3. Conclusion

However, given the significant morbidity and mortality still associated with SSc-PAH, ongoing studies are now exploring alternative strategies, including the novel approach of combining these therapies (Table 5). [74] In addition, because approximately 50–70% of the pulmonary vasculature needs to be affected or obstructed before resting mPAP is elevated, investigators are also now exploring the treatment of exercise pulmonary hypertension (abnormal hemodynamic response to exercise), which is likely a marker of early pulmonary vascular disease. Determining whether the initiation of therapy at this earlier stage of PAH is beneficial for patients is another key focus of ongoing investigation [74]. Data from the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry suggest that patients with SSc-related PAH have a significantly shorter time to clinical worsening when treated with phosphodiesterase-5 inhibitor (PDE5i) monotherapy compared to patients treated with endothelin receptor antagonists (ERA) and PDE5i combination therapy [75]. Such data have fueled interest in the study of combination therapy for PAH in SSc.

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Upfront combination therapy with phosphodiesterase inhibitors and endothelial receptor antagonists was recently studied in the a treatment-naïve group of patients with SSc-PAH. In this multi-center, open-label, clinical trial, patients were treated for 36 weeks with tadalafil 20 mg daily and ambrisentan 5 mg daily, with medication up-titration occurring at week 4 as tolerated. Investigators then compared the change in RV mass on cardiac MRI (standard volumetric cine images) from baseline to 36-week follow-up within subjects. They found that measures of right and left ventricular systolic and diastolic function were improved after treatment. In addition, combination therapy was associated with significant improvements in RV and LV function as measured by cardiac MRI [76], suggesting that combining these medications is a promising therapeutic strategy. [74] In addition, because approximately 50–70% of the pulmonary vasculature needs to be affected or obstructed before resting mPAP is elevated, investigators are also now exploring the treatment of exercise pulmonary hypertension (abnormal hemodynamic response to exercise), which is likely a marker of early pulmonary vascular disease.

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Determining whether the initiation of therapy at this earlier stage of PAH is beneficial for patients is another key focus of ongoing investigation [74]. Data from the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry suggest that patients with SSc-related PAH have a significantly shorter time to clinical worsening when treated with phosphodiesterase-5 inhibitor (PDE5i) monotherapy compared to patients treated with endothelin receptor antagonists (ERA) and PDE5i combination therapy [75].

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Although trials comparing the efficacy of combination therapy vs. monotherapy for pulmonary hypertension in SSc are limited, one study compared the efficacy and safety of monotherapy with phosphodiesterase inhibitors (sildenafil) versus initial combination therapy with phosphodiesterase inhibitors and endothelial receptor antagonists (sildenafil and bosentan) for treatment of SSc-PAH. In this single-center, double-blind, RCT, 34 patients with SSc-PAH (Pulmonary Artery Systolic Pressures >35 mmHg by echocar-diography), with a forced vital capacity >60% were randomized to receive either sildenafil plus placebo or to combination therapy with sildenafil plus bosentan for 24 weeks. Ultimately, there were no significant changes between groups in pulmonary artery pressures at 24 weeks from baseline, or in secondary end points including change in 6 Minute Walk Distance or Time To Clinical Worsening (TTCW is defined as the first occurrence of all-cause deaths, PAH related hospitalization, worsening of symptoms defined as a decrease of >15% in 6 min walk distance and worsening of NYHA functional class); however, the investigators recommended larger, better powered studies, as combination therapy was well-tolerated in these patients [77] (NCT03053739). Because of the interest in treating early PAH, investigators have also explored the role of treating exercise-induced pulmonary hypertension (PH) in SSc.

2.4. Pulmonary hypertension

In cardiology, stress tests are increasingly utilized to better characterize hemodynamic changes, and a strong rationale now exists to suggest that a reduction in pulmonary vascular reserve may be an early signal of subclinical pulmonary hypertension [78]. Some studies now suggest that among SSc patients with normal resting mPAP, an excessive increase in mPAP during exercise coupled with an impairment in vascular dispensability may be indicative of an early stage of pulmonary vasculopathy, associated with reduced survival similar to patients with PH measured at rest [79,80]. A pilot study recently evaluated whether treatment of exercise-induced PH open-label daily ambrisentan positively affects changes in a 24-week interval in hemodynamics and exercise capacity in patients with SSc. Exercise-induced PH was defined as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. Patients had normal hemodynamics at rest and were treated with 5–10 mg of ambrisentan daily. Such data have fueled interest in the study of combination therapy for PAH in SSc. Upfront combination therapy with phosphodiesterase inhibitors and endothelial receptor antagonists was recently studied in the a treatment-naïve group of patients with SSc-PAH. In this multi-center, open-label, clinical trial, patients were treated for 36 weeks with tadalafil 20 mg daily and ambrisentan 5 mg daily, with medication up-titration occurring at week 4 as tolerated. Investigators then compared the change in RV mass on cardiac MRI (standard volumetric cine images) from baseline to 36-week follow-up within subjects. They found that measures of right and left ventricular systolic and diastolic function were improved after treatment. In addition, combination therapy was associated with significant improvements in RV and LV function as measured by cardiac MRI [76], suggesting that combining these medications is a promising therapeutic strategy. Although trials comparing the efficacy of combination therapy vs. monotherapy for pulmonary hypertension in SSc are limited, one study compared the efficacy and safety of monotherapy with phosphodiesterase inhibitors (sildenafil) versus initial combination therapy with phosphodiesterase inhibitors and endothelial receptor antagonists (sildenafil and bosentan) for treatment of SSc-PAH.

Auswirkungen auf die Gesellschaft

In this single-center, double-blind, RCT, 34 patients with SSc-PAH (Pulmonary Artery Systolic Pressures >35 mmHg by echocar-diography), with a forced vital capacity >60% were randomized to receive either sildenafil plus placebo or to combination therapy with sildenafil plus bosentan for 24 weeks.

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Patient symptoms may result from a variety of factors including underlying GI dysmotility and microbiota dysbiosis [84,85]. Recent studies have therefore focused on evaluating the role of probiotics in SSc, as well as identifying novel medications that can be used to enhance GI transit in this population. The role of probiotics in patients with GI complications and SSc is unclear. The effects of probiotics on GI symptoms and on the immune system in patients with SSc with moderate-to-severe total scores on the UCLA GIT 2.0 were recently reported [86]. Patients were randomly assigned to receive a daily dose of probiotics (several strains of Lactobacillus) or placebo for 8 weeks.

Nicht-medizinische Verwendung

Seventy-three patients were randomized to receive probiotics or placebo. While there was no difference in UCLA GIT 2.0 scores, the probiotic group showed a significant decrease in the proportion of Th17 cells compared to placebo, suggesting a possible immunomodulatory effect in SSc. In another probiotic RCT, 37 patients with SSc with a moderate to severe total score on the UCLA GIT 2.0 were randomized to receive probiotics (containing Lactobacillus and Bifidobacterium) and 36 patients were randomized to placebo. Both groups were followed for 8 weeks, completed UCLA GIT 2.0 questionnaires and HAQ-DI surveys. Because probiotics are thought to act by modulating the microbiome and the immune response, the authors also collected serum samples to explore changes in the circulating levels of Th1, Th2, Th17, and regulatory T cells. Ultimately, there were no significant changes between groups in pulmonary artery pressures at 24 weeks from baseline, or in secondary end points including change in 6 Minute Walk Distance or Time To Clinical Worsening (TTCW is defined as the first occurrence of all-cause deaths, PAH related hospitalization, worsening of symptoms defined as a decrease of >15% in 6 min walk distance and worsening of NYHA functional class); however, the investigators recommended larger, better powered studies, as combination therapy was well-tolerated in these patients [77] (NCT03053739). Because of the interest in treating early PAH, investigators have also explored the role of treating exercise-induced pulmonary hypertension (PH) in SSc. In cardiology, stress tests are increasingly utilized to better characterize hemodynamic changes, and a strong rationale now exists to suggest that a reduction in pulmonary vascular reserve may be an early signal of subclinical pulmonary hypertension [78]. Some studies now suggest that among SSc patients with normal resting mPAP, an excessive increase in mPAP during exercise coupled with an impairment in vascular dispensability may be indicative of an early stage of pulmonary vasculopathy, associated with reduced survival similar to patients with PH measured at rest [79,80]. A pilot study recently evaluated whether treatment of exercise-induced PH open-label daily ambrisentan positively affects changes in a 24-week interval in hemodynamics and exercise capacity in patients with SSc.

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The safety and efficacy of riociguat were recently evaluated in an exploratory analysis using the 12-week, phase III Pulmonary Arterial hypertension sGC-stimulator Trial (PATENT)-1, and the long-term extension PATENT-2 data. Investigators specifically examined the results of the study in the subset of patients enrolled who had PAH-associated with SSc or another defined connective tissue disease. In the prospectively planned analysis, it was determined that riociguat was well-tolerated and associated with positive trends in several endpoints, including 6-minute walk distance, and that these findings were sustained at 2 years in this patient subgroup, though further studies need to be done [82]. A similar approach was taken to examine the effects of selexipag using the GRIPHON study population, specifically looking at the subset of patients with PAH-associated connective tissue disease. Of the 334 patients with PAH from connective tissue disease in this population, 170 patients had SSc.

2.3. Raynaud phenomenon

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Placebo-controlled studies are now needed to confirm that these findings are attributable to a drug effect and to define the optimal therapeutic regimen for these patients [81]. The application of statin therapy is novel in the management of PAH. Statins have a vasoprotective effect, and may therefore add value to the management of PAH, a condition in which vascular dysfunction is prominent. The effects of rosuvastatin on ameliorating vascular dysfunction in SSc-related pulmonary hypertension were recently examined in a study of 40 patients with SSc randomized to receive either rosuvastatin or placebo. All participants completed transthoracic echocardiography, 6 minute walk tests, were categorized by WHO functional class, and had tolerability and safety monitored. The results of this phase-3 trial are not yet reported (NCT00984932). A new study is now seeking to understand patients with interstitial lung disease (ILD) and scleroderma who develop pulmonary hypertension (PH) and how they fit into the treatment schema in SSc. Investigators from National Jewish and the University of Pittsburgh are using pressure-volume loops to derive right ventriculo-vascular coupling, pulmonary impedance, and invasive cardiopulmonary exercise testing to compare the efficacy of chronic macitentan therapy in improving right ventricular hemodynamics, exercise capacity, and symptoms in scleroderma ILD-PH patients with and without PVL. As connective tissue disease-associated PAH has a relatively poor prognosis relative to PAH from other causes, recent trials have focused on identifying novel therapies to improve outcomes for such patients. The safety and efficacy of riociguat were recently evaluated in an exploratory analysis using the 12-week, phase III Pulmonary Arterial hypertension sGC-stimulator Trial (PATENT)-1, and the long-term extension PATENT-2 data.

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At week 8, there was no significant difference in total or subdomain UCLA GIT 2.0 scores between the two groups, in the HAQ-DI score, or in the proportion of Th1, Th2, and regulatory T cells; however, the probiotic group did have a significantly decreased proportion of Th17 cells compared to placebo (p = 0.003). Investigators specifically examined the results of the study in the subset of patients enrolled who had PAH-associated with SSc or another defined connective tissue disease.

Bedeutung des Handelsnamens Viagra

From sildenafil 100mg blue pill baseline to 24 weeks, significant changes were identified in mean exercise pulmonary vascular resistance, mean 6 minute walk distance, mean exercise cardiac output, mean pulmonary artery pressure, and total pulmonary resistance. Placebo-controlled studies are now needed to confirm that these findings are attributable to a drug effect and to define the optimal therapeutic regimen for these patients [81]. The application of statin therapy is novel in the management of PAH. Statins have a vasoprotective effect, and may therefore add value to the management of PAH, a condition in which vascular dysfunction is prominent. The effects of rosuvastatin on ameliorating vascular dysfunction in SSc-related pulmonary hypertension were recently examined in a study of 40 patients with SSc randomized to receive either rosuvastatin or placebo.

2.5. Gastrointestinal disease

All participants completed transthoracic echocardiography, 6 minute walk tests, were categorized by WHO functional class, and had tolerability and safety monitored. The results of this phase-3 trial are not yet reported (NCT00984932). A new study is now seeking to understand patients with interstitial lung disease (ILD) and scleroderma who develop pulmonary hypertension (PH) and how they fit into the treatment schema in SSc. Investigators from National Jewish and the University of Pittsburgh are using pressure-volume loops to derive right ventriculo-vascular coupling, pulmonary impedance, and invasive cardiopulmonary exercise testing to compare the efficacy of chronic macitentan therapy in improving right ventricular hemodynamics, exercise capacity, and symptoms in scleroderma ILD-PH patients with and without PVL. As connective tissue disease-associated PAH has a relatively poor prognosis relative to PAH from other causes, recent trials have focused on identifying novel therapies to improve outcomes for such patients. In the prospectively planned analysis, it was determined that riociguat was well-tolerated and associated with positive trends in several endpoints, including 6-minute walk distance, and that these findings were sustained at 2 years in this patient subgroup, though further studies need to be done [82]. A similar approach was taken to examine the effects of selexipag using the GRIPHON study population, specifically looking at the subset of patients with PAH-associated connective tissue disease.

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Of the 334 patients with PAH from connective tissue disease in this population, 170 patients had SSc.

Property	Description	Value	Notes
Active ingredient	Sildenafil citrate	-	Main component
Mechanism of action	PDE5 inhibitor	-	Enhances blood flow
Half-life	Approximately 4 hours	3-5 hours	Duration of effect
Absorption	Rapid, peaks in 30-120 minutes	-	After oral intake

Selexipag was associated with delayed progression of PAH, as measured by a reduction in PAH related morbidity/mortality events, and was well-tolerated among the PAH-connective tissue disease population, including patients with SSc [83]. The sildenafil generic majority of patients with SSc experience gastrointestinal tract involvement. The gastrointestinal (GI) complications of SSc are variable, and include dysmotility, sphincter dysfunction, vascular malformations, and dysbiosis, each of which is managed differently. As there are no measures of immune-mediated disease activity in the GI tract, differentiating disease activity from damage is a major challenge. Furthermore, since no proven disease-modifying therapies exist for SSc-related GI involvement, the management of SSc-GI complications is currently focused on addressing and ameliorating patient symptoms. Patient symptoms may result from a variety of factors including underlying GI dysmotility and microbiota dysbiosis [84,85]. Recent studies have therefore focused on evaluating the role of probiotics in SSc, as well as identifying novel medications that can be used to enhance GI transit in this population. The role of probiotics in patients with GI complications and SSc is unclear. The effects of probiotics on GI symptoms and on the immune system in patients with SSc with moderate-to-severe total scores on the UCLA GIT 2.0 were recently reported [86]. Patients were randomly assigned to receive a daily dose of probiotics (several strains of Lactobacillus) or placebo for 8 weeks. Seventy-three patients were randomized to receive probiotics or placebo. While there was no difference in UCLA GIT 2.0 scores, the probiotic group showed a significant decrease in the proportion of Th17 cells compared to placebo, suggesting a possible immunomodulatory effect in SSc. In another probiotic RCT, 37 patients with SSc with a moderate to severe total score on the UCLA GIT 2.0 were randomized to receive probiotics (containing Lactobacillus and Bifidobacterium) and 36 patients were randomized to placebo. Both groups were followed for 8 weeks, completed UCLA GIT 2.0 questionnaires and HAQ-DI surveys. Because probiotics are thought to act by modulating the microbiome and the immune response, the authors also collected serum samples to explore changes in the circulating levels of Th1, Th2, Th17, and regulatory T cells. At week 8, there was no significant difference in total or subdomain UCLA GIT 2.0 scores between the two groups, in the HAQ-DI score, or in the proportion of Th1, Th2, and regulatory T cells; however, the probiotic group did have a significantly decreased proportion of Th17 cells compared to placebo (p = 0.003).

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