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Similar to other complex connective tissue diseases that employ combination therapy (e.g. systemic lupus erythematosus and rheumatoid arthritis), patients with SSc may also benefit from this approach. Research studies are therefore needed to understand the optimal timing to add on certain therapies and to determine whether this should be done upfront or whether treatments should be added sequentially over specified time frames.

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In the last decade, the number of therapeutic options available to treat the unique clinical dimensions of SSc has dramatically increased. As highlighted in this review, these agents target different aspects of the immune system and elicit differential effects on various organ systems within and between individual patients. Data from all of the clinical trials conducted to date suggest that SSc is a heterogeneous disease both in terms of manifestations and response to therapies. This heterogeneity is perhaps the most challenging component of drug discovery and development in this field. It is our opinion that future therapeutic studies should consider combining therapies that target different aspects of the immune system (e.g. In addition, improved clinical and biological phenotyping may help homogenize study cohorts to increase the likelihood of detecting significant treatment effects. Our clinical experience has shown us that certain patients derive benefit from IL-6 inhibition, even though the phase III RCT of the IL-6 inhibitor, tocilizumab, did not meet its primary endpoint. To us, this suggests that we need to do a better job of enriching study cohorts to include the patients who may derive the most benefit from the therapeutic intervention under study. While this may constrain local enrollment into studies, improved global recruitment efforts, as demonstrated in the SENSCIS trial [25], may overcome this limitation. Another hurdle in SSc therapeutics is identifying and defining objective treatment-responsive endpoints.

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While we have several valid endpoints to study ILD in SSc, endpoints for the other clinical manifestations of SSc are lacking. The GI tract is the perfect example of this.

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‘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. In patients who screen positive, referrals to a nutritionist and gastroenterologist should be considered. Supplemental enteral or parenteral nutrition may be necessary to sustain nutrition and weight in patients with severe disease [89]. An expanding pipeline of investigational therapeutic agents now exists for treating the unique clinical manifestations of SSc.

Expert opinion:

This review highlighted products in development in phase 3 and phase 4 clinical trials. However, our growing understanding of the pathogenesis of SSc supports the clinical application of several novel therapies, including anti-fibrotic therapies and biologic agents. While these interventions have the potential to change the clinical course of the disease, determining the optimal drug and/or combination of drugs will remain an ongoing focus of future work. In addition, the early identification of organ involvement and application of targeted therapy, prior to the development of severe organ damage, will remain an important priority. We remain optimistic that current drug development and clinical trials will continue to yield promising therapeutic strategies for improving health outcomes for all patients with SSc. How can we determine whether biologics or anti-fibrotics modify the course of GI disease in SSc if no valid, objective SSc-GI endpoints exist? To this end, we are currently conducting studies to investigate whether the GI microbiome may be a marker of GI disease activity in SSc.

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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 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.

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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.

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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 sildenafil citrate drug 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. However, additional dedicated research efforts primarily aimed at developing and validating endpoints in SSc are greatly needed.

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

Finally, a significant unmet therapeutic need in SSc is prevention. The collective efforts to halt inflammation, fibrosis, and vascular changes in SSc are typically initiated after there is already evidence of end-organ damage (i.e.

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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.

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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 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.

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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). loss of lung function, renal insufficiency, etc.).

• The medication may cause a burning sensation or rash.
• It’s not recommended for use in women.
• Sildenafil is sometimes used off-label for pulmonary hypertension.
• Do not share your medication with others.
• Monitor blood pressure regularly during use.

Furthering our knowledge of the pathobiology of SSc may help uncover treatment targets that could curtail the progression of early SSc.

• The medication is often prescribed for age-related erectile issues.
• Avoid grapefruit or grapefruit juice while using this drug.
• It may cause mild headaches or indigestion.
• Not suitable for women or children.
• Discontinue use if adverse reactions occur.

The goal here would be to intervene early with an agent that could selectively target key mediators of profibrotic and proinflammatory pathways to reduce the likelihood of a patient developing specific clinical manifestations of SSc, such as ILD.

• Sildenafil 100mg Hexal may cause interactions with blood pressure medicines.
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• Report any chest pain or prolonged erection immediately.
• The medication can cause flushing or nasal congestion.
• Follow your healthcare provider’s instructions precisely.

In summary, despite the fact that the number of clinical trials in SSc has increased in recent years, there is still a great deal more work to do in SSc research to: (a) understand the optimal timing to initiate therapy in SSc; (b) discover how to combine therapies; (c) improve our ability to phenotype patients; (d) define new disease-specific endpoints; and (e) determine the best preventative treatment strategies.

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