even in SSc patients, in case of refractory evolution.. Randomized control trials with sildenafil and selective endothelin-1 receptor antagonists are ongoing.

Topics: Antihypertensive Agents; Bosentan; Calcium; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Scleroderma, Systemic; Sulfonamides

Systemic sclerosis is an autoimmune disease of unknown origin affecting multiple organ systems. The management of this disease is challenging. Many therapeutic attempts have only been moderately successful. Iloprost, a stable prostacyclin analogue, with its antifibrotic effect can influence an important step in the pathogenesis of systemic sclerosis. In this review we analyze the published data for the optimal dose and duration of treatment. In three different studies, iloprost given for 5 days in the highest tolerated dose of 1-2 ng/kg/min provided a significant improvement of the disease measured by the number and intensity of Raynaud attacks, healing of digital ulcers, and digital perfusion. This improvement lasted for about one month. When the infusions were repeated once a month, treatment effect could be maintained. Although the effect of this treatment regimen should be proven in further long-term studies, we think that an intermittent continuous therapy with iloprost could result in an improvement or stabilization of systemic sclerosis.

Topics: Controlled Clinical Trials as Topic; Forecasting; Humans; Iloprost; Platelet Aggregation Inhibitors; Raynaud Disease; Scleroderma, Systemic; Time Factors; Vasodilator Agents

Most patients with systemic sclerosis (SSc) have Raynaud's phenomenon (RP), which is often more severe than idiopathic RP. This study was a meta-analysis to determine the efficacy of calcium-channel blockers for the treatment of RP in SSc. The primary outcome measures were frequency and severity of ischemic attacks, digital skin temperature, patient and physician global assessments, and digital ulcers.. The Cochrane search strategy was used to ascertain all trials in all languages. Primary data sources included Medline, Current Contents, and the Cochrane Controlled Trials Register. Studies that met the inclusion criteria were randomized controlled trials of >2 days' duration with a dropout rate of <35%. Twenty-nine studies were found, of which 8 randomized controlled trials were eligible for inclusion. The total number of patients included was small (n = 109). Most trials included primary and secondary RP, and the main reasons for trial exclusion were inability to extract subset data on SSc patients (18 trials), data published previously (2 trials), and lack of a control group (1 trial). Data were abstracted independently by 2 reviewers, and either a weighted mean difference (WMD) or a standardized mean difference (SMD) was calculated for all continuous outcomes; however, information was not available for all outcomes within trials.. The WMD of all calcium-channel blockers versus placebo (6 trials) and of nifedipine alone versus placebo (5 trials) for the reduction in the frequency of ischemic attacks over a 2-week period was -8.31 (95% confidence interval [95% CI] -15.71, -0.91) and -10.21 (95% CI -20.09, -0.34), respectively. The SMD of all calcium-channel blockers versus placebo (3 trials) and of nifedipine alone versus placebo (2 trials) for the reduction in the severity of ischemic attacks was -0.69 (95% CI -1.21, -0.17) and -0.99 (95% CI -1.74, -0.24), respectively.. Calcium-channel blockers for RP in SSc have been tested in several small clinical trials and appear to lead to significant clinical improvement in both the frequency and the severity of ischemic attacks. Most trials were crossover trials in which order effect was not studied. This could have introduced bias. The results of this study suggest that the efficacy of calcium-channel blockers in reducing the severity and frequency of ischemic attacks in RP secondary to SSc is moderate at best (mean reduction of 8.3 attacks in 2 weeks and 35% less severity), and a further large, randomized controlled trial needs to be conducted.

Topics: Calcium Channel Blockers; Cross-Over Studies; Humans; Iloprost; Injections, Intravenous; Ischemia; Losartan; Randomized Controlled Trials as Topic; Raynaud Disease; Scleroderma, Systemic; Skin Temperature; Skin Ulcer

To assess the effects and toxicity of the following agents:Prostaglandin analogues together with other agents proposed for the treatment of Raynaud's phenomenom (RP) in scleroderma.. We searched the Cochrane Controlled Trials Register, and Medline up to 1996 using the Cochrane Collaboration search strategy developed by Dickersin et al.(1994). Key words included: raynaud's or vasospasm, scleroderma or progressive systemic sclerosis or connective tissue disease or autoimmune disease. Current Contents were searched up to and including April 7, 1997. All bibliographies of articles retrieved were searched and key experts in the area were contacted for additional and unpublished data. The initial search strategy included all languages.. All randomized controlled trials comparing prostaglandin analogues versus placebo were eligible if they reported clinical outcomes within the start of therapy, and if the dropout rate was less than 35%.. Data were abstracted independently by two reviewers (DF, AT). Peto's odds ratios were calculated for all dichotomous outcomes and a weighted mean difference was calculated for all continuous outcomes. A fixed effects or random effects model was used if the data were homogeneous or heterogeneous, respectively.. Seven randomized trials and 332 patients were included. Five of the seven trials were of parallel design. Five trials compared I.V. Iloprost and one trial studied p.o. Iloprost and another p.o. Cisaprost. Some trials were dose finding trials so various doses of Iloprost were used. Due to different efficacies of I.V. Iloprost, oral Iloprost and oral Cisaprost, the overall efficacy of these drugs was somewhat diluted. Intravenous Iloprost appears to be effective in the treatment of secondary Raynaud's phenomenon.. Intravenous Iloprost is effective in the treatment of Raynaud's phenomenon secondary to scleroderma at decreasing the frequency and severity of attacks and preventing or healing digital ulcers. The effect seems to be prolonged after the intravenous infusion is given. Oral Iloprost may have less efficacy than intravenous Iloprost. However, Cisaprost has minimal or no efficacy when given orally for the treatment of Raynaud's phenomenon secondary to scleroderma.

Topics: Humans; Iloprost; Raynaud Disease; Scleroderma, Systemic; Vasodilator Agents

A 57-years old female patient with systemic sclerosis underwent a prolonged intravenous therapy during 21 consecutive days with iloprost, a stable analogue of prostacyclin. Beginning with 0.5 ng/ kg/minute the dose was increased every 2 days up to 2 ng/kg/minute. At the end of follow up, Iloprost was shown to enhance the perfusion of the finger and to improve pulmonary-function tests including the diffusion-capacity. Furthermore, the Erythrocyte Sedimentation Rate and the C-reactive protein decreased. The case report shows the necessity of a controlled study of prolonged iloprost therapy.

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Iloprost; Middle Aged; Scleroderma, Systemic; Treatment Outcome; Vasodilator Agents

The last few years have brought a resurgence in interest in managing systemic sclerosis. In the past year, there have been reports of small series of patients and several well-designed, double-blind, controlled trials. Treatment has been directed at a variety of potential pathogenic mechanisms. Stanazol, iloprost, plasmapheresis, thyroxine, and calcitonin were felt to have positive effects on vascular aspects of disease, ie, Raynaud's phenomenon. Immune-mediated treatment using antithymocyte and antilymphocyte globulin, cyclosporine, and methotrexate were encouraging in a small number of patients, but controlled studies of plasma exchange, extracorporeal phototherapy, and 5-fluorouracil were not very exciting. Changing fibroblast function was used with some success in some patients with D-penicillamine and interferon gamma, but not ketotifen. A very dramatic improvement in the survival of renal crisis occurred with the use of angiotensin-converting enzyme inhibitor. Hopefully, this improvement in survival will also occur in the other visceral abnormalities. All this activity in the therapy of systemic sclerosis will certainly lead to improvement in the overall management of disease.

Topics: Calcitonin; Humans; Iloprost; Scleroderma, Systemic; Thyroxine

Systemic sclerosis (SSc) is a systemic multi-organ disease. Raynaud's phenomenon (RP) and digital ulcers (DUs) in SSc patients can be resistant to usual treatments. We studied the clinical benefits, capillaroscopy changes, and cost-effectiveness of local injection of botulinum toxin-A (BTX-A) and intravenous prostaglandin analogs (iloprost/alprostadil) in patients with SSc with resistant DUs.. In a clinical trial study, we evaluated 26 patients fulfilling the ACR/EULAR SSc criteria with resistant DUs. Visual analog scale of pain and RP, skin color and type of ulcers, and capillaroscopy were assessed before and 1 month after treatment. In the first group, 20 units of BTX-A was injected at the base of each involved fingers by a dermatologist. In the second group, 20 µg iloprost or 60 µg alprostadil was infused daily. The cost of these treatments was compared.. In 26 patients (43 fingers), there were 16 patients (22 fingers) in the BTX-A and 10 patients (21 fingers) in the prostaglandin group. In 95.5% of the BTX-A and 90.5% of the prostaglandin group, the ulcers were healed. In both groups, a significant decrease in pain was seen (p < 0.0001). Capillaroscopy patterns in both groups were not changed although the microhemorrhages disappeared significantly (p value: BTX-A: 0.03 and prostaglandin: 0.002). The cost was significantly lower in the BTX-A injection group (p < 0.0001).. Both BTX-A and prostaglandins helped in the healing and pain control of DUs. In capillaroscopy, microhemorrhages were significantly decreased in both groups. In the BTX-A group, the cost was significantly lower as an outpatient treatment and was more time-saving.. • BTX-A and prostaglandin analogs both contributed to the healing of digital tip ulcers and improving the pain • In capillaroscopy, microhemorrhages were significantly decreased or disappeared after both treatments • There was no significant side effect in both groups • Comparing both groups, in the BTX-A group, the cost was significantly lower when performed on an outpatient treatment and more time-saving.

Topics: Botulinum Toxins, Type A; Cost-Benefit Analysis; Fingers; Humans; Iloprost; Microscopic Angioscopy; Prostaglandins; Raynaud Disease; Scleroderma, Systemic; Skin Ulcer; Ulcer

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

Systemic sclerosis (SSc)-related Raynaud's phenomenon (RP) and digital ulcers (DU) can impair health-related quality of life (HRQoL). The aim of our study was to estimate HRQoL in SSc patients treated with two different intravenous (IV) iloprost (ILO) regimens and in patients not treated with IV ILO. 96 consecutive SSc patients were enrolled in a pragmatic, prospective and non-randomized study, and divided into 3 groups: not requiring therapy with IV ILO (N=52), IV ILO once monthly (N=24) or IV ILO for 5 consecutive days every 3 months (N=20). Patients were followed up for three months. We assessed HRQoL using the generic preference-based questionnaire EQ-5D-5L. We conducted multiple regression analyses to estimate, in each treatment group, the mean general health (GH) and the mean utility index of the EQ-5D-5L, adjusting for possible confounders. The mean adjusted utility index and GH score, after three months' follow-up, were not different in the three groups: IV ILO was able to make patients requiring IV ILO similar to those not requiring it. Moreover, there was no difference in this model between the two ILO regimens (1 day monthly vs 5 consecutive days every 3 months). The two different IV ILO regimens (the most appropriate regimen was decided according to patients' characteristics and needs) were able to stabilize HRQoL in RP secondary to SSc non-adequately controlled by oral therapy.

Topics: Administration, Intravenous; Cost of Illness; Drug Administration Schedule; Female; Humans; Iloprost; Male; Middle Aged; Prospective Studies; Quality of Life; Scleroderma, Systemic

I.v. iloprost (ILO) may be used in the treatment of refractory RP and digital ulcers. We aim to evaluate the acute and chronic effects of two different ILO regimens by power Doppler US (PDUS) and nailfold videocapillaroscopy.. In this 3-month single-centre pragmatic non-randomized trial, 96 SSc patients were included and stratified according to ILO treatment as: no ILO (group A), ILO once monthly (group B) and ILO for five consecutive days (group C). Resistivity index (RI), finger pulp blood flow and periungual vascularization by PDUS, and sum of capillaries apex width in 1 mm by nailfold videocapillaroscopy were evaluated. Results were adjusted for the average outdoor temperature at the place of residence.. An acute ILO effect was observed for only finger pulp blood flow in groups B and C (P < 0.001 and P < 0.005, respectively). An acute effect was observed for RI and periungual vascularization only in group B. A progressive increase was observed for other parameters without statistical difference. ILO effects were not observed any longer before the following infusion. Some parameters (finger pulp blood flow in group B and RI in group C) showed a statistically higher increase the lower the outdoor temperature was.. ILO had an acute effect as assessed by PDUS, especially in group B. By contrast, an ILO chronic effect was not detectable before the following infusion in both treatment groups. More studies are needed to define how often ILO should be administered.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Fingers; Follow-Up Studies; Humans; Iloprost; Laser-Doppler Flowmetry; Male; Microscopic Angioscopy; Middle Aged; Regional Blood Flow; Retrospective Studies; Scleroderma, Systemic; Time Factors; Treatment Outcome; Vasodilator Agents; Young Adult

Bosentan is a dual endothelin receptor antagonist initially introduced for the treatment of pulmonary arterial hypertension and recently approved for the treatment of digital ulcers in patients with systemic sclerosis (SSc). Our clinical observations indicate that bosentan therapy may be associated with an increased frequency of centrofacial telangiectasia (TAE). Here, we sought to analyze the frequency of TAE in patients with SSc who were treated with either bosentan or the prostacyclin analog iloprost.. We conducted a retrospective analysis in 27 patients with SSc undergoing therapy with either bosentan (n = 11) or iloprost (n = 16). Standardized photodocumentations of all patients (n = 27) were obtained at a time point ten months after therapy initiation and analyzed. A subgroup of patients (bosentan: n = 6; iloprost: n = 6) was additionally photodocumented prior to therapy initiation, enabling an intraindividual analysis over the course of therapy.. After ten months of therapy patients with SSc receiving bosentan showed a significantly (P = 0.0028) higher frequency of centrofacial TAE (41.6 ± 27.8) as compared to patients with SSc receiving iloprost (14.3 ± 13.1). Detailed subgroup analysis revealed that the frequency of TAE in the bosentan group (n = 6 patients) increased markedly and significantly (P = 0.027) by 44.4 after ten months of therapy (TAE at therapy initiation: 10.8 ± 5.1; TAE after ten months of therapy: 55.2 ± 29.8), whereas an only minor increase of 1.9 was observed in the iloprost group (n = 6 patients; TAE at therapy initiation: 18.3 ± 14.5; TAE after ten months of therapy: 20.2 ± 15.5), yet without reaching statistical significance (P = 0.420).. The use of bosentan may be associated with an increased frequency of TAE in patients with SSc. Patients should be informed about this potential adverse effect prior to therapy. Treatment options may include camouflage or laser therapy.

Topics: Adult; Aged; Aged, 80 and over; Bosentan; Face; Female; Humans; Iloprost; Linear Models; Male; Middle Aged; Retrospective Studies; Scleroderma, Systemic; Sulfonamides; Telangiectasis

To evaluate the longterm effects of endothelin-1 (ET-1) antagonism on peripheral blood perfusion (PBP) in patients with systemic sclerosis (SSc).. Twenty-six patients with SSc already receiving cyclic intravenous iloprost (ILO) for severe Raynaud phenomenon were enrolled. Thirteen patients continued the treatment for a further 3 years (ILO group) and 13 patients, because of the appearance of digital ulcers, received in addition bosentan (BOS; 125 mg twice/day) for 3 years (ILO + BOS group). Both PBP at fingertips and nailfold microangiopathy were evaluated yearly by laser Doppler flowmetry and nailfold videocapillaroscopy, respectively.. A progressive significant increase of PBP was observed in the ILO + BOS group during the 3 followup years (p = 0.0007, p = 0.0002, p = 0.01, respectively). In contrast, an insignificant progressive decrease of PBP was observed in the ILO group. Difference of perfusion between the PBP evaluations at basal temperature and at 36 °C (to test capillary dilation capacity), was found progressively decreased during the 3-year followup only in the ILO group (p = 0.05, p = 0.26, p = 0.09, respectively). A progressive increase of nailfold capillary number was observed only in the ILO + BOS group after 2 and 3 years of followup (p = 0.05).. Longterm treatment of SSc patients with ET-1 antagonism, in combination with ILO, seems to increase fingertip blood perfusion, as well as both capillary dilation capacity and number.

Topics: Aged; Bosentan; Endothelin Receptor Antagonists; Female; Fingers; Humans; Iloprost; Laser-Doppler Flowmetry; Male; Microscopic Angioscopy; Middle Aged; Prospective Studies; Regional Blood Flow; Scleroderma, Systemic; Sulfonamides; Time Factors; Treatment Outcome; Vasodilator Agents

Iloprost has been reported to reduce Raynaud`s phenomenon (RP) and to inhibit progression of systemic sclerosis (SSc).. The aim of our study was to compare monthly iloprost infusions with placebo in patients treated long-term.. Seventeen patients, six with RP and 11 with SSc on monthly treatment with iloprost, received either a 3-hour intravenous infusion of iloprost or an equal volume of placebo once per month for 4 months in a monocentric, randomized, placebo-controlled, double-blind study. Raynaud attacks as measured by diary entries, skin temperature, skin sclerosis, fist closure, mouth opening, and digital ulcers were recorded during the observation period.. Whereas mouth opening improved significantly (p = 0.043) in the iloprost-treated group, RS improved in both patient groups. However, no significant differences were found in the outcome measures.. Although iloprost influences the inflammatory cascade in SSc, no statistical differences were seen in our study, indicating that treatment strategies with iloprost should be modified.

Topics: Adult; Aged; Double-Blind Method; Female; Humans; Iloprost; Infusions, Intravenous; Male; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Vasodilator Agents

Topics: Adult; Aged; Capillaries; Female; Humans; Iloprost; Male; Microscopic Angioscopy; Middle Aged; Nails; Pilot Projects; Raynaud Disease; Scleroderma, Systemic; Vasodilator Agents

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

Circulating endothelial cells are increased in patients affected by systemic sclerosis (SSc) and their number strongly correlates with vascular damage. The effects of iloprost in systemic sclerosis are only partially known. We aimed at studying the gene expression profile of circulating endothelial cells and the effects of iloprost infusion and gene expression in patients with systemic sclerosis.. We enrolled 50 patients affected by systemic sclerosis, 37 patients without and 13 patients with digital ulcers. Blood samples were collected from all patients before and 72 hours after either a single day or five days eight hours iloprost infusion. Blood samples were also collected from 50 sex- and age-matched healthy controls. Circulating endothelial cells and endothelial progenitors cells were detected in the peripheral blood of patients with systemic sclerosis by flow cytometry with a four-colour panel of antibodies. Statistical analysis was performed with the SPSS 16 statistical package.Circulating endothelial cells were then isolated from peripheral blood by immunomagnetic CD45 negative selection for the gene array study.. The number of both circulating endothelial cells and progenitors was significantly higher in patients affected by systemic sclerosis than in controls and among patients in those with digital ulcers than in patients without them. Circulating endothelial cells and progenitors number increased after iloprost infusion. Gene array analysis of endothelial cells showed a different transcriptional profile in patients compared to controls. Indeed, patients displayed an altered expression of genes involved in the control of apoptosis and angiogenesis. Iloprost infusion had a profound impact on endothelial cells gene expression since the treatment was able to modulate a very high number of transcripts.. We report here that circulating endothelial cells in patients with systemic sclerosis show an altered expression of genes involved in the control of apoptosis and angiogenesis. Moreover we describe that iloprost infusion has a strong effect on endothelial cells and progenitors since it is able to modulate both their number and their gene expression profile.

Topics: Apoptosis; Endothelial Cells; Female; Flow Cytometry; Gene Expression Profiling; Hematopoietic Stem Cells; Humans; Iloprost; Male; Neovascularization, Pathologic; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Scleroderma, Systemic; Skin Ulcer; Vasodilator Agents

Iloprost has been suggested to possess anti-inflammatory and immunomodulating actions and it is widely use as a vasodilatator in systemic sclerosis (SSc). In this study we evaluate the effect of iloprost on immune response in SSc patients. To this extend we enrolled 15 women affected by SSc and infused iloprost for 5 days. The effect of iloprost on T cells and monocytes was measured by flow cytometry, Real time PCR and measuring cytokines production in vivo and in vitro by ELISA.. Our results demonstrate that Iloprost reduces T cell and TNF alpha production both in vivo and in vitro. It reduces T regulatory cells number, but increases their activity after immune stimulation. It increases serum IL-2 and this increase persists 28 days after the last infusion, also RANKL was increased both in vivo and in vitro. We observed no effect on IFN gamma production.. These results suggest that iloprost has anti-inflammatory and immunomodulating effects, reducing TNF alpha production by T cells and the number of T regulatory cells and increasing IL-2 and RANKL.

Topics: Female; Humans; Iloprost; Immunologic Factors; Interferon-gamma; Middle Aged; Phytohemagglutinins; RANK Ligand; Scleroderma, Systemic; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

We compared the efficacy of different dosages of longterm iloprost treatment on Raynaud's phenomenon (RP), ulcer healing, skin thickening, and progression of internal organ sclerosis in patients with systemic sclerosis (SSc).. Fifty patients with SSc were randomized 1:1 for the maximally tolerated dose up to 2 ng/kg body weight per minute or low-dose (0.5 ng/kg bw per min) intravenous iloprost administration, applied for 6 hours daily over 21 days. Effects on RP, ulcer healing, skin thickness, esophageal function, and lung involvement assessed by forced vital capacity (FVC) and DLCO were measured, as well as side effects.. Both regimens yielded 70% reduction of digital ulcers, 40% reduction in frequency of RP, and 30% reduction in duration of RP. One year after therapy, the modified Rodnan skin score appeared to be unchanged. FVC and DLCO-SB were stable in 87% and 74% of the patients, respectively. The effect of iloprost on skin thickness and lung function was sustained in a subgroup of patients receiving several courses of iloprost. As assessed by a patient questionnaire, 12% of all patients did not respond to iloprost therapy, but 78% experienced a longlasting effect. Mild side effects were common in both groups, but did not lead to discontinuation of therapy.. Low-dose iloprost was shown to be equally effective as high-dose iloprost in longterm treatment and was very effective in therapy of digital ulcers. Registered in www.ClinicalTrials.gov (registration no. NCT00622687).

Topics: Adult; Aged; Disease Progression; Dose-Response Relationship, Drug; Female; Humans; Iloprost; Lung; Male; Middle Aged; Raynaud Disease; Respiratory Function Tests; Scleroderma, Systemic; Skin; Skin Ulcer; Surveys and Questionnaires; Treatment Outcome; Vasodilator Agents

Systemic sclerosis is a connective tissue disease in which oxidative stress represents an important player among the complex pathogenetic mechanisms of the disease. Iloprost, an analogue of natural prostacyclin, is used in systemic sclerosis for the treatment of severe Raynaud's phenomenon and ischemic ulcers. There is a clear evidence that iloprost attenuates oxidative damage induced by ischemia-reperfusion phenomena. The aim of this study is to evaluate the effect of iloprost on oxidative status in ten patients with systemic sclerosis by measuring urinary levels of 8-isoprostaglandin-F(2alpha), a member of F(2)-isoprostanes. We found that systemic sclerosis patients cyclically treated with iloprost showed increased urinary level of 8-isoprostaglandin-F(2alpha )in comparison with healthy subjects; urinary 8-isoprostaglandin-F(2alpha) did not diminish soon after the iloprost infusion as well as 3, 15 and 30 days after the drug administration. Unlike experimental studies, in vivo the strong vasodilator effect of iloprost infusion did not reduce oxidative status.

Topics: Dinoprost; Female; Humans; Iloprost; Infusions, Parenteral; Male; Middle Aged; Oxidative Stress; Scleroderma, Systemic; Time Factors; Treatment Outcome; Up-Regulation; Vasodilator Agents

Oxidative stress is involved in pathogenesis of Raynaud's phenomenon (RP), a hallmark of systemic sclerosis (SSc). Frequent episodes of ischemia-reperfusion may lead to release of free radicals and enhanced lipid peroxidation reflected by elevated levels of malondialdehyde (MDA). The failure of native antioxidants (Catalase [CAT], Superoxide dismutase [SOD], and Ceruloplasmin [CP]) might be crucial in endothelial cells damage in RP. Iloprost (IL) synthetic prostacyclin analogue is currently used in the treatment of SSc patients with RP. The objectives of this study were to compare the serum levels of MDA and CP, CAT and SOD activity in red blood cells hemolysate in SSc patients compared to healthy controls; and to study the effect of 5-days IL infusions on MDA and CP levels, and CAT and SOD activity in SSc patients with RP. Twelve SSc patients were treated with 50 mug IL for 5 days. Blood samples were taken before and after day 1st and after day 5th of IL infusions. Levels of CAT were measured according to the Aebi's method; SOD, according to the Misra and Fridovich method; MDA, according to Slater's method; and CP, according to Ravin's method. Activities of CAT (p < 0.001) and SOD (p < 0.04) were significantly reduced; levels of CP (p < 0.006) and MDA (p < 0.06) were raised in SSc compared to controls. IL infusions caused reduction in MDA (p < 0.0001) levels and enhanced production of SOD (p < 0.006) and CAT (p < 0.003). The levels of CP did not change (p = 0.48). Oxidant status in SSc patients with RP is impaired. Therapy with IL led to normalization of antioxidant activity. We suggest that CAT may be a sensitive and reliable laboratory marker of oxidative stress severity in RP. We found that IL, in addition to its vasoactive properties, has a potential to activate inner antioxidant system. Activation of inner antioxidant activity may explain long-term effect of IL instead of its very short half-life time.

Topics: Adult; Antioxidants; Catalase; Ceruloplasmin; Female; Humans; Iloprost; Malondialdehyde; Middle Aged; Oxidative Stress; Platelet Aggregation Inhibitors; Raynaud Disease; Scleroderma, Systemic; Superoxide Dismutase

To evaluate the clinical efficacy and the effects on the quality of life of iloprost, a prostacyclin analogue, used according to a new protocol in patients with Raynaud's phenomenon secondary to systemic sclerosis.. In this randomized study, we treated 30 patients with iloprost, given by intravenous infusion, at progressively increasing doses (from 0.5 to 2 ng/kg/min) over a period of 6 h each day for 10 days in two consecutive weeks, with repeated cycles at regular intervals of 3 months for 18 months. The results were compared with those obtained in 30 other patients who received the same drug but with different dosing schemes.. The total average daily duration of the attacks, the average duration of a single attack and the average daily frequency of the attacks were reduced significantly in all treatment groups, but the comparison between the groups demonstrated significant differences between patients treated with the new protocol and the others at later times (12 and 18 months). The effects on the quality of life in the group treated with the new protocol, evaluated with the Short Form-36, demonstrated a marked improvement regarding both the scale relating to the physical aspect of the illness and, especially, the scale relating to the mental aspect.. In patients with systemic sclerosis, cyclic intravenous iloprost infusion is efficacious in the treatment of Raynaud's phenomenon. The protocol that we used, compared with others, not only has favourable clinical effects but also leads to a marked improvement in the quality of life.

Topics: Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Iloprost; Infusions, Intravenous; Male; Middle Aged; Prospective Studies; Quality of Life; Raynaud Disease; Scleroderma, Systemic; Severity of Illness Index; Time Factors; Treatment Outcome; Vasodilator Agents

The objective of this study was to present our clinical experience about scleroderma-related pulmonary hypertension in the patients treated with intermittent iloprost infusions. Eighty-one patients affected by systemic sclerosis (12 men, 69 women; 30 with diffuse pattern and 51 with limited pattern; mean age 55.1 years; mean duration of disease 105.3 months) have been treated with cyclic iloprost infusions for at least 15 months (range 15-126 months). During the last 4 months all patients underwent Doppler echocardiography in order to estimate the value of systolic pulmonary artery pressure. In 14 subjects (17.2%) systolic pulmonary artery pressure was = or > 35 mmHg. Four patients presented high systolic pulmonary artery pressure associated with pulmonary fibrosis (mean value 40.5 +/- 4.5 mmHg). Ten women (one with diffuse pattern of disease and nine with limited form) showed isolated high systolic pulmonary artery pressure; one of these patients underwent right heart catheterization which resulted normal. The remaining nine patients (mean age of 67.1 years; age at the onset of scleroderma 52.2 years) showed estimated systolic pulmonary artery pressure values between 35 and 50 mmHg. Among these patients affected by isolated pulmonary hypertension only one has been receiving bosentan in association with iloprost infusions. None of our scleroderma patients treated with cyclic iloprost infusions developed severe isolated pulmonary hypertension. In systemic sclerosis the multiple effects of iloprost on endothelium, platelets and cytokine network may counteract the vasospastic profile of lung microvasculature in pulmonary arterial hypertension and the consequent vascular wall remodelling, thus preventing the development of severe illness.

Topics: Adult; Aged; Aged, 80 and over; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Pilot Projects; Scleroderma, Systemic; Vasodilator Agents

The aim of this study was to evaluate pulmonary function in patients suffering from scleroderma treated for 3 years with cyclic iloprost infusions.. Thirty patients affected by scleroderma (five men and 25 women, mean age 49.3 years, mean disease duration 8 years, 19 with limited and 11 with diffuse disease patterns) were treated for 5 consecutive days every 4 months for 3 years with iloprost. Pulmonary function was evaluated at baseline and after 3 years. At the end of the trial, color Doppler echocardiography was performed in 26 of the patients.. Spirometric parameters did not significantly change after 3 years of therapy when expressed as percentage of the predicted normal value. Diffusing lung capacity for carbon monoxide decreased at the limit of statistical significance. No patients developed clinical pictures suggestive of severe pulmonary arterial hypertension, which was confirmed in 26 subjects by evaluation of estimated pulmonary artery systolic pressure.. This long-term study showed that lung function remained substantially stable after 3 years of treatment with cyclic iloprost infusions. No cases of severe pulmonary hypertension were observed.

Topics: Adult; Echocardiography, Doppler, Color; Female; Humans; Iloprost; Infusions, Intravenous; Lung; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Respiratory Function Tests; Scleroderma, Limited; Scleroderma, Systemic; Treatment Outcome; Vasodilator Agents

Patients with systemic sclerosis (SSc) develop often acral ulcers which are resistant to therapy and may result in gangrene and amputation. We investigated the effects of iloprost infusion on the acral ulcers and necrosis in patients with five patients with SSc and one with mixed connective tissue disease who had been previously treated with various modalities without improvement. All patients had Raynaud phenomenon, acral ulcers and necrosis. Iloprost 25 microg per day was administered intravenously daily over six hours for ten consecutive days. Eight weeks later all patients were treated with a second iloprost therapy cycle for five days. Two patients with severe ulceration received a third cycle until remission occurred. In all cases acral ulcers healed completely and no patient relapsed during an observation period of 6 months.

Topics: Adult; Aged; Drug Administration Schedule; Drug Resistance; Female; Fingers; Humans; Iloprost; Infusions, Intravenous; Middle Aged; Necrosis; Scleroderma, Systemic; Secondary Prevention; Skin Ulcer; Treatment Outcome

Iloprost has beneficial effects on microcirculation by preventing platelet and leukocyte reciprocal activation, which is known to lead to endothelial damage and acute thrombosis. This drug also reduces inflammatory system activation by decreasing alpha M beta 2 integrin expression on the phagocyte membrane, might have a role in the protection and restoration of endothelial integrity and might interact with coagulation cascade activation.. Forty patients were enrolled: 29 with systemic sclerosis (SSc) and 11 with peripheral artery disease (PAD). Iloprost was administered for 5 days in the first group and for 21 days in second group of patients. To ascertain whether iloprost modifies the parameters of endothelial and coagulation cascade activations, the plasma concentrations of S-ICAM-1 and F1 + 2 were detected in patients at baseline, after 5 days and, in PAD patients only, after 21 days of iloprost therapy. S-ICAM-1 is the endothelial counter receptor for alpha M beta 2 integrin and is a marker of endothelial cell activation; and F1 + 2 is a marker of coagulation cascade activation.. After infusion of iloprost a significant decrease of S-ICAM-1 was observed in both the SSc (P < 0.002) and PAD patients (P < 0.004). Similarly, a significant decrease of F1 + 2 was observed in the SSc (P < 0.0004) and PAD patients (P < 0.003).. The study provides evidence that iloprost reduces endothelial cells and coagulation cascade activations. Both of these mechanisms are responsible for improvement in microvascular functional capacity and for the long-term clinical benefit observed. After iloprost infusion, the SSc patients showed marked reductions in F1 + 2 and S-ICAM-1 concentrations that were statistically more significant relative to the PAD patients.

Topics: Adult; Aged; Case-Control Studies; Cell Adhesion Molecules; Endothelium, Vascular; Female; Humans; Iloprost; Male; Middle Aged; Peptide Fragments; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Prothrombin; Scleroderma, Systemic; Statistics, Nonparametric

Patients with scleroderma receiving Iloprost as a treatment for severe Raynaud's phenomenon report a reduction in skin tightness, suggesting that this drug inhibits skin fibrosis. Connective tissue growth factor (CTGF), a recently described profibrotic cytokine, acts downstream and in concert with TGF-beta to stimulate the fibrotic process and is involved in the fibrosis seen in scleroderma. Here we show that Iloprost, acting by elevation of cAMP, blocks the induction of CTGF and the increase in collagen synthesis in fibroblasts exposed to TGF-beta. The potency of Iloprost with respect to suppression of CTGF far exceeds that of other prostanoid receptor agonists, suggesting that its effect is mediated by the prostacyclin receptor IP. By sampling dermal interstitial fluid using a suction blister device, we show that CTGF levels are greatly elevated in the dermis of scleroderma patients compared with healthy controls and that Iloprost infusion causes a marked decrease in dermal CTGF levels. These studies suggest that Iloprost could be reducing the level of a key profibrotic cytokine in scleroderma patients and that endogenous production of eicosanoids may limit the fibrotic response to TGF-beta.

Topics: Cells, Cultured; Collagen; Connective Tissue Growth Factor; Cyclic AMP; Down-Regulation; Drug Administration Schedule; Fibroblasts; Growth Substances; Humans; Iloprost; Immediate-Early Proteins; Infusions, Intravenous; Intercellular Signaling Peptides and Proteins; Prostaglandins; Receptors, Prostaglandin; RNA, Messenger; Scleroderma, Localized; Scleroderma, Systemic; Skin; Transforming Growth Factor beta

Iloprost is a chemically stable, pharmacologically highly potent prostacyclin-minietic. The therapeutic efficacy of the intravenous preparation was proven in patients with peripheral arterial occlusive disease or with Raynaud's phenomenon (RP). Recently, a sustained release oral preparation was developed for outpatient therapy. The purpose of the current study was to investigate whether the oral drug has a different pharmacokinetic profile in patients with RP secondary to systemic sclerosis (SSc) in comparison with healthy volunteers. Ten patients with RP secondary to SSc and 10 healthy volunteers (matched for age and sex) participated. Oral iloprost 50 microg was given twice daily for 8 days with dosing intervals of 5 h and plasma levels were taken over 10 h on Day 1 and 8. Plasma levels of iloprost were determined by a validated specific and sensitive radio-immunoassay. Compared with healthy volunteers, patients with SSc exhibited higher AUC values (by mean factors of 2. 1 and 2.0 on Day 1 and 8) and maximum plasma levels (by mean factors of 1.6 and 1.8 on Day 1 and 8). The increased systemic iloprost exposure was observed after both daily doses and on both monitored study days. Mean AUC values did not show accumulation over the 8 days. These findings are in agreement with a reduced total clearance of iloprost given by i.v. route in SSc patients compared to healthy volunteers, although no participant with severe renal impairment was included. A weak but significant correlation was found between individual creatinine clearance and AUC values. In conclusion, RP secondary to SSc is associated with an increased systemic iloprost exposure which is probably caused by changes of the metabolic clearance of iloprost. These effects cannot be explained by changes of renal function alone.

Topics: Administration, Oral; Delayed-Action Preparations; Female; Humans; Iloprost; Male; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Time Factors; Vasodilator Agents

Endothelial vascular tone modulators are thought to be involved in aetiopathogenesis of systemic sclerosis (SS) and of peripheral artery occlusive disease (PAOD). Iloprost, a prostacyclin (PGI2) analogue, induces clinical benefit in patients suffering from peripheral ischaemia. This study was performed to investigate the effect of this drug on endothelial function in vivo to elucidate the role of vascular tone modulators.. Fourteen PAOD and 15 SS patients were treated for 24 and 10 days respectively. On the first day, before and after therapy, nitric oxide metabolites (NO2-/NO3-) and endothelin-1 (ET-1) plasma concentrations were detected; moreover, the endothelium-dependent vasodilatation in response to artificial ischaemia was evaluated by means of an echo-Doppler device.. The echo-Doppler evaluation showed that the percentage of arterial reactive dilatation was not modified by placebo or by iloprost, and that the increase in blood velocity flow lasted for a significant longer time after drug infusion (226.79 +/- 17.49 vs. 310.71 +/- 36.32 s; P > 0.04). NO2-/NO3- and ET-1 plasma concentration were higher in patients than in control subjects (P < 0.004). After 6 h of iloprost infusion, no significant modifications were detected.. This study provides evidence that iloprost enhances the microvascular functional capacity and clinical benefit for patients. The effects of the drug seem to be independently or not directly correlated with its interactions with vascular tone modulators such as NO2-/NO3- or ET-1.

Topics: Adult; Aged; Arterial Occlusive Diseases; Chronic Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Iloprost; Infusions, Intravenous; Ischemia; Male; Microcirculation; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Scleroderma, Systemic; Ultrasonography; Vasodilator Agents

The main aim was to analyse the long-term therapeutic effects on systemic sclerosis (SSc) patients of treatment with either (i) iloprost alone or (ii) low-dose oral cyclosporin A (CyA) associated with iloprost. A secondary aim was to analyse interleukin-6 (IL-6) serum levels in SSc patients before and after 1 yr of treatment.. A clinical trial was performed in which 20 consecutive SSc patients were alternately randomized into two homogeneous groups receiving either monthly i.v. iloprost (1 ng/kg/min in 6 h i.v. infusion, for 5 consecutive days, 1 week per month) (Group I) or low-dose CyA (2.5 mg/kg/day) associated with iloprost administration (Group II). IL-6 concentrations were evaluated by ELISA in the sera of each patient before and after 1 yr of therapy and in 20 healthy subjects.. After 1 yr of therapy, a significant improvement of skin (P=0.008), microvascular (P=0.004) and oesophageal (P=0.05) morphological and functional parameters was observed only in Group II patients. Furthermore, after 1 yr of treatment, a significant reduction (P=0.007) of IL-6 serum concentration was observed only in Group II patients.. Collectively, our data suggest that the combination of low-dose CyA with iloprost administration may be of clinical utility in SSc and that a mechanism of action of CyA in SSc may include the decrease in IL-6 production.

Topics: Adolescent; Adult; Aged; Child; Cyclosporine; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Humans; Iloprost; Immunosuppressive Agents; Interleukin-6; Male; Middle Aged; Platelet Aggregation Inhibitors; Scleroderma, Systemic

To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma).. A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary.. Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058).. Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Data Interpretation, Statistical; Double-Blind Method; Female; Headache; Humans; Iloprost; Male; Middle Aged; Nausea; Placebos; Raynaud Disease; Recurrence; Scleroderma, Systemic; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents

To identify the optimal dose of oral iloprost on the basis of efficacy and tolerability in patients with Raynaud's phenomenon secondary to systemic sclerosis.. Multicentre, randomized, parallel-group comparison of two different doses of oral iloprost and placebo.. European university hospitals.. A total of 103 patients with Raynaud's phenomenon secondary to systemic sclerosis.. Patients received one of three treatments for 6 weeks: placebo, oral iloprost 50 microg or oral iloprost 100 microg. Each treatment was taken twice daily, giving total daily doses of iloprost of 100 and 200 microg.. The frequency, total daily duration and severity of Raynaud's attacks were recorded in a specially designed patient diary; physician's global assessment and adverse events were recorded at visits to the clinic. Analysis was performed on an intention-to-treat population.. A total of 103 patients were recruited, 89 completed the assessments throughout the treatment period and 82 completed an additional 6 weeks of follow-up after treatment. Thirty-five patients received placebo, 33 received iloprost 50 microg and 35 received iloprost 100 microg. The mean percentage reductions in the frequency, total daily duration and severity of Raynaud's attacks were numerically greater in the iloprost groups at the end of treatment and at the end of follow-up. At the end of treatment (6 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.03), but not in the severity (P = 0.07) or the frequency of attacks (P = 0.37). At the end of follow-up (12 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.001) and in the severity of attacks (P = 0.007), but not in the frequency of attacks (P = 0.07). Percentages of patients improved at the end of treatment as assessed by the physician were 44% placebo, 57% iloprost 50 microg and 64% iloprost 100 microg (not significant). Side-effects were reported by 80% of patients on placebo, 85% on oral iloprost 50 microg and 97% on oral iloprost 100 microg. Premature discontinuations of treatment in each group were 9, 30 and 51%, respectively, with 6, 27 and 51% being due to adverse events.. The results on the daily duration of Raynaud's attacks suggest that both 50 and 100 microg oral iloprost twice daily may be effective in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. The 50 microg iloprost dose was better tolerated in this patient group.

Topics: Administration, Oral; Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Iloprost; Male; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Treatment Outcome; Vasodilator Agents

To evaluate the safety and efficacy of cyclic intravenous iloprost therapy in diffuse or limited scleroderma.. Twenty patients, 14 women and 6 men with a mean age of 47.8 +/- 8.2 years, were given iloprost infusions for six hours a day during five consecutive days, at a rate of 0.5 to 2 ng/kg/min. The course was repeated every three months for one year. Efficacy was evaluated based on a scleroderma skin lesion score, an ischemic lesion score, a well-being self-assessment score, and lung function tests including measurement of the diffusing capacity of the lung for carbon monoxide. Safety was assessed based on adverse event collection.. The scleroderma skin lesion and ischemic lesion scores decreased significantly over the one-year treatment period, from 37.1 +/- 16.5 to 10.2 +/- 6.9 (P < 0.001) and from 31.8 +/- 19.1 to 2.2 +/- 2.0 (P < 0.05), respectively. The well-being self-assessment score also showed a significant improvement, from 71.4 +/- 16.5 to 15.0 +/- 6.6 (P < 0.001). The diffusing capacity for carbon monoxide was decreased in 11 patients at baseline and showed a slight, non significant increase in these patients after the treatment period. No serious or persistent side effects were recorded.. Cyclic intravenous iloprost therapy was associated with improvements in skin changes and in general health, as well as with a slight increase in the diffusing capacity of the lung for carbon monoxide. Our data suggest that iloprost may act on some of the pathogenetic mechanisms of scleroderma in a way that improves the course of the disease.

Topics: Female; Fingers; Humans; Iloprost; Infusions, Intravenous; Lung; Male; Microcirculation; Middle Aged; Pilot Projects; Prospective Studies; Respiratory Function Tests; Safety; Scleroderma, Localized; Scleroderma, Systemic; Skin; Toes; Treatment Outcome

To investigate the effect of iloprost, a stable prostacycline analog, on kidney blood flow in patients with systemic sclerosis (SSc), using color flow Doppler sonography.. The acute effect of the drug was studied in 10 patients with SSc with elevated resistance index (RI) levels (all RI values reported are multiplied by 100). Iloprost was administered intravenously (2 ng/kg/min for a period of 8 h). To study the effects of chronic drug administration, 16 patients with SSc were randomly assigned to 2 groups of 8 cases each. The first group was treated with 9 infusions of iloprost in 6 mo. The second group was treated with slow release nifedipine (40 mg/day) for 6 mo.. Interlobar artery RI (median 67 vs 61; p = 0.02) and cortical vessel RI (median 65 vs 54; p = 0.001) were reduced after acute treatment. In chronic drug administration, RI values were not modified by nifedipine, while iloprost reduced the RI of the interlobar (median 69 vs 61; p < 0.03) and cortical arteries (median 66 vs 58: p < 0.01).. Our findings suggest iloprost might be useful for treatment of scleroderma renal vasospasm.

Topics: Brachial Artery; Female; Humans; Iloprost; Kidney Cortex; Middle Aged; Nifedipine; Prospective Studies; Renal Circulation; Scleroderma, Systemic; Ultrasonography, Doppler, Color; Vascular Resistance

Twelve patients with systemic sclerosis were treated with intravenous infusions of the prostacyclin-stable analogue iloprost 0.5-2.0 ng/kg/min for 6 h from 8 to 13 days. Imminent gangrene was stopped in 2 patients and followed by healing. In 4 of 6 patients iloprost led to complete healing of ischaemic ulcers and in the remaining 2 patients to partial healing. One patient with severe Raynaud's phenomenon discontinued the study after 3 days due to severe headache. The 2 remaining patients with Raynaud's phenomenon as an indication improved, while no improvement was recorded in a patient with vasculitis of the lower leg. Side-effects such as headache, nausea and flushing were the reason that only 5 patients reached the maximum infusion rate. No statistical differences were recorded in digital bloodflow before and after the study or in plasma endothelin in the 9 patients investigated. Three of the 6 patients with healing ulcers, however, showed a pronounced decrease in plasma endothelin. Iloprost appears useful as a treatment of imminent gangrene and ischaemic ulcers in systemic sclerosis. This reparatory capacity could also be of a more general importance in therapy of this disease.

Topics: Adult; Aged; Endothelins; Female; Fingers; Gangrene; Humans; Iloprost; Infusions, Intravenous; Ischemia; Male; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Ulcer; Vasodilator Agents

This study has been designed to demonstrate the in vivo effects of iloprost therapy on expression of adhesion molecules on phagocytes. Sixty patients suffering from peripheral arterial occlusive disease (PAOD) and/or from skin ulcers due to secondary progressive systemic sclerosis (PSS) were enrolled in a double-blind controlled parallel study. Thirty patients (group I) underwent iloprost infusion and 30 patients (group II) were treated with aspirin. Clinical assessment and measurement of phagocyte activation in vivo, using quantitative flow cytometry, were performed on entry and after 6 h on the first day of therapy. After 3 months of therapy, complete healing of all cutaneous lesions was observed in 84% of the patients treated with iloprost compared with the control patients (P < 0.001). Neutrophils and monocytes of PAOD and PSS patients showed a significant decrease in the expression of the alpha M beta 2 integrin adhesion receptor after 6 h of iloprost infusion. Neutrophils and monocytes released a lower amount of anion superoxide (O2-) after 6 h of iloprost treatment. These data confirm other clinical observations but demonstrate that in vivo this drug modifies the expression of the alpha M beta 2 integrin of phagocytes that has a key role in leukocyte-endothelium interactions in cases of inflammation and thrombosis.

Topics: Adult; Aged; Arterial Occlusive Diseases; Double-Blind Method; Female; Humans; Iloprost; Macrophage-1 Antigen; Male; Middle Aged; Phagocytes; Scleroderma, Systemic; Skin Temperature

To compare the efficacy, tolerance and safety of 50-150 micrograms orally administered iloprost given twice a day versus placebo in patients with Raynaud's syndrome.. The study was multicentre (n = 3), double blind and placebo controlled. Sixty three patients who had eight or more vasospastic attacks per week were enrolled. After a one week run-in period, all patients received either iloprost or placebo treatment to a maximum tolerated dose of 150 micrograms twice a day for 10 days. Diary cards assessed the duration and severity of the vasospastic attacks. Side effects were monitored by direct questioning. A global assessment of treatment efficacy was made by the patient at the end of treatment and two weeks later.. Patient opinion tended to favour iloprost at the end of the 10 day treatment phase (p = 0.09) and this was significant at day 24 (the follow up visit) (p = 0.011). Although the duration and severity of attacks tended to decrease in the iloprost treated group, these results tended not to reach statistical significance (for severity p = 0.06 at end of treatment, p = 0.09 on day 24).. Iloprost administered intravenously has been shown to be of benefit in the treatment of the Raynaud's syndrome associated with systemic sclerosis, but this route of administration is inconvenient. This study evaluated the use of iloprost administered orally to patients with Raynaud's syndrome. Patient documented improvement was significantly improved by iloprost. Diary card analysis showed a trend in favour of iloprost, but these results did not reach statistical significance.

Topics: Administration, Oral; Adult; Attitude to Health; Double-Blind Method; Female; Humans; Iloprost; Male; Middle Aged; Patients; Raynaud Disease; Scleroderma, Systemic; Time Factors

To evaluate the efficacy and safety of iloprost, a prostacyclin analog, administered intravenously in patients with Raynaud phenomenon secondary to systemic sclerosis.. Multicenter, randomized, parallel placebo-controlled, double-blind study.. University medical centers.. 131 patients with systemic sclerosis (101 women, 30 men) ages 20 to 79 years.. Patients were randomly assigned to receive one of two parallel treatments of five daily sequential, 6-hour intravenous infusions of iloprost (0.5 to 2.0 ng/kg per min) or to receive a similar volume of placebo.. Frequency of Raynaud attacks, Raynaud severity score, physician's overall rating of treatment effect, and digital cutaneous lesion healing.. Of the 131 patients enrolled, 126 completed the 5-day infusion and 114 (87%) completed at least 6 weeks of follow-up. Sixty-four patients were randomly assigned to receive iloprost and 67 patients, to receive placebo. The mean weekly number of Raynaud attacks decreased 39.1% with iloprost and 22.2% with placebo (P = 0.005). In addition, the mean percentage of improvement in a global Raynaud severity score during the entire 9-week follow-up was greater in patients given iloprost (34.8%) than in those receiving placebo (19.7%) (P = 0.011). The physician's overall rating of treatment effect showed greater improvement with iloprost than with placebo at week 6 (52.4% compared with 27.4%; P = 0.008) and week 9 (60.9% compared with 26.9%; P < 0.001). At week 3, 14.6% more patients receiving iloprost had 50% or more lesions heal compared with those given placebo (95% CI, 0.9% to 30%). During the infusion, 59 (92%) of the patients receiving iloprost had one or more side effects compared with 38 (57%) of the patients receiving placebo.. Iloprost is effective for the short-term palliation of severe Raynaud phenomenon in patients with systemic sclerosis.

Topics: Adult; Aged; Analysis of Variance; Cold Temperature; Double-Blind Method; Drug Administration Schedule; Female; Humans; Iloprost; Infusions, Intravenous; Male; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Severity of Illness Index; Treatment Outcome

We conducted this study to assess the clinical usefulness and physiologic effects of intravenous iloprost in patients with Raynaud's phenomenon secondary to systemic sclerosis.. Thirty-five patients with Raynaud's phenomenon secondary to systemic sclerosis, including 11 with digital ischemic ulcerations, were enrolled in a double blind placebo controlled parallel study in 2 centers. Following a 2 week washout, subjects received intravenous iloprost (0.5-2.0 ng/kg/min) or saline by continuous infusion for 6 h on 5 consecutive days. Clinical assessments, status of digital ulcers, measures of in vivo platelet activation and detailed studies of peripheral vascular response to cold challenge, were performed at entry, at 5 days of therapy and at biweekly intervals for 10 weeks.. Complete healing of all cutaneous lesions (ulcers, fissures, and paronychia) was observed 10 weeks after treatment in 6 of 7 patients receiving iloprost versus none of 4 receiving placebo (p = 0.015). Ischemic digital tip ulcers completely healed in all 4 patients with ulcers in the iloprost group, but none in the placebo group (p = 0.029). Patient diaries of frequency, duration and symptoms of Raynaud's phenomenon showed improvement in both groups. Critical ischemic temperature (finger temperature during controlled cold challenge at which Raynaud's or loss of detectable digital blood flow occurred) progressively decreased in the iloprost group from 21.3 +/- 7.3 degrees C at baseline to a minimum of 16.1 +/- 3.2 degrees C at 8 weeks after treatment (p = 0.076), whereas no consistent changes were observed in the placebo group. Treatment was associated with improvement in the rate of skin temperature recovery following cold challenge. No changes were noted in ambient digital skin temperature, total digital blood flow, finger systolic pressure or in measures of in vivo platelet activation. One subject dropped out with chest pain, but adverse effects of nausea, vomiting, headache and jaw pain were otherwise limited to the 5 days of drug infusion.. Iloprost appears useful for the treatment of digital ulcers in systemic sclerosis and is associated with evidence of prolonged physiologic improvement although the mechanism of this effect remains unclear.

Topics: Adult; Aged; Double-Blind Method; Female; Fingers; Hemodynamics; Humans; Iloprost; Infusions, Intravenous; Ischemia; Male; Middle Aged; Platelet Activation; Raynaud Disease; Scleroderma, Systemic; Skin; Temperature; Ulcer

Patients with systemic sclerosis (SSc) do not exhibit a normal increase in the diffusing capacity for carbon monoxide (DLCO) on assuming the supine position. We sought to determine whether a potent prostacyclin derivative and vasodilator, iloprost, would reverse this defect.. Fourteen patients with SSc were enrolled in a randomized, double-blind, placebo-controlled study of iloprost. Patients were tested before and during 3 days of iloprost or placebo infusion with both upright and supine pulmonary function studies.. The results of baseline pulmonary function studies including DLCO were not significantly altered by iloprost. Furthermore, iloprost did not alter the abnormal postural DLCO response.. These results suggest that the pulmonary vascular defects seen in this group of patients are not a consequence of reversible pulmonary vasospasm.

Topics: Adult; Aged; Carbon Monoxide; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Prospective Studies; Pulmonary Diffusing Capacity; Respiratory Function Tests; Scleroderma, Systemic; Supination

To compare the long term effects of short term intravenous infusions of iloprost with those of oral nifedipine in patients with Raynaud's phenomenon associated with systemic sclerosis.. Double blind, placebo controlled, randomised group comparison.. Dermatology outpatient clinic.. Twenty three patients with Raynaud's phenomenon associated with well documented systemic sclerosis (American Rheumatism Association criteria) and with typical abnormalities in fingernail folds on capillaroscopy.. Twelve patients were randomised to receive intravenous infusions of iloprost starting at 0.5 ng/kg/min and increased by 0.5 ng/kg/min every 15 minutes to a maximum of 2.0 ng/kg/min for eight hours on three consecutive days with a further single infusion at week 8. Placebo capsules were given concurrently. Eleven patients were randomised to receive nifedipine, starting at 30 mg daily and increased to 60 mg daily after four weeks for another 12 weeks. Infusions of placebo were given in the same manner as the infusions of iloprost. One patient from each group withdrew because of social reasons and three patients receiving nifedipine withdrew because of side effects.. Reduction in number, duration, and severity of attacks of Raynaud's phenomenon, reduction in number of digital lesions, increase in digital blood flow.. Measurements were taken at 0, 4, 8, 12, and 16 weeks. Both regimens produced a reduction in the number, duration, and severity of attacks of Raynaud's phenomenon. The mean (SE) number of digital lesions was reduced with iloprost (from 3.5 (1.6) to 0.6 (0.3] and with nifedipine (from 4.3 (0.8) to 1.4 (0.5] after 16 weeks. Hand temperature and digital and microcirculatory blood flow were increased with iloprost but not with nifedipine.. Both iloprost and nifedipine are beneficial in the treatment of Raynaud's phenomenon. With nifedipine, however, side effects are common. Short term infusions of iloprost provide longlasting relief of symptoms, and side effects occur only during the infusions and are dose dependent.

Topics: Administration, Oral; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Epoprostenol; Female; Hemodynamics; Humans; Iloprost; Infusions, Intravenous; Male; Nifedipine; Random Allocation; Raynaud Disease; Regional Blood Flow; Scleroderma, Systemic

Iloprost, a stable prostacyclin analogue, was given by intravenous infusion to 29 patients with severe Raynaud's phenomenon, 26 of whom had systemic sclerosis (SS), and compared with placebo infusion in a double blind crossover trial. Iloprost significantly lessened the number and the severity of attacks compared with placebo. Nine patients expressed a preference for effectiveness of treatment, eight of these in favour of Iloprost. Thermography failed to show any long term effect of Iloprost. Side effects of headache, flushing, nausea, and vomiting were common, and the inconvenience of intravenous administration may limit its routine use.

Topics: Clinical Trials as Topic; Double-Blind Method; Epoprostenol; Female; Humans; Iloprost; Injections, Intravenous; Male; Raynaud Disease; Scleroderma, Systemic

Topics: Humans; Iloprost; Raynaud Disease; Scleroderma, Systemic

Iloprost (ILO) is recommended for the treatment of systemic sclerosis (SSc) microangiopathy, but there is no common consensus on its optimal dosage. The aim of this study is to evaluate the kinetics of response to ILO administered in a daily outpatient scheme in SSc subjects using laser speckle contrast analysis (LASCA).. Adult SSc patients in stable therapy with ILO administered for 6 h for 2 consecutive days every 4 weeks were enrolled. Peripheral finger perfusion was assessed by LASCA. Each patient underwent five LASCA evaluations: before and after each day of ILO (D1pre, D1post, D2pre, and D2post) and after 4 weeks (D30).. Twenty-seven SSc patients (77.8% female, mean age 61.5 years) were enrolled. LASCA showed an increase in perfusion at the end of each ILO course, but on the second day (both D1pre vs D2pre and D2pre vs D2post) the increase was no longer significant in half of the fingers. Moreover, compared to D1post, at the beginning of the second ILO day most of the fingers had already shown a significant reduction in perfusion. After 1 month, there were no statistically significant differences between the perfusion values of D1pre and D30.. This LASCA study highlights the transience of the vasoactive effect of ILO, with a perfusion benefit that is completely lost after 1 month. The brevity of the perfusion effect of ILO and the use of LASCA are elements to consider in the design of future SSc trials to determine the optimal ILO dosage.

Topics: Adult; Capillaries; Female; Fingers; Humans; Iloprost; Lasers; Male; Middle Aged; Scleroderma, Systemic

To assess the feasibility of a new device for telemonitoring vital parameters during iloprost infusion.. In a pilot study, patients with systemic sclerosis received iloprost infusion while being telemonitored with Umana T1 Heart Monitor, within the hospital, under the supervision of family/community nurses and rheumatologists. Patients were administered a questionnaire to obtain information on satisfaction, practicability, and compliance with the new monitoring device.. Data recorded by the device for blood pressure, heart rate, and oximetry were concordant with those registered directly by nurses. Most patients found the device useful and thought it could be used at home, even while working.. Umana Heart Monitor T1 could be a valuable aid in at-home iloprost therapy in patients with systemic sclerosis.

Topics: Blood Pressure; Feasibility Studies; Humans; Iloprost; Pilot Projects; Scleroderma, Systemic; Vasodilator Agents

Intravenous iloprost is currently recommended in the treatment of Raynaud's phenomenon (RP) refractory to oral therapy and of digital ulcers (DUs) related to systemic sclerosis (SSc). In real-life practice there is a huge heterogeneity about the Iloprost regimens used.. A survey was carried out on SSc patients that interrupted Iloprost infusion to compare acral vascular symptoms just before Iloprost withdrawal and just after the missed infusion. Severity, and frequency of RP, new DUs onset or aggravation of those pre-existing were reported. Last available capillaroscopic images were also evaluated.. The analysis includes 50 patients. After iloprost withdrawal, 11 patients reported a RP worsening because of enhanced intensity (p = 0.007). Only 8 patients of them also complained of an increased frequency (p = 0.07). None of the patients experienced digital ulcers for the first-time during quarantine. Among the 27 patients with a history of digital ulcers, 9 reported worsening and 7 recurrence of DUs. Overall, 17 patients (34.0 %) complained of a worsening of SSc vascular acral manifestations, namely RP or DUs. Reduced capillary density was associated with RP worsening, in particular, each unit increase of capillary density corresponds to an average 44 % decrease in the odds of RP worsening (OR 0.56, CI 95 % 0.36-0.97, p = 0.037). As for RP worsening, the aggravation of DU was associated with a lower capillary density.. Low capillary density can predict a worsening of both RP and DUs in controlled quarantine conditions within a month after iloprost discontinuation in SSc patients.

Topics: COVID-19; Humans; Iloprost; Pandemics; Raynaud Disease; Scleroderma, Systemic; Skin Ulcer; Ulcer

Topics: Chemokine CXCL10; Chemokines; Endothelial Cells; Epoprostenol; Humans; Iloprost; Scleroderma, Systemic; Tumor Necrosis Factor-alpha

This study aims at evaluating the disease progression, specifically in terms of cardiopulmonary function, in a group of consecutively enrolled systemic sclerosis (SSc) patients treated with the approved iloprost regimen.. A retrospective observational study was performed on 68 SSc patients treated with 5-6 infusions of iloprost per month for 6 hours per day at a dosage of 0.5-2.0 ng/kg/min through a portable syringe pump. All patients were evaluated for modified Rodnan skin score, systolic pulmonary arterial pressure, tricuspid annular plane systolic excursion, diffusing capacity of the lungs for carbon monoxide, forced vital capacity, alveolar volume, diffusing capacity of the lungs for carbon monoxide/alveolar volume, pro-brain natriuretic peptide (pBNP), New York Heart Association class, and the presence or absence of digital ulcers (DUs).. After a follow-up period of 9.9±2.9 years, all patients improved in frequency and severity of the Raynaud phenomenon and showed a stabilization or improvement of cardiopulmonary parameters. The pulmonary arterial pressure and pBNP improved significantly from baseline (30.91±6.4 mmHg vs. 27.36±7.1 mmHg, and 97.20±69.3 pg/ml vs. 66.65±44.3 pg/ml, respectively; p<0.0001 for both). A significant improvement was observed in the modified Rodnan skin score in 57 patients who continued the treatment during the entire follow-up (5.09±5.7 vs. 3.30±4.2, p<0.0001).. Despite the retrospective design and the lack of a control group, the regular and continued administration of iloprost maintained the stability of the cardiopulmonary and cutaneous parameters in SSc. It significantly reduced pBNP levels, a prognostic cardiac biomarker of SSc. Future research should be addressed to demonstrate a stronger causality of this effect.

Topics: Carbon Monoxide; Humans; Iloprost; Raynaud Disease; Retrospective Studies; Scleroderma, Systemic

Endothelial cell injury is an early event in systemic sclerosis (SSc) pathogenesis and several studies indicate oxidative stress as the trigger of SSc-associated vasculopathy. Here, we show that circulating factors present in sera of SSc patients increased reactive oxygen species (ROS) production and collagen synthesis in human pulmonary microvascular endothelial cells (HPMECs). In addition, the possibility that iloprost, a drug commonly used in SSc therapy, might modulate the above-mentioned biological phenomena has been also investigated. In this regard, as compared to sera of SSc patients, sera of iloprost-treated SSc patients failed to increased ROS levels and collagen synthesis in HPMEC, suggesting a potential antioxidant mechanism of this drug.

Topics: Adult; Collagen; Endothelial Cells; Female; Humans; Iloprost; Male; Microvessels; Oxidative Stress; Reactive Oxygen Species; Scleroderma, Systemic; Serum

Topics: Aged; Analgesics, Opioid; Anti-Bacterial Agents; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Foot Ulcer; Humans; Iloprost; Naloxone; Nifedipine; Oxycodone; Rivaroxaban; Scleroderma, Systemic; Vasodilator Agents

Vasculopathy is a crucial feature of systemic sclerosis (SSc), and Raynaud's phenomenon (RP) and digital ulcers (DU) have a deep impact on the quality of patients' life. The management of vascular disease can be challenging for the clinician because of the suboptimal tolerability of the treatments and lack of consensus on the best therapeutic approach. Intravenous iloprost, a synthetic analogue of prostacyclin, is broadly used for the treatment of RP and ischemic ulcers secondary to SSc. However, no standardized protocol on iloprost use is currently available and, consequently, the management of this treatment is largely based on the experience of each single center. The PROSIT project is an observational, multicenter study aiming to investigate the current treatments for SSc vasculopathy, the use of prostanoids, with special regard to iloprost, and the perception of the treatment from a patient's perspective. The study was conducted on a cohort of 346 patients from eight Italian centers and included a structured survey addressed to physicians, data collected from patient's medical records and two patient-administered questionnaires assessing the level of satisfaction, tolerability and perception of the efficacy of Iloprost. PROSIT data confirmed that in the contest of SSc iloprost represents the first-line choice for the management of severe RP and DU. Moreover, it is a well-tolerated treatment as reported by patients' experience. Although a standard protocol for the treatment of SSc-related vasculopathy is lacking, PROSIT study identified different therapeutic approaches largely supported by tertiary Italian centers. Further studies are needed in order to optimize the best treatment for SSc vascular diseases, in particular to improve the best iloprost schedule management.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Disease Management; Female; Humans; Iloprost; Italy; Male; Middle Aged; Peripheral Vascular Diseases; Retrospective Studies; Scleroderma, Systemic; Tertiary Care Centers; Treatment Outcome; Vasodilator Agents; Young Adult

Iloprost plays an important role in the treatment of Raynaud's phenomenon (RP), but has transient vasodilatory effects owing to its very short half-time. We aimed to evaluate short- and medium-term haemodynamic effects of iloprost by measuring dorsal finger microvessel blood flow using laser Doppler flowmetry (LDF), in patients with RP associated with systemic sclerosis (SSc).. In 24 consecutive SSc patients with RP (disease duration 10.5 ± 1.3 years), LDF with heating probes was used to measure blood flow in four fingers by occlusive and heating tests, at baseline, after 3 consecutive days of iloprost infusion, and at 24 h and 7 days after last iloprost infusion. Nailfold videocapillaroscopy (NVC) patterns of microvascular damage were investigated. Sixteen healthy controls were studied to compare baseline flows.. Compared to controls, SSc patients showed significantly impaired axon reflex vasoregulation and nitric oxide responses at baseline (p = 0.001 and p = 0.03, respectively). After iloprost, a prompt but transient significant improvement in endothelial-dependent vasodilation (occlusive test) was seen only in SSc patients with an 'active' NVC pattern (p ≤ 0.05). The iloprost effects vanished within 7 days after the last infusion. No significant differences were found, in the whole study, between patients with and without digital ulcers.. Microcirculatory blood flow increases following 3 days of iloprost infusion but fades shortly after treatment. Although iloprost is effective in reducing the severity of RP in SSc, the most suitable regimen and timing to obtain longer lasting vasodilatory benefits remain to be established.

Topics: Adult; Aged; Case-Control Studies; Female; Fingers; Humans; Iloprost; Infusions, Intravenous; Laser-Doppler Flowmetry; Longitudinal Studies; Male; Microcirculation; Microscopic Angioscopy; Middle Aged; Regional Blood Flow; Scleroderma, Systemic; Vasodilation; Vasodilator Agents

Iloprost (ILO) is employed intravenously for the treatment of severe Raynaud phenomenon (RP) and digital ulcers (DU) in systemic sclerosis (SSc). The aim of this study was to evaluate the safety and tolerability of the intravenous treatment with ILO in different phases of SSc. Eighty-one consecutive non-selected SSc patients, all on nifedipine, with moderate RP, treated with ILO infusion, were retrospectively evaluated. Patients were sub classified according to the edematous or fibrotic/atrophic cutaneous phase of the disease. ILO was infused with a progressive increase of the dosage up to the achievement of patient's tolerance, 1 day/week. In cases of slower infusion regimen due to adverse events (AE) at the beginning of the administration, patients received a lower dose of the drug (not possible to quantify precisely the final cumulative dosage). 16/81 SSc patients presented digital edema, 5 developed diarrhea, and 9 developed transient hypotension during the infusion at 20 ml/h that ameliorated when the drug was withdrawn. Moreover, 10/16 edematous patients experienced significant and painful digital swelling, unlike patients in the fibrotic group (p < 0.0001); 11/16 patients reported flushing and 7/16 headache, always controlled with dose tapering below 10 ml/h. In the atrophic/fibrotic phase patients (65/81), 10 developed diarrhea and 24 hypotension at infusion rate of 20 ml/h that led to temporary withdrawal of the drug. When ILO was restarted and kept below 10 ml/h, no side effects were experienced. 23/65 patients experienced flushing and 8/65 headache, all controlled with infusion reduction below 10 ml/h. In these patients, adverse events were significantly less frequent than in the edematous group (p = 0.023 and p = 0.008, respectively). Our data suggest that calcium channel blockers should be transitorily stopped while using ILO and that a pre-treatment approach might reduce or control adverse events. In patients with digital edema, ILO infusion should be carefully employed after the evaluation of patient's drug tolerance.

Topics: Adult; Diarrhea; Female; Fingers; Humans; Iloprost; Male; Microscopic Angioscopy; Middle Aged; Raynaud Disease; Retrospective Studies; Scleroderma, Systemic; Skin Ulcer; Treatment Outcome

Colour Doppler ultrasonography (CDUS) is very important in general vascular diagnostic procedures. Its role in determining the extent of vasculopathy in Systemic Sclerosis (SSc) needs further investigation. The aim of this study was to compare the presence of altered arteries with nailfold capillaroscopy and clinical signs of ischaemia, that is, digital ulcers or pitting scars (DU/PS). A feasible CDUS protocol is provided.. Two thousand five hundred and twenty-eight arteries of the fingers, palms and wrists from 79 SSc patients (32 arteries per patient) were examined using CDUS. Furthermore, nailfold capillaroscopy, clinical and laboratory data were evaluated.. Narrowed or occluded lumens were seen in 39.8% of all assessable arteries (n = 2489) and 48.9% of all proper palmar digital arteries (n = 1564) but only 15.6% (P < 0.0001) of proximal arteries (n = 924). Fingerwise analyses presented significant coincidence of pathological CDUS findings and DU/PS (P = 0.0009). Pathological CDUS findings were also associated with elevated CRP concentrations, current or past smoking with ⩾20 pack-years, male gender and present or past DU/PS. Receiver operating characteristic curve analysis (area under the curve = 0.727) suggested a cut-off value of ⩾20% pathological vessels (sensitivity: 90.7%; specificity: 47.8%) for the presence of DU/PS. An examination protocol focusing on the right-hand digits II-V (proper palmar digital arteries) revealed similar results (area under the curve = 0.751; sensitivity: 93.0%; specificity: 43.5%).. CDUS of hand and finger arteries allows measurement of the extent of SSc vasculopathy, which is associated with clinical signs of chronic malperfusion. A shortened examination protocol of CDUS (right-hand digits II-V; 15 min instead of 45 min examination time) could complement vascular diagnostics in SSc.

Topics: Adrenergic alpha-Antagonists; Adult; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; C-Reactive Protein; Calcium Channel Blockers; Endothelin Receptor Antagonists; Female; Fingers; Humans; Iloprost; Male; Microscopic Angioscopy; Middle Aged; Peripheral Arterial Disease; Phosphodiesterase 5 Inhibitors; ROC Curve; Scleroderma, Systemic; Sensitivity and Specificity; Skin Ulcer; Smoking; Ultrasonography, Doppler, Color; Vasodilator Agents

Laser speckle contrast analysis (LASCA) is a good tool to evaluate the variation in peripheral blood perfusion during long-term follow-up and is able to safely monitor digital ulcer evolution in scleroderma patients. It evaluates blood perfusion in different areas within the skin lesions and surrounding them during standard treatment.

Topics: Bosentan; Female; Fingers; Humans; Iloprost; Lasers; Methotrexate; Microcirculation; Microscopic Angioscopy; Middle Aged; para-Aminobenzoates; Raynaud Disease; Scattering, Radiation; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Tramadol; Treatment Outcome

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.. 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.. 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). 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).. 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.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Capillaries; Drug Therapy, Combination; Female; Humans; Iloprost; Male; Microscopic Angioscopy; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Sulfonamides; Treatment Outcome

Intravenous iloprost is a first-line option for the treatment of scleroderma-related digital vasculopathy, and some studies have suggested its favourable role on disease progression. The aim of our study is to evaluate the disease progression, specifically in terms of cardiopulmonary function, in a group of consecutive patients chronically treated with intravenous iloprost. Our retrospective study enrolled 68 scleroderma patients (68 F, 54.4 ± 12.3 years) treated with iloprost for 7.1 ± 2.9 years, with a schedule of 5-6 consecutive daily infusions per month (6 h/day, 0.5-2.0 ng/kg/min). In all patients, modified Rodnan skin score (4.7 ± 5.3 vs. 3.7 ± 5.3, p < 0.0001), systolic pulmonary arterial pressure (sPAP) (30.9 ± 6.4 vs. 24.0 ± 3.2 mmHg, p < 0.0001), tricuspid annular plane systolic excursion (22.1 ± 2.4 vs. 23.8 ± 3.5 mm, p = 0.0001), pro-brain natriuretic peptide (97.2 ± 69.3 vs. 65.8 ± 31.7 pg/ml, p = 0.0005) showed statistically significant improvement from baseline. In the subgroup of patients with baseline sPAP ≥36 mmHg (n = 17), a significant sPAP reduction was observed (from 39.5 ± 3.8 to 25.1 ± 4.5 mmHg, p < 0.0001) after 7.6 ± 2.5 years of follow-up. The number of patients with digital ulcers (DUs) at follow-up was reduced from baseline (42.6 vs. 11.8%, p < 0.001), and none of the free-DU patients at baseline presented DUs at follow-up. An intensive and chronic regimen of IV iloprost administration seems to stabilize and potentially improve the long-term development of disease in SSc patients, as suggested by stabilization or significant improvement of cardiopulmonary parameters and vasculopathy.

Topics: Adult; Aged; Disease Progression; Female; Humans; Iloprost; Infusions, Intravenous; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Skin Ulcer; Treatment Outcome; Vasodilator Agents

Topics: Administration, Intravenous; Connective Tissue Diseases; Disease Management; Humans; Iloprost; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Raynaud Disease; Scleroderma, Systemic

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 guidelines for digital ulcers (DUs) management in systemic sclerosis (SSc) indicate the use of iloprost to induce wound healing and bosentan to prevent the onset of new DU. The aim of our study was to evaluate whether the combination treatment may surmount the effect of the single drug.. We analyzed data regarding 34 patients with SSc and at least one active DU persisting despite 6 months of iloprost therapy, and treated for other 6 months with a combination therapy, i.e. iloprost plus bosentan.. Overall, patients initially presented 69 DUs (58 on the fingers and 11 on the legs). At the end of the study 34 (49.3%) DUs were completely healed (responding, R), 18 (26.1%) started the healing process (partially responding, PR), and 17 (24.6%) did not respond (NR) to therapy. No new DU was recorded and the ulcers localized on the legs did not respond to the combination therapy. Finally, data have been analyzed by dividing the patients in two groups according to the fibrosis level on the finger. In the group with mild fibrosis, 83.4% of DUs resulted with showing complete healing while, in the group with severe fibrosis, only 18% of DUs were healed (P = 0.024).. The treatment with iloprost plus bosentan is effective in determining healing of DUs in SSc patients with mild digital skin fibrosis. Conversely, the severity of skin fibrosis strongly influences the healing process of DUs. The study confirmed the efficacy of bosentan to prevent onset of new DUs.

Topics: Adult; Bosentan; Female; Fingers; Humans; Iloprost; Leg; Male; Middle Aged; Retrospective Studies; Scleroderma, Localized; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Treatment Outcome; Wound Healing

To quantify in patients with systemic sclerosis (SSc) the absolute nailfold capillary number/mm (the absolute number of capillaries, observable in the first row, in 1 mm per field) and fingertip blood perfusion (FBP) during longterm therapy with the endothelin receptor antagonist bosentan (BOSE) and the synthetic analog of prostacyclin PGI. Thirty patients with SSc already receiving intravenous ILO (80 μg/day) for 5 continuous days (every 3 mos) were recruited in the clinic. Fifteen patients continued such treatment (ILO group), while in 15 patients BOSE (125 mg twice/day) was added (ILO + BOSE group) because of the onset of pulmonary arterial hypertension or digital ulcers (DU). The followup period was 4 years (T0-T4). Every year the following were evaluated: absolute nailfold capillary number/mm by nailfold videocapillaroscopy, FBP by laser Doppler flowmetry, DU incidence, DLCO, systolic pulmonary arterial pressure (sPAP), renal arterial resistive index, and other biomarkers. From T2 to T4, laser speckled contrast analysis was added. Nonparametric tests were used for statistical analysis.. Limited to the ILO + BOSE group, absolute capillary number/mm and FBP showed a progressive increase independently from other variables. In addition, during followup there was a significant reduction (80%) in the incidence of new DU, whereas DLCO and sPAP did not worsen.. The study shows in patients with SSc with up to 4 years of combined therapy a progressive significant recovery in structure and function of microvasculature linked to improved clinical outcomes, independent of disease severity.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Bosentan; Capillaries; Drug Therapy, Combination; Female; Fingers; Humans; Iloprost; Male; Microscopic Angioscopy; Middle Aged; Prospective Studies; Regional Blood Flow; Scleroderma, Systemic; Sulfonamides; Treatment Outcome; Vasodilator Agents

The aim of this study was to visualize soft tissue inflammation using FOI on patients with Systemic Sclerosis (SSc) characterized by SSc-related Raynaud's phenomenon and to detect the therapeutic response to treatment with iloprost or alprostadil.. Twenty-one patients with SSc and Raynaud's phenomenon and twenty-six healthy controls were prospectively included. The SSc patients were intravenously treated with iloprost or alprostadil over seven days. FOI was performed at baseline and after seven days using an intravenous application of indocyanine green (ICG). The hands were divided into nineteen segments per hand. All segments were quantitatively evaluated to determine changes in ICG.. The sensitivity and specificity of FOI in the detection of ICG enhancement in patients with SSc were 95% versus 96%. At baseline, 31.5% hand segments showed ICG enhancement. After seven days of either iloprost or alprostadil therapy a significant reduction in the ICG was observed which ranged from 40.9% to 24.7%.. The study demonstrates that the FOI technique is able to visualize soft-tissue inflammation with both high sensitivity and specificity. The anti-inflammatory therapeutic effects of iloprost were slightly stronger than alprostadil. FOI offers promising benefits in the diagnosis and therapy of patients with SSc-associated Raynaud's phenomenon.

Topics: Adult; Alprostadil; Case-Control Studies; Female; Fluorescence; Humans; Iloprost; Indocyanine Green; Inflammation; Male; Optical Imaging; Prospective Studies; Raynaud Disease; Scleroderma, Systemic; Sensitivity and Specificity; Vasodilator Agents; Young Adult

Digital ulcers (DUs) occur in up to 50% of patients with Systemic Sclerosis (SSc). DUs are painful, recurring and lead to functional disability. Management of DUs includes pharmacologic and local therapy, the healing process is slow and the ulcer can become infected or evolve to gangrene. Autologous fat grafting (AFG) is a technique used to promote tissues repair. We used AFG to treat DUs refractory to conventional treatment to enhance healing process.. We treated 9 SSc patients for a total of 15 ulcers. All 9 patients were treated with iv Iloprost. The purified fat tissue was injected at the border of larger ulcers or at the finger base of smaller DUs. The AFG was performed from 2 to 8 months since the ulcer onset.. Complete healing occured in 10 DUs and size reduction ≥50% in 2, within 8-12 weeks. In all but 2 patients the pain improved allowing a reduction of analgesics. In the majority of the cases AFG was able to hasten ulcer healing and to reduce pain and the need of pharmacological therapy. The lack of efficacy on healing and pain reduction was observed when the ulcers were long-lasting, located on legs and with concurrent atherosclerotic macroangiopathy.. Surgical resective treatment for finger ulcers in patients affected by SSc is fraught with morbidity and long prolonged recovery. This study introduces a novel minimally invasive approach. The procedure is safe and effective, with short recovery time and local deficient vascularization improvement.

Topics: Adipose Tissue; Adult; Aged; Amputation, Surgical; Combined Modality Therapy; Female; Fingers; Hand Deformities, Acquired; Humans; Iloprost; Infusions, Intravenous; Italy; Male; Middle Aged; Necrosis; Plastic Surgery Procedures; Scleroderma, Systemic; Skin Ulcer; Treatment Outcome; Wound Healing

Digital ulcers (DU's) are one of the main symptoms of systemic scleroderma and occur in approximately 60% of all scleroderma patients. Due to possible complications such as infections, gangrene or amputation, they require regular medical attention and a good wound treatment by doctors and nursing staff. A definition of DU's has not yet been established. In 2009 the European League Against Rheumatism (EULAR) published guidelines for the treatment of DU's. An improvement of the healing of active ulcers has been described with Iloprost. Bosentan significantly reduced the frequency of occurrence of new DU's. In some small studies PDE-5 inhibitors appear helpful. Further studies with other therapeutic approaches will follow in the next few years.

Topics: Bosentan; Fingers; Hand Dermatoses; Humans; Iloprost; Phosphodiesterase 5 Inhibitors; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Wound Healing

Aim of the study was to assess whether Iloprost treatment summer suspension modifies systemic cytokines levels, cutaneous thermal properties and functional response to a cold-induced stress in patients affected by systemic sclerosis (SSc).. Twenty-eight patients fulfilling the American College of Rheumatology (ACR) criteria for SSc were included in the study. Patients recorded number, duration and pain-severity of Raynaud phenomenon (RP). Pain-severity was determined by a visual analog scale. Cytokines expression and production in peripheral blood mononuclear cells and serum were evaluated by RT-PCR and ELISA assay. Basal finger temperature (Tb), distal-dorsal difference temperature (DTdd) and thermal recovery time (tr) from cold stress were measured by means of functional infrared imaging (fIR). Measurements were performed in late spring, during routine Iloprost therapy (1-3 days infusion of 0.5-2 ng/kg every month), and in late summer after a therapy-withdrawal period.. Deterioration of SSc patients' skin thermal properties was observed in the period of therapy withdrawal (Tb reduction and tr enhancement; no DTdd differences) despite the improvement in symptoms of RP. A reduction in IL-12/23p40 gene expression was recorded after therapy withdrawal and a direct correlation between IL-12/23p40 and IL-23p19 gene expression was observed, stronger after therapy suspension.. Our data suggest that Iloprost treatment summer suspension may induce the loss of the therapy beneficial effect on microcirculation despite the objective reduction of RP, thus favouring a continuous use of Iloprost in absence of severe side effects. Iloprost showed to modulate only IL-23 expression corroborating the idea that this cytokine is crucial for SSc development and progression.

Topics: Adjuvants, Immunologic; Aged; Biomarkers; Cold Temperature; Cytokines; Female; Humans; Iloprost; Interleukin-12; Interleukin-23; Male; Middle Aged; Pain Measurement; Raynaud Disease; Scleroderma, Systemic; Seasons; Time Factors; Transforming Growth Factor beta; Treatment Outcome; Tumor Necrosis Factor-alpha; Vasodilator Agents; Withholding Treatment

Systemic sclerosis (SSc) is characterized by microvascular injury, fibrosis, and hypoxia of involved tissues. The vasoactive peptide endothelin-1 (ET-1) seems to be implicated in these events. Using nailfold videocapillaroscopy (NVC), we evaluated longterm effects of ET-1 antagonist treatment on nailfold microvascular damage in patients with SSc, over a 3-year followup period.. Thirty patients with SSc (mean age 64 ± 5 yrs, mean disease duration 8 ± 1 yrs) were recruited during their programmed standard treatment protocols. At baseline (T0), 15 patients with SSc (mean age 63 ± 15 yrs, mean disease duration 7 ± 3 yrs), already receiving cyclic intravenous infusion of iloprost (5 continuous days, average 80 μg/day, every 3 mo), continued the treatment for a further 3 years (ILO group). The remaining 15 patients with SSc (mean age 68 ± 13 yrs, mean disease duration 8 ± 4 yrs), although they continued the same cyclic intravenous iloprost treatment as the previous group, also received bosentan 125 mg twice a day for 3 years (ILO+BOS group). Qualitative analysis (scleroderma patterns) and semiquantitative scoring of the microvascular damage were performed by validated routine NVC methods.. During followup, a statistically significant increase of capillary number was observed in the ILO+BOS group (p < 0.02), with a significant and progressive increase of angiogenesis (p < 0.01). In contrast, the ILO group showed a statistically significant decrease of capillary number (p < 0.05). After 3 years the number of capillaries was significantly higher in the ILO+BOS group than in the ILO group (p < 0.05). The score for giant capillaries decreased significantly in both groups of patients with SSc (p < 0.05).. In this open study, longterm treatment with ET-1 receptor antagonist in combination with iloprost was found to interfere with progression of nailfold microvascular damage in patients with SSc, as assessed by NVC over a 3-year followup period.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Bosentan; Capillaries; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Follow-Up Studies; Humans; Iloprost; Male; Microscopic Angioscopy; Microvessels; Middle Aged; Nails; Scleroderma, Systemic; Sulfonamides; Treatment Outcome

The objective of this study was to evaluate the incidence of the most severe vascular complications, such as pulmonary arterial hypertension, scleroderma renal crisis, and digital necrosis requiring amputation, in a monocentric group of systemic sclerosis (SSc) patients cyclically treated with intravenous iloprost. We reviewed the record-charts of 115 patients affected by SSc (18 men and 97 women, mean age 58.9.1 ± 14.2 years) regularly receiving iloprost for at least 3 years; the mean duration of the treatment was 98.8 ± 37.5 months (a total of 946.8 years of therapy). Demographic and clinical features were recorded. None of the patients died of SSc-associated vascular complications. After iloprost administration digital gangrene requiring amputation developed in 2 patients who had concomitant peripheral arterial disease (a total of 3 episodes; annual incidence of 0.31 for 100 years of iloprost therapy). Four patients were diagnosed with pulmonary arterial hypertension during iloprost treatment (annual incidence of 0.42 for 100 years of drug therapy); in none of the cases did the complication show a progressive course. No cases of scleroderma renal crisis were observed. With the limits of an observational study and in the absence of a control group, our experience suggests that prolonged cyclic iloprost therapy may limit the incidence/progression of severe digital and visceral SSc-vasculopathy.

Topics: Adult; Aged; Amputation, Surgical; Familial Primary Pulmonary Hypertension; Female; Finger Injuries; Gangrene; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Peripheral Arterial Disease; Scleroderma, Systemic; Severity of Illness Index; Toes; Vasodilator Agents

Systemic sclerosis (SSc) is a chronic disease of unknown etiology which affects the vascular system and connective tissue. A wide series of studies showed an increased prevalence of cancer in patients with SSc than the normal population. Prostacyclin (PGI2) is an endogenously produced element that is basically synthesized by arachiodonic acid through prostacyclin synthesis in vascular system endothelial cells. Iloprost is a stable analogue of PGI2 which is used in the treatment of pulmonary arterial hypertension (PAH). In a limited number of animal models, the anti-metastatic activity of PGI2 is observed. Herein, we report iloprost treatment of a 60-year-old-woman with SSc, who lately developed PAH as a complication of her disease and lung adenocarcinoma as a co-incidence simultaneously. These two mortal complications were both treated successfully with inhaled iloprost until her death due to gastrointestinal complications of SSc.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Administration, Inhalation; Antihypertensive Agents; Antineoplastic Agents; Biopsy; Disease Progression; Familial Primary Pulmonary Hypertension; Fatal Outcome; Female; Gastrointestinal Diseases; Humans; Hypertension, Pulmonary; Iloprost; Immunohistochemistry; Lung Neoplasms; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Scleroderma, Systemic; Tomography, X-Ray Computed; Treatment Outcome; Vasodilator Agents

Topics: Bosentan; Botulinum Toxins, Type A; Calcium Channel Blockers; Education, Medical, Continuing; Endothelin Receptor Antagonists; Evidence-Based Medicine; Female; Fingers; Humans; Iloprost; Ischemia; Life Style; Middle Aged; Orthopedics; Phosphodiesterase 5 Inhibitors; Prostaglandins; Randomized Controlled Trials as Topic; Raynaud Disease; Scleroderma, Systemic; Sulfonamides; Vascular Resistance; Vasodilator Agents

Among pleiotropic effects, the capacity of prostaglandin I(2) (PGI(2)) analogues to affect adaptive immunity remains poorly characterised. The purpose of this study was to assess whether PGI(2) analogues could affect T helper (Th) cell responses in patients with systemic sclerosis (SSc) and healthy donors (HD).. Peripheral blood mononuclear cells (PBMC) were obtained from 33 patients with SSc and 29 HD. Cytokine levels in PBMC and monocyte/CD4 T cell cultures were quantified by immunoassays. The frequencies of interleukin (IL)-17A, IL-22, interferon γ (IFNγ) and IL-4-producing CD4 T cells were assessed by multiparametric flow cytometry. Selective receptor antagonists, cytokine blocking antibodies and signalling protein inhibitors were used to identify the receptors and signalling pathways mediating PGI(2) analogue effects.. Th17 and Th22 cells were more abundant in individuals with SSc than in HD. PGI(2) analogues (iloprost, treprostinil and beraprost) significantly increased IL-17A and IL-22 in vitro while decreasing IFNγ production both in SSc and HD PBMC. These effects relied on the specific expansion of Th17 and Th22 and inhibition of Th1 cells. The enhanced Th17 cell responses depended on increased IL-23 production by monocytes, involved the IP prostacyclin receptor and required protein kinase A activation. Importantly, in vivo administration of iloprost in individuals with SSc presenting with digital ulcers resulted in a significant increase in the frequency of Th17 cells.. These findings demonstrate that PGI(2) analogues affect Th cell differentiation/expansion programmes, favouring Th17 and inhibiting Th1 cell responses in SSc. The impact of these changes on the disease course needs to be taken into consideration and further exploited to improve SSc.

Topics: Adaptive Immunity; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Cell Proliferation; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Epoprostenol; Female; Humans; Iloprost; Interferon-gamma; Interleukin-17; Interleukin-22; Interleukin-23 Subunit p19; Interleukins; Male; Middle Aged; Monocytes; Platelet Aggregation Inhibitors; Scleroderma, Systemic; Th1 Cells; Th17 Cells; Young Adult

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

Topics: Humans; Hypertension, Pulmonary; Iloprost; Scleroderma, Systemic; Skin Ulcer; Ulcer

The European League Against Rheumatism/EULAR Scleroderma Trials and Research group (EULAR/EUSTAR) has published recommendations for the management of systemic sclerosis (SSc). Members of the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group were surveyed regarding their level of agreement with the recommendations.. A survey containing the 14 EULAR/EUSTAR recommendations asked participants to indicate their level of agreement with each on a 10-point scale, from 0 (not at all) to 9 (completely agree). The survey was sent to 117 people, and 66 replies were received (56% response rate).. Exceptions to generally high agreement included the use of iloprost and bosentan for digital vasculopathy, methotrexate for skin involvement, and bosentan and epoprostenol for pulmonary arterial hypertension (PAH; all < 69% agreement, defined as ≥ 7 rating). Vasculopathy and PAH treatment had differences in agreement between North America and Europe (p < 0.006). Respondents who were EULAR/EUSTAR recommendation authors shared a similar level of agreement compared to those who were not, except for the use of proton pump inhibitors for the prevention of SSc-related gastroesophageal reflux disease, esophageal ulcers, and strictures.. EULAR/EUSTAR recommendations were relatively well accepted among SSc experts. Overall reduced agreement may be due to the modest efficacy of some agents (such as methotrexate for the skin). Some regional disagreement is likely because of access differences.

Topics: Bosentan; Canada; Epoprostenol; Europe; Health Surveys; Humans; Hypertension, Pulmonary; Iloprost; Methotrexate; North America; Practice Guidelines as Topic; Scleroderma, Systemic; Skin Diseases; Societies, Medical; Sulfonamides; Treatment Outcome; Vascular Diseases

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Bosentan; Drug Therapy, Combination; Female; Fingers; Humans; Iloprost; Infusions, Intravenous; Male; Middle Aged; Retrospective Studies; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Time Factors; Treatment Outcome; Vasodilator Agents; Wound Healing; Young Adult

Topics: Female; Fingers; Health Care Costs; Hospitalization; Humans; Iloprost; Injections, Intravenous; Male; Middle Aged; Pilot Projects; Retrospective Studies; Scleroderma, Systemic; Skin Ulcer; Social Responsibility; Vasodilator Agents

To investigate possible correlations between fingertip blood perfusion (FBP) status, assessed by laser Doppler flowmetry (LDF), and morphological microvascular abnormalities, detected by nailfold videocapillaroscopy (NVC), in patients with systemic sclerosis (SSc). The effects on FBP of intravenous (IV) treatment with the prostacyclin analog iloprost were also investigated.. Thirty-four consecutive patients with SSc and 16 healthy subjects were evaluated. LDF was performed by analyzing blood perfusion at the fingertips in both hands. Patients with SSc were distributed into the appropriate NVC pattern of microangiopathy (early, active, and late). Iloprost was administered to inpatients with SSc by 24-hour IV infusion for 7 consecutive days (4 microg/h).. FBP was significantly lower in patients with SSc (p < 0.05) compared to controls. Heating of the LDF probe at 36 degrees C induced a significant increase of FBP in all subjects (p < 0.001), but the slope of variation was significantly lower in patients with SSc compared to controls (p < 0.05). Patients with SSc showing the late NVC pattern of microangiopathy had significantly lower FBP than patients with the active and early NVC patterns (p < 0.05). A negative correlation was observed between FBP and NVC rating of the microvascular damage (p < 0.05). After iloprost treatment, a significant increase of FBP was observed in patients with SSc (p < 0.05).. Patients with SSc show a decreased FBP partially reversible by local skin heating. The FBP correlated negatively with the extent of nailfold microvascular damage, and IV iloprost treatment increased the FBP.

Topics: Capillaries; Female; Humans; Hyperthermia, Induced; Iloprost; Injections, Intravenous; Laser-Doppler Flowmetry; Microcirculation; Microscopic Angioscopy; Middle Aged; Nails; Raynaud Disease; Scleroderma, Systemic; Vasodilation; Vasodilator Agents

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.

Topics: Female; Fingers; Humans; Iloprost; Ischemia; Male; Middle Aged; Raynaud Disease; Risk Factors; ROC Curve; Scleroderma, Systemic; Skin; Ulcer; Vasodilator Agents

Systemic sclerosis is a connective tissue disorder with unclear aetiology and pathogenesis. However, there is evidence that microvascular changes belong to the early symptoms of the disease. These are associated with increased serum levels of markers of endothelium activation, such as adhesion molecules and growth factors. The stable prostacyclin analogue iloprost is licensed for vascular symptoms (Raynaud's phenomenon) and was recently shown to exert short-term effects on these markers. In this study, serum samples (n = 13) from patients with systemic sclerosis were examined for serum levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1, E-selectin, endothelin-1 and vascular endothelial growth factor over 6 months after iloprost infusions in order to detect possible long-term effects. Iloprost significantly reduced initially elevated levels of these markers, partly until the end of the observation period (E-selectin, VCAM-1, endothelin-1). These effects provide serological evidence for the benefits of iloprost infusions that are seen clinically in patients with systemic sclerosis.

Topics: Adult; Aged; Biomarkers; E-Selectin; Endothelin-1; Female; Humans; Iloprost; Infusions, Intravenous; Intercellular Adhesion Molecule-1; Middle Aged; Scleroderma, Systemic; Statistics, Nonparametric; Time Factors; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A; Vasodilator Agents

Altered angiogenesis is a characteristic feature in SSc and remains ill-understood. VEGF is believed to play a central role. Serum VEGF is elevated in SSc patients but questions remain concerning the source of circulating VEGF. Here we investigated platelet activation and the role of platelets as a source of VEGF and other angiogenic mediators in this disease.. A cohort of 40 patients with SSc was included. Age- and sex-matched healthy subjects and subjects presenting a primary RP were included as controls. Platelets were isolated, activated with thrombin and the secretion of VEGF, platelet derived growth factor, homodimeric form BB (PDGF-BB), TGF-beta1 and angiopoietins-1 and -2 measured. Plasma concentrations of these mediators and the functionality of platelet-derived VEGF were also studied. Platelet activation was assayed by measuring plasma beta-thromboglobulin and expression of P-selectin on platelets. The effect of iloprost on VEGF secretion by platelets was studied.. Platelets from SSc patients, in contrast to controls, secreted large amounts of VEGF when activated, but not PDGF-BB, TGF-beta1 or angiopoietins. Increased expression of membrane P-selectin confirmed platelet activation in the patients. Iloprost inhibited VEGF secretion by platelets both in vivo and in vitro, through inhibition of platelet activation.. Platelets transport high levels of VEGF in SSc. They may contribute to circulating VEGF because of ongoing activation in the course of the disease. If activated at the contact of injured endothelium, platelets may be important in the altered angiogenesis associated with the disease through the secretion of high levels of VEGF.

Topics: Angiopoietin-1; Angiopoietin-2; Becaplermin; Biological Transport; Blood Platelets; Cells, Cultured; Female; Humans; Iloprost; Male; Neovascularization, Pathologic; Platelet Activation; Platelet Aggregation Inhibitors; Platelet-Derived Growth Factor; Prospective Studies; Proto-Oncogene Proteins c-sis; Scleroderma, Systemic; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Topics: Bosentan; Fingers; Humans; Iloprost; Scleroderma, Systemic; Skin Ulcer; Sulfonamides; Vasodilator Agents

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

Topics: Adult; Bosentan; Endothelin Receptor Antagonists; Female; Fingers; Humans; Iloprost; Necrosis; Platelet Aggregation Inhibitors; Recurrence; Scleroderma, Systemic; Sulfonamides; Vasodilator Agents

Topics: Adult; Aged; Axons; Female; Humans; Iloprost; Middle Aged; Nerve Degeneration; Oxygen Consumption; Scleroderma, Systemic; Skin; 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

To evaluate by computerized digital thermometry (CDT) the effect of cyclic iloprost infusions on finger skin temperature (FST) in scleroderma patients.. Twenty-two scleroderma outpatients (one man, 21 women, mean age 54.2 years) underwent three computerized digital thermometries, the first one 3 days before a 5-day cycle of iloprost infusion, the second the day of the fifth infusion soon after the end of the therapy and the third 1 month after. FST was evaluated under basal conditions, immediately after a cold test and after an 18 min recovery period. For comparison CDT was performed in 10 sex and age matched control subjects.. FST was lower in scleroderma patients before iloprost infusion than in the control group either after cold test either at the end of the recovery period while no difference was found before the cold test. Soon after iloprost infusion and 1 month later the FST at the end of the recovery period increased from the pre-treatment value of 27.8 +/- 5.3 to 30.4 +/- 3.5 degrees C and to 30.0 +/- 4.5 degrees C, respectively (P < 0.05 for both values). No substantial differences were found concerning FST before and at the end of the cold test.. Iloprost administration for 5 days allows to normalize the FST value after cold exposition not only immediately after the infusions but even at 1 month distance from the therapy. Despite its short half-life the effect of the drug on endothelium is protracted.

Topics: Drug Administration Schedule; Female; Fingers; Follow-Up Studies; Humans; Iloprost; Infusions, Intravenous; Male; Middle Aged; Outpatients; Scleroderma, Systemic; Skin Temperature; Vasodilator Agents

Topics: Adult; Aged; Autonomic Nervous System; Electrocardiography; Female; Heart; Humans; Iloprost; Male; Middle Aged; Scleroderma, Systemic; Vasodilator Agents

Topics: Anticoagulants; Female; Heparin, Low-Molecular-Weight; Humans; Iloprost; Middle Aged; Raynaud Disease; Scleroderma, Systemic; Skin Ulcer; Vasodilator Agents

Topics: Aged; Humans; Iloprost; Infusions, Intravenous; Male; Raynaud Disease; Scleroderma, Systemic; Vasodilator Agents

To determine the prevalence of systemic sclerosis associated pulmonary arterial hypertension (SScPAH), evaluate outcome, and identify predictors of mortality in a large patient cohort.. A prospective four year follow up study of 794 patients (722 from our own unit and 72 referrals). All patients screened for PAH using a combination of echocardiography, lung function testing, and clinical assessment. Patients with suspected raised pulmonary artery systolic pressures of >35 mm Hg, carbon monoxide transfer factor (TLCO) <50% predicted, or a precipitous fall in TLCO >20% over a one year period with no pulmonary fibrosis, and patients with SSc with breathlessness with no pulmonary fibrosis found were investigated with right heart catheterisation. All patients with SScPAH were treated in accordance with current best practice.. The prevalence of PAH was 12% (89/722) by right heart catheter. The survival was 81%, 63%, and 56% at 1, 2, and 3 years from the diagnosis (in 89 patients from our own cohort and 59/72 referrals). Haemodynamic indices of right ventricular failure--raised mRAP (hazard ratio 21), raised mPAP (hazard ratio 20), and low CI (hazard ratio 11) predicted an adverse outcome There was no significant difference in survival between patients with SScPAH with (n=40) and without (n=108) pulmonary fibrosis (p=0.3).. The prevalence of SScPAH in this cohort was similar to that of other catheter based studies and lower than that of previous echo based studies. The 148 patients with SScPAH actively treated had comparable outcomes to those of the cohorts with primary pulmonary hypertension. A high mRAP was the strongest haemodynamic predictor of mortality. To improve prognosis, future treatments need to be implemented at an earlier disease stage to prevent right ventricular decompensation.

Topics: Aged; Cardiac Catheterization; Echocardiography; Epidemiologic Methods; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Pulmonary Wedge Pressure; Registries; Scleroderma, Systemic; Vasodilator Agents; Ventricular Dysfunction, Right

Iloprost is useful in the short-term treatment of severe Raynaud's phenomenon and ischaemic ulcers in patients with systemic sclerosis (SSc), but its long-term effects are largely unknown. The aim of this study was to report long-term outcome (median follow-up 36 months) in a prospective observational study of a cohort of 30 consecutive patients with SSc who received iloprost therapy with maintenance infusions every 3 weeks after an initial cycle of 5 consecutive days. At the end of the observation, compared to the pretreatment point, we observed complete healing of digital ulcers in 19/21 patients (90%), a decrease of the Raynaud's phenomenon visual analogue score from 10/10 (25th-75th percentile 7-10) to 5/10 (4-6.75) ( P <0.001) and, in patients with diffuse cutaneous involvement, of the modified Rodnan skin thickness score from 25.5 (16.5-31.5) to 16 (13.5-20) ( P = 0.02), minimal improvement of the Health Assessment Questionnaire from 0.87 (0.68-1.37) to 0.75 (0.62-1.25), which was neither statistically nor clinically significant. The forced vital capacity was not significantly changed, but the diffusion capacity corrected for the alveolar volume decreased from 71% (54-76.7) of the expected value to 62% (51.5-71) ( P = 0.02). In one patient with limited SSc a positive effect on pulmonary hypertension was observed. Six patients, after a median of 25 months of treatment and healing of digital ulcers, discontinued the therapy; after a median of 10 months ulcers did not recur in five of these six. Other reasons for discontinuation were: tolerability (1), disease progression (normotensive renal crisis: 1), and death due to intracranial haemorrhage (1). This same patient had previously suffered a central retinal vein thrombosis. In conclusion, long-term therapy with iloprost in patients with SSc has a durable effectiveness on ischaemic ulcers and Raynaud's phenomenon, but it is not possible to conclude that the natural history of the disease was modified.

Topics: Adult; Aged; Cohort Studies; Female; Fingers; Humans; Hypertension, Pulmonary; Iloprost; Ischemia; Longitudinal Studies; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Raynaud Disease; Respiratory Function Tests; Scleroderma, Systemic; Skin; Ulcer; Vasodilator Agents

We conducted this study to analyze endothelial cell function within intact thoracic aorta of the systemic sclerosis murine model, the heterozygous tight-skin mice 1: (i) assessing the distribution and activation intensity of endothelial cells, responsive to endothelium-dependent vasodilators (acetylcholine, adenosine triphosphate, bradykinin, and substance P) and Iloprost, using laser line confocal microscopy in combination with two Ca2+ fluorescent dyes; (ii) evaluating en-dothelium-dependent vasodilator- and Iloprostinduced relaxation, using isometric tension measurement; and (iii) investigating the role of nitric oxide in mediating relaxation to acetylcholine and adenosine triphosphate. The number of activated endothelial cells was significantly lower in heterozygous tight-skin mice 1, compared with controls, for adenosine triphosphate and Iloprost. Maximal increase of Ca2+ fluorescence intensity ratio in activated endothelial cells was decreased for adenosine triphosphate, bradykinin, and Iloprost, in heterozygous tight-skin mice 1. Adenosine triphosphate- and Iloprost-mediated aortic relaxation was further impaired in heterozygous tight-skin mice 1. Finally, aortic relaxation to acetylcholine and adenosine triphosphate was markedly decreased by nitric oxide synthase inhibitor in heterozygous tight-skin mice 1. This study suggests that endothelial cell receptors for endothelium-dependent vasodilators and Iloprost may not be homogeneously distributed or continuously expressed in thoracic aorta of heterozygous tight-skin mice 1, resulting in endothelium-dependent vasodilatation dysfunction. Moreover, because endothelium-dependent relaxation was highly dependent on nitric oxide release in heterozygous tight-skin mice 1, endothelium-dependent relaxation may differ from that of controls by increased production of nitric oxide. In turn, in heterozygous tight-skin mice 1, the resulting elevated nitric oxide levels may contribute to nitric oxide-mediated free radical endothelial cytotoxicity, although endothelium impairment may be related to other factors, particularly: Fbn-1 gene mutation and transforming growth factor-beta.

Topics: Acetylcholine; Adenosine Triphosphate; Animals; Aorta, Thoracic; Bradykinin; Calcium; Disease Models, Animal; Endothelium, Vascular; Iloprost; In Vitro Techniques; Isometric Contraction; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Confocal; Nitric Oxide; Nitric Oxide Synthase; Scleroderma, Systemic; Skin; Substance P; Vasodilation; Vasodilator Agents

Topics: Aged; CREST Syndrome; Female; Humans; Iloprost; Masseter Muscle; Pain; Platelet Aggregation Inhibitors; Raynaud Disease; Scleroderma, Systemic; Vasodilator Agents

Topics: Humans; Iloprost; Scleroderma, Systemic; Vasodilator Agents

Topics: Alprostadil; Angiotensin-Converting Enzyme Inhibitors; Cold Temperature; Humans; Iloprost; Microcirculation; Microscopic Angioscopy; Outcome Assessment, Health Care; Raynaud Disease; Regional Blood Flow; Scleroderma, Systemic; Vasodilator Agents

Topics: Female; Humans; Iloprost; Male; Middle Aged; Platelet Aggregation Inhibitors; Scleroderma, Systemic; Thrombosis; Vasodilator Agents

Topics: Administration, Inhalation; Breath Tests; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Nitric Oxide; Scleroderma, Systemic; Vasodilator Agents

Topics: Airway Resistance; Capillaries; Humans; Iloprost; Infusions, Intravenous; Lung; Nitric Oxide; Nitroglycerin; Pulmonary Circulation; Respiration; Scleroderma, Systemic; Tidal Volume; Vasodilator Agents

Topics: Cyclophosphamide; Epoprostenol; Humans; Iloprost; Interferon-alpha; Scleroderma, Systemic

Topics: Adult; Drug Administration Schedule; Humans; Iloprost; Infusions, Intravenous; Male; Metallurgy; Scleroderma, Systemic; Vasodilator Agents

Topics: Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intra-Arterial; Male; Pilot Projects; Scleroderma, Systemic; Time Factors; Vasodilator Agents

One of the most appealing current pathogenetic concepts is that progressive systemic sclerosis (PSS) is a reaction to repeated episodes of endothelial cell injury. Injury of small arteries and capillary endothelium initiates reactions which involve increased permeability of the vessels, platelet adherence, myointimal cell proliferation, luminal narrowing and heightened sensitivity of the vessel wall. Clinical evidence of the vessel damage is Raynaud's phenomenon, involving both skin and viscera. The Authors evaluated the effects of iloprost on Raynaud's phenomenon in patients with PSS. This drug provides prolonged vasodilation, reduces platelet aggregation and promotes endothelial lining function repair. This last pattern is of primary importance because it may stop the vicious circle: endothelial injury-platelet hyperaggregation-microangiospasm. Five females were recruited, aged 41-66 years, suffering from well-documented (ARA criteria) PSS, associated with typical Raynaud's phenomenon. The trial provided for intravenous infusion of iloprost at a rate of 1-2 ng/kg/min. First treatment consisted of six-hour infusions on six successive days. After this first treatment, weekly infusions during the winter months were carried on. Drug effectiveness was considered through subjective and objective parameters. All patients showed prominent reduction of number, duration and severity of attacks of Raynaud's phenomenon, improvement of prehensile strength, healing of finger ulcerations and improvement or normalization of digital photoplethysmography. So far, the treatment has been prolonged for years in our patients and still goes on. The side effects of iloprost (headache, flushing, nausea) have been very poor. Therefore, iloprost proved to be a valid drug in the management of Raynaud's phenomenon in patients with PSS, but the inconvenience of intravenous administration may limit its routine use.

Topics: Adult; Aged; Female; Humans; Iloprost; Infusions, Intravenous; Middle Aged; Photoplethysmography; Raynaud Disease; Scleroderma, Systemic; Time Factors

Topics: Aged; Humans; Iloprost; Middle Aged; Scleroderma, Localized; Scleroderma, Systemic

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

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: Adult; Aged; Epoprostenol; Female; Humans; Iloprost; Male; Middle Aged; Mixed Connective Tissue Disease; Platelet Aggregation; Scleroderma, Systemic

Vascular prostacyclin (PGI2) regulates platelet function and blood flow. In systemic sclerosis (SS) there is increased platelet aggregation (PA) but no information is available on the platelet/PGI2 relationship. We evaluated platelet sensitivity to a PGI2 analogue ZK36374 in 17 SS patients and 18 controls. The percentage (%) inhibition of PA was measured at two doses of ZK36374 with saline giving the 100% baseline. In the SS group 2 ng ZK36374 produced a percentage inhibition of 19 + 14 compared to a control value of 60 + 21, and 3 ng a percentage inhibition of 47 + 21 in the SS group and 82 + 20 in the controls. In 11 SS patients treated with either prostaglandin E or nifedipine the sensitivity approached normal. These data suggest that SS platelets are less sensitive to the inhibitory effect of PGI2 on PA. This may contribute to the vascular lesions of SS. Other cells are resistant to the effects of PGI2 and our findings support this picture of cellular resistance.

Topics: Adult; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Humans; Iloprost; Middle Aged; Nifedipine; Platelet Aggregation; Prostaglandins E, Synthetic; Prostaglandins, Synthetic; Raynaud Disease; Scleroderma, Systemic