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Prucalopride was significantly associated with more intestinal evacuations and improved orocecal transit times, as well as significant improvements in the UCLA GIT 2.0 constipation, reflux, and bloating scores, suggesting that it may be effective in treating dysmotility symptoms in SSc patients. Interestingly, buspirone, an oral 5-HT1A receptor agonist, may improve the dysfunction of the lower esophageal sphincter in patients with SSc. In an open-label trial, the effects of buspirone on esophageal motor function and symptoms in SSc patients with esophageal involvement were evaluated. All 30 patients enrolled had symptomatic esophageal involvement, despite PPI use, and underwent high-resolution manometry and CT chest for assessment of motor function and esophageal dilatation, respectively. Visual analog scales were used to score GI symptom severity.

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In the 22 patients who completed the trial, lower esophageal sphincter resting pressure significantly increased after buspirone administration. Scores for heartburn and regurgitation significantly decreased at 4 weeks compared to baseline. These findings suggest that buspirone could improve symptoms in patients with SSc who report reflux symptoms despite under-going standard treatment [88]. While several other agents have been proposed in case series to target dysmotility in SSc GI disease (e.g. IVIG, pyr-idostigmine), large prospective placebo-controlled trials are lacking and should be a focus of future research. 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. From 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].

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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.

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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. 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].

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A similar approach was taken to examine the effects of selexipag using the GRIPHON sildenafil citrate 200mg price 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. 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 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.

Anwendungsbeschränkungen und Nebenwirkungen

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). Overall, the authors concluded that probiotics did not improve GI symptoms in SSc patients [86], however the use of the UCLA GIT total score as an outcome measure may not have been a sensitive enough tool sildenafil pick up to detect improvement in symptoms of distention, bloating, and diarrhea.

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Another study, which focused on a more homogenous SSc population, recently determined that the addition of probiotics may enhance existing therapeutic GI strategies [87]. In this open-label pilot trial, investigators sought to evaluate how treatment with probiotics, antibiotics, or a combination of both compare in the management of GI symptoms in 40 SSc patients with small intestinal bacterial overgrowth (SIBO) assessed by hydrogen breath test. Patients were assigned to one of the three treatment groups (Saccharomyces boulardii, metronidazole, or combination therapy) for 24 weeks, and patient-reported outcomes were collected (NIH-GI PROMIS). Interestingly, at the end of the 2 month period, SIBO was eradicated in 55% of the combination therapy group, 33% of the probiotic group, and 25% of the antibiotic treatment group. In addition, the probiotic group and combination therapy groups had decreased diarrhea, abdominal pain, and gas, bloating, and flatulence.

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These symptomatic improvements were not identified in the antibiotic group. Reductions in expired hydrogen at 45 to 60 min were 48% and 44% in the combination group, 18% and 20% in the antibiotic group, and 53% and 60% in the probiotic groups in the first and second months, respectively (p < 0.01). These data support a role for probiotics to alleviate clinical symptoms in a subset of patients with SSc. The safety and efficacy of prucalopride, a 5HT4 sildenafil 50 mg india receptor agonist was recently demonstrated in a cross-over 2 × 2 study [67]. Patients with mild to moderately severe SSc-GI symptoms were enrolled (n = 40) and randomized 1:1 to prucalopride 2 mg/day or no treatment for 1 month and vice versa after a 2-week washout period. 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].

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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.

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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 sildenafil citrate 200mg price 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. 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 majority of patients with SSc experience gastrointestinal tract involvement.

2.1. Cutaneous sclerosis

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.

2.3. Raynaud phenomenon

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. 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.

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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. From 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].

Erektile Dysfunktion (ED)

2.5. Gastrointestinal disease

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. 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 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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Overall, the authors concluded that probiotics did not improve GI symptoms in SSc patients [86], however the use of the UCLA GIT total score as an outcome measure may not have been a sensitive enough tool sildenafil pick up to detect improvement in symptoms of distention, bloating, and diarrhea. Another study, which focused on a more homogenous SSc population, recently determined that the addition of probiotics may enhance existing therapeutic GI strategies [87]. In this open-label pilot trial, investigators sought to evaluate how treatment with probiotics, antibiotics, or a combination of both compare in the management of GI symptoms in 40 SSc patients with small intestinal bacterial overgrowth (SIBO) assessed by hydrogen breath test. Patients were assigned to one of the three treatment groups (Saccharomyces boulardii, metronidazole, or combination therapy) for 24 weeks, and patient-reported outcomes were collected (NIH-GI PROMIS). Interestingly, at the end of the 2 month period, SIBO was eradicated in 55% of the combination therapy group, 33% of the probiotic group, and 25% of the antibiotic treatment group. In addition, the probiotic group and combination therapy groups had decreased diarrhea, abdominal pain, and gas, bloating, and flatulence. These symptomatic improvements were not identified in the antibiotic group. Reductions in expired hydrogen at 45 to 60 min were 48% and 44% in the combination group, 18% and 20% in the antibiotic group, and 53% and 60% in the probiotic groups in the first and second months, respectively (p < 0.01). These data support a role for probiotics to alleviate clinical symptoms in a subset of patients with SSc.

3. Conclusion

Among patients with severe GI disease, it is important to ensure nutritional goals are met, as the prevalence of malnutrition in SSc is estimated to be between 15% and 58% [89]. A validated screening tool to assess for malnutrition is the Malnutrition Universal Screening Tool (a.k.a. ‘MUST’), and it has been recommended by some experts that all SSc patients should be screened [90,91]. This tool includes body mass index (BMI), uninten-tional weight loss in the preceding 3–6 month period, and an acute disease effect score to estimate the risk of malnutrition. The safety and efficacy of prucalopride, a 5HT4 sildenafil 50 mg india receptor agonist was recently demonstrated in a cross-over 2 × 2 study [67]. Patients with mild to moderately severe SSc-GI symptoms were enrolled (n = 40) and randomized 1:1 to prucalopride 2 mg/day or no treatment for 1 month and vice versa after a 2-week washout period. Prucalopride was significantly associated with more intestinal evacuations and improved orocecal transit times, as well as significant improvements in the UCLA GIT 2.0 constipation, reflux, and bloating scores, suggesting that it may be effective in treating dysmotility symptoms in SSc patients. Interestingly, buspirone, an oral 5-HT1A receptor agonist, may improve the dysfunction of the lower esophageal sphincter in patients with SSc.

This medication is available by prescription only.
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Sildenafil 100mg Hexal is not for recreational use.
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In an open-label trial, the effects of buspirone on esophageal motor function and symptoms in SSc patients with esophageal involvement were evaluated. All 30 patients enrolled had symptomatic esophageal involvement, despite PPI use, and underwent high-resolution manometry and CT chest for assessment of motor function and esophageal dilatation, respectively. Visual analog scales were used to score GI symptom severity. In the 22 patients who completed the trial, lower esophageal sphincter resting pressure significantly increased after buspirone administration. Scores for heartburn and regurgitation significantly decreased at 4 weeks compared to baseline.

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

These findings suggest that buspirone could improve symptoms in patients with SSc who report reflux symptoms despite under-going standard treatment [88]. While several other agents have been proposed in case series to target dysmotility in SSc GI disease (e.g. IVIG, pyr-idostigmine), large prospective placebo-controlled trials are lacking and should be a focus of future research. Among patients with severe GI disease, it is important to ensure nutritional goals are met, as the prevalence of malnutrition in SSc is estimated to be between 15% and 58% [89]. A validated screening tool to assess for malnutrition is the Malnutrition Universal Screening Tool (a.k.a.

Guidance Aspect	Recommendation	Potential Risks	Additional Advice
Take on an empty stomach	Preferably	Delayed absorption if high-fat meal	Avoid heavy meals before intake
Avoid alcohol	Yes	Increased chance of side effects	Limit or avoid alcohol
Physical activity	Adequate rest before sex	Dizziness or hypotension	Be cautious with activities
Follow prescribed dose	Strictly adhere	Overdose risk (e.g., priapism)	Consult doctor if in doubt

‘MUST’), and it has been recommended by some experts that all SSc patients should be screened [90,91]. This tool includes body mass index (BMI), uninten-tional weight loss in the preceding 3–6 month period, and an acute disease effect score to estimate the risk of malnutrition.