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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diarrhea, and 9 developed transient hypotension during the infusion at 20 ml/h that ameliorated when the drug was withdrawn.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. [ABSTRACT FROM AUTHOR]

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

Bosentan, a dual endothelin receptor antagonist, may reduce blood pressure by blocking the vasoconstrictor effect of endothelin-1. In systemic sclerosis (SSc) nailfold videocapillaroscopy (NVC); allows diagnostic and follow-up of microvascular damage. Distinct NVC patterns have been identified for the evaluation of severity of SSc microvascular damage. The objective of this study is to evaluate the modification of the microvasculature under Bosentan therapy in SSc patients with pulmonary arterial hypertension (PAH). Nine patients with PAH related to SSc in New York Heart Association classes III-IV were treated with Bosentan 125 mg twice a day. NVC optical probe videocapillaroscopy equipped with 100× and 200× contact lenses and connected to image analyse software was performed before and after 12 months of Bosentan therapy to evaluate the modification of microvasculature. Nine PAH SSc patients treated with Iloprost were used as controls. Before Bosentan therapy, seven patients showed at NVC severe loss of capillaries with large avascular areas and vascular architectural disorganisation which are typically 'late' SSc pattern. After 12 months of Bosentan, NVC pattern changed in seven patients from 'late' into 'active' SSc pattern. The disappearance of avascular areas and capillary haemorrhages was the most striking result. Two patients had an 'active' SSc pattern, not modified by Bosentan treatment. These data show that Bosentan may improve NVC pattern in SSC and the presence of new capillaries suggests that it may favour angiogenesis. Bosentan may improve and stabilise the microvasculature in long-term treatment modulating the structural modifications detected by NVC. [ABSTRACT FROM AUTHOR]

Introduction: 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. Method: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Abstract: Raynaud's phenomenon (RP) is a functional vascular disorder involving extremities. In his practice, the dermatologist may frequently encounter RP which affects mainly women and is categorized into a primary benign form and a secondary form associated with different diseases (infections, drugs, autoimmune and vascular conditions, haematologic, rheumatologic and endocrinologic disorders). Still today, the differential diagnosis is a clinical challenge. Therefore, a careful history and a physical examination, together with laboratory tests and nailfold capillaroscopy, is mandatory. RP is generally benign, but a scheduled follow‐up for primary RP patients should be established, due to risk of evolution to secondary RP. A combination of conservative measures and medications can help in the management of RP. The importance of avoiding all potential physical, chemical and emotional triggers, as well as quitting smoking, should be strongly suggested to the patient. As first‐line treatment, dihydropyridine calcium channel blockers should be used. If this approach is not sufficient, prostacyclin derivatives, phosphodiesterases inhibitors and endothelin receptor antagonists can be considered as second‐line treatment. In cases of acute ischaemia, nifedipine and intravenous prostanoids are helpful. In refractory cases, botulinum injections have shown a significant benefit. The approach to the RP patients requires therefore a coordinated care of specialists together with the primary care physician. [ABSTRACT FROM AUTHOR]

Haemophilic arthropathy ( HA) is characterized by chronic proliferative synovitis leading to cartilage destruction and shares some pathological features with rheumatoid arthritis ( RA). Apoptosis has been implicated in RA pathogenesis, and an agonistic anti-Fas monoclonal antibody ( mAb) was found to induce RA fibroblast-like synoviocyte ( FLS) apoptosis and suppress synovial hyperplasia in animal models of RA. The aim of this study was to evaluate the effect of anti-Fas mAb on HA- FLS. FLS were isolated from knee synovial biopsies from six HA patients, six RA patients and six healthy subjects. The expression of Fas in synovial biopsies was investigated by immunohistochemistry. FLS were stimulated with anti-Fas mAb at different concentrations, alone or in combination with tumour necrosis factor-α ( TNF-α) and basic fibroblast growth factor ( bFGF). Fas expression in FLS was assessed by Western blot. Cell viability was studied with the WST-1 assay. Active caspase-3 levels were measured using ELISA and Western blot. A strong Fas-immunoreactivity was observed in different cells of HA synovium, including FLS, inflammatory cells and endothelial cells. Fas antigen was constitutively overexpressed in cultured HA- FLS. Anti-Fas mAb had a significant cytotoxicity on HA- FLS in a dose-dependent manner, either alone or in combination with TNF-α and bFGF. These cytotoxic effects were due to the ability of anti-Fas to induce HA- FLS apoptosis, as shown by the increased active caspase-3 levels. Anti-Fas mAb exhibited a more pronounced pro-apoptotic effect on HA- FLS than RA- FLS. Fas antigen is highly expressed on HA- FLS and its stimulation by anti-Fas mAb may be an effective strategy to induce HA- FLS apoptosis. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells can differentiate into endothelial cells and participate in angiogenesis in adults. In experimental models of acute myocardial infarction, mesenchymal stem cells led to the recovery of cardiac function through the formation of a new vascular network. Objective: To describe treatment with intravenous infusions of expanded autologous mesenchymal stem cells in 1 patient with critical limb ischemia due to systemic sclerosis. Design: Case report. Setting: The rheumatology unit at the University of Florence, Florence, Italy. Patient: A woman, aged 34 years, with systemic sclerosis who developed acute gangrene of the upper and lower limbs. Intervention: 3 intravenous pulses of expanded autologous mesenchymal stem cells. Measurements: Angiography, skin histopathology, and immunohistochemistry. Results: Areas of necrotic skin were reduced after the first mesenchymal stem-cell infusion. After the third infusion, angiography showed revascularization of the patient's extremities. Skin section analysis revealed cell clusters with tubelike structures, and angiogenic factors were strongly expressed. Limitation: Causality cannot be established by a single case. Conclusion: In patients with systemic sclerosis who have severe peripheral ischemia, intravenous infusion of expanded autologous mesenchymal stem cells may foster the recovery of the vascular network, restore blood flow, and reduce skin necrosis. Primary Funding Source: Fondazione Cassa di Risparmio di Pistoia e Pescia (partial funding). [ABSTRACT FROM AUTHOR]