Anwendungsbeschränkungen und Nebenwirkungen

Controlling the complex biological network, progressive vasculopathy and fibrosis, as well as manifestations of end-organ dysfunction are all critical considerations when determining the best treatment approach for SSc. Keywords: Scleroderma, systemic sclerosis, treatment, therapy, update Systemic sclerosis (SSc) is a multi-dimensional connective tissue disease of unknown etiology. The pathological hallmarks of this condition (e.g. fibrosis, inflammation, autoimmunity, vasculopathy) uniquely converge to cause varying degrees of organ system dysfunction and damage. The skin is the most common organ system affected in SSc, followed by the gastro-intestinal (GI) tract and then the lungs.

Erektile Dysfunktion (ED)

While SSc often presents with the onset of Raynaud phenomenon, the evolution of the disease vastly differs based on a number of defined (i.e. SSc cutaneous subtype, sex, auto-antibody profile) and yet to be defined (i.e. General treatment algorithms have been proposed [1]; however, emerging and experimental therapies are changing the land-scape of the treatment paradigm for SSc [2,3]. Selection of therapy is often guided by the extent and severity of organ involvement (Figure 1). For example, if a patient has diffuse cutaneous sclerosis and interstitial lung disease (ILD), preferred interventions would target both organ systems simultaneously.

Cite this chapter

Beyond the extent and severity of organ involvement, other factors affect treatment decisions, such as the duration of disease and its current activity. For instance, the approach to managing an SSc patient with long-standing ILD and stable lung function may contrast with the approach adopted to treat an SSc patient with new-onset ILD presenting with a decline in lung function. The latter scenario suggests active disease and would likely require a more aggressive treatment strategy, while the former scenario may require a close monitoring approach. In addition, specific patient characteristics may also contribute to treatment decisions. Factors such as sex and auto-antibody status may confer a heightened or lessened risk for the progression of disease within certain organ systems. The pathological hallmarks of this condition (e.g. fibrosis, inflammation, autoimmunity, vasculopathy) uniquely converge to cause varying degrees of organ system dysfunction and damage. The skin is the most common organ system affected in SSc, followed by the gastro-intestinal (GI) tract and then the lungs. While SSc often presents with the onset of Raynaud phenomenon, the evolution of the disease vastly differs based on a number of defined (i.e. SSc cutaneous subtype, sex, auto-antibody profile) and yet to be defined (i.e. General treatment algorithms have been proposed [1]; however, emerging and experimental therapies are changing the land-scape of the treatment paradigm for SSc [2,3].

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Selection of therapy is often guided by the extent and severity of organ involvement (Figure 1). For example, if a patient has diffuse cutaneous sclerosis and interstitial lung disease (ILD), preferred interventions would target both organ systems simultaneously. Beyond the extent and severity of organ involvement, other factors affect treatment decisions, such as the duration of disease and its current activity. For instance, the approach to managing an SSc patient with long-standing ILD and stable lung function may contrast with the approach adopted to treat an SSc patient with new-onset ILD presenting with a decline in lung function. The latter scenario suggests active disease and would likely require a more aggressive treatment strategy, while the former scenario may require a close monitoring approach. In addition, specific patient characteristics may also contribute to treatment decisions. Factors such as sex and auto-antibody status may confer a heightened or lessened risk for the progression of disease within certain organ systems. As an example, male patients with SSc have an increased risk of progression of ILD compared with female patients [4], while patients who possess the centromere antibody seem to have a decreased risk of ILD progression compared with patients who do not possess these antibodies [5]. Table 1 summarizes some of the key factors that often affect treatment decisions in SSc patients beyond the organ system affected.

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The present review describes the current, as well as late-stage, investigational therapies for SSc. While the review is organized by organ system, we encourage a holistic management approach that targets treating the patient as a whole, considering the factors outlined in Table 1. Where applicable, we will point out certain therapies that may treat multiple dimensions of this disease, as well as therapies that may be combined in potentially synergistic ways. The review will conclude with a review of the areas where more drug discovery and development are needed. This review specifically focuses on late-stage clinical trials, and therefore preclinical sildenafil pink pill and earlier stages of investigations are not in the scope of this review but have been recently summarized else-where [3,6].

1. Introduction

In a phase II study of 43 patients with dcSSc, treatment with lenabasum was associated with an improvement in the American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score (33% achieved a positive response in the lenabasum arm compared with 0% in the placebo arm) and there was a trend for a significant treatment effect on mRSS (P = 0.085) [21]. The CRISS is a composite response index derived from patients with dcSSc and is comprised of the following endpoints with differential weighting: mRSS, forced vital capacity (FVC)%-predicted, Health Assessment Questionnaire Disability Index (HAQ-DI), Patient Global Assessment, and Physician Global Assessment [22]. In the open-label extension to the Phase II study, a clinically meaningful improvement in mRSS was observed under treatment with lenabasum (−8.4 points at 6 months, −9.8 points at 12 months, and −10.7 points at 18 months), although given that there was no placebo arm in the extension study, it is unclear whether this represents a continued treatment effect versus the natural history of the disease [23]. The drug appears to be well-tolerated, and the phase III study (NCT03398837) has completed enrollment (N = 365), and the expected study completion date is in 2020. The anti-fibrotic, pirfenidone, is currently under investigation in a phase II trial for SSc-ILD (SLS III), in which a key secondary endpoint is a change in mRSS (NCT03221257).

7.2 An Old Success Story—Aspirin

An open-label phase II study of pirfenidone in SSc-ILD suggested an acceptable safety and tolerability profile of this agent [24]. In SLS III, pirfenidone is combined with upfront MMF therapy to determine whether combining an anti-fibrotic with MMF leads to an improvement in skin and lung outcomes compared with MMF alone. Nearly all patients with SSc have cutaneous involvement. The extent of cutaneous involvement varies immensely with some patients presenting with rapidly evolving diffuse cutaneous sclerosis (dcSSc) and others presenting with stable limited cutaneous sclerosis (lcSSc).

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In patients with dcSSc, skin thickening occurs in the hands and feet and extends proximally beyond the elbows or knees and often involves the trunk; whereas in patients with lcSSc, skin thickening is confined to the distal extremities, or may only affect the fingers (i.e.

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The cutaneous manifestations of SSc not only cause functional disability but they substantially contribute to pain, psychological distress, and body image dissatisfaction [8]. While the natural history of cutaneous sclerosis in dcSSc often involves a gradual improvement over time [9], randomized-controlled trials (RCTs) have demonstrated that treatment with immunosuppression can lead to a greater reduction in the extent of cutaneous sclerosis [10]. The mRSS is a measure of skin thickness and is often used as the primary outcome in clinical trials of patients with dcSSc. For instance, in Scleroderma Lung Study (SLS) I (12 months of oral cyclophosphamide [CYC] versus 12 months of placebo for SSc-ILD), patients with dcSSc randomized to CYC had an improvement in their mRSS of −5.3 at 12 months; whereas the dcSSc patients randomized to placebo group had an improvement in mRSS of only −1.7 at 12 months (P = 0.008) [10].

Auswirkungen auf die Gesellschaft

As an example, male patients with SSc have an increased risk of progression of ILD compared with female patients [4], while patients who possess the centromere antibody seem to have a decreased risk of ILD progression compared with patients who do not possess these antibodies [5]. Table 1 summarizes some of the key factors that often affect treatment decisions in SSc patients beyond the organ system affected. The present review describes the current, as well as late-stage, investigational therapies for SSc. While the review is organized by organ system, we encourage a holistic management approach that targets treating the patient as a whole, considering the factors outlined in Table 1. Where applicable, we will point out certain therapies that may treat multiple dimensions of this disease, as well as therapies that may be combined in potentially synergistic ways.

Areas covered:

The review will conclude with a review of the areas where more drug discovery and development are needed. This review specifically focuses on late-stage clinical trials, and therefore preclinical sildenafil pink pill and earlier stages of investigations are not in the scope of this review but have been recently summarized else-where [3,6]. Nearly all patients with SSc have cutaneous involvement. The extent of cutaneous involvement varies immensely with some patients presenting with rapidly evolving diffuse cutaneous sclerosis (dcSSc) and others presenting with stable limited cutaneous sclerosis (lcSSc). In patients with dcSSc, skin thickening occurs in the hands and feet and extends proximally beyond the elbows or knees and often involves the trunk; whereas in patients with lcSSc, skin thickening is confined to the distal extremities, or may only affect the fingers (i.e.

Idiopathische pulmonal-arterielle Hypertonie

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A number of studies have demonstrated that it is sensitive to change in the context of SSc clinical trials; however, it should ideally be performed by the same examiner in a trial who has experience with this assessment to reduce inter-observer variability [11]. In addition to CYC, studies have demonstrated that treatment with mycophenolate mofetil (MMF) leads to improvements in cutaneous sclerosis [12,13]. In SLS II (12 months of CYC, followed by 12 months of placebo versus 24 months of MMF), change in mRSS was a key secondary outcome and improved in a clinically meaningful manner in both treatment groups (CYC: −5.35; MMF: −4.90) [11,12]. In a post-hoc analysis comparing the MMF arm of SLS II, with the placebo arm of SLS I, patients in the MMF arm experienced a greater reduction in the extent of cutaneous sclerosis at 24 months (−4.9 versus −2.4, respectively) in all patients, and in patients with dcSSc (−6.3 versus −3.9, respectively), and this difference was statistically significant [14]. In this post-hoc analysis, mRSS was also a key secondary outcome. In light of the evidence from the aforementioned studies, MMF and CYC are often considered first-line therapies for the treatment of cutaneous sclerosis in patients with dcSSc, with CYC typically reserved for patients with severe cutaneous sclerosis who do not respond to MMF. Although the most recent EULAR treatment guidelines for SSc [15] include methotrexate as a first-line treatment for cutaneous sclerosis in SSc, the evidence for this approach is poor as there have been no RCTs comparing methotrexate sildenafil oral jelly 100mg with placebo for the treatment of cutaneous sclerosis in SSc. Hematopoietic stem cell transplant (HSCT) is a potentially viable option for patients with rapidly evolving dcSSc refractory to treatment with immunosuppression.

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2.4. Pulmonary hypertension

In light of the evidence from the aforementioned studies, MMF and CYC are often considered first-line therapies for the treatment of cutaneous sclerosis in patients with dcSSc, with CYC typically reserved for patients with severe cutaneous sclerosis who do not respond to MMF. Although the most recent EULAR treatment guidelines for SSc [15] include methotrexate as a first-line treatment for cutaneous sclerosis in SSc, the evidence for this approach is poor as there have been no RCTs comparing methotrexate sildenafil oral jelly 100mg with placebo for the treatment of cutaneous sclerosis in SSc. Hematopoietic stem cell transplant (HSCT) is a potentially viable option for patients with rapidly evolving dcSSc refractory to treatment with immunosuppression. treatment-related side effects and early treatment-related mortality) associated with this procedure, this option is typically reserved for patients with rapidly progressive cutaneous sclerosis and underlying organ involvement refractory to treatment with immunosuppression. In the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial (autologous HSCT versus monthly intravenous CYC for 12 months), the mean improvement in mRSS from baseline to 24 months was greater in the HSCT group (−19.9) than in the control group (−9.8) (P < .001) [16].

2.2. Interstitial lung disease

In the Scleroderma: Cyclophosphamide Or Transplantation (SCOT) trial (autologous HSCT versus monthly intravenous CYC for 12 months) [17], numerically more patients in the HSCT arm experienced a clinically meaningful improvement in mRSS compared with patients in the CYC arm. There was also a long-term survival benefit associated with HSCT in the SCOT trial; however, the results of the survival analysis should be interpreted with caution since the comparator arm only received CYC for 12 months, and typically patients with SSc receive immunosuppression beyond 1 year. In clinical practice, a considerable proportion of patients with dcSSc do not respond adequately or are intolerant to treatment with CYC or MMF. New treatment options are needed for patients who possess a progressive, treatment-resistant phenotype of cutaneous sclerosis. Promising therapeutic agents, such as tocilizumab [18] and abatacept [19], have failed to meet the primary endpoint of change in mRSS in RCTs, leaving an unmet clinical need (Table 2). treatment-related side effects and early treatment-related mortality) associated with this procedure, this option is typically reserved for patients with rapidly progressive cutaneous sclerosis and underlying organ involvement refractory to treatment with immunosuppression. In the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial (autologous HSCT versus monthly intravenous CYC for 12 months), the mean improvement in mRSS from baseline to 24 months was greater in the HSCT group (−19.9) than in the control group (−9.8) (P < .001) [16]. In the Scleroderma: Cyclophosphamide Or Transplantation (SCOT) trial (autologous HSCT versus monthly intravenous CYC for 12 months) [17], numerically more patients in the HSCT arm experienced a clinically meaningful improvement in mRSS compared with patients in the CYC arm. There was also a long-term survival benefit associated with HSCT in the SCOT trial; however, the results of the survival analysis should be interpreted with caution since the comparator arm only received CYC for 12 months, and typically patients with SSc receive immunosuppression beyond 1 year. In clinical practice, a considerable proportion of patients with dcSSc do not respond adequately or are intolerant to treatment with CYC or MMF. New treatment options are needed for patients who possess a progressive, treatment-resistant phenotype of cutaneous sclerosis. Promising therapeutic agents, such as tocilizumab [18] and abatacept [19], have failed to meet the primary endpoint of change in mRSS in RCTs, leaving an unmet clinical need (Table 2). In a phase II study of 43 patients with dcSSc, treatment with lenabasum was associated with an improvement in the American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score (33% achieved a positive response in the lenabasum arm compared with 0% in the placebo arm) and there was a trend for a significant treatment effect on mRSS (P = 0.085) [21]. The CRISS is a composite response index derived from patients with dcSSc and is comprised of the following endpoints with differential weighting: mRSS, forced vital capacity (FVC)%-predicted, Health Assessment Questionnaire Disability Index (HAQ-DI), Patient Global Assessment, and Physician Global Assessment [22]. In the open-label extension to the Phase II study, a clinically meaningful improvement in mRSS was observed under treatment with lenabasum (−8.4 points at 6 months, −9.8 points at 12 months, and −10.7 points at 18 months), although given that there was no placebo arm in the extension study, it is unclear whether this represents a continued treatment effect versus the natural history of the disease [23]. The drug appears to be well-tolerated, and the phase III study (NCT03398837) has completed enrollment (N = 365), and the expected study completion date is in 2020. The anti-fibrotic, pirfenidone, is currently under investigation in a phase II trial for SSc-ILD (SLS III), in which a key secondary endpoint is a change in mRSS (NCT03221257). An open-label phase II study of pirfenidone in SSc-ILD suggested an acceptable safety and tolerability profile of this agent [24].

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In SLS III, pirfenidone is combined with upfront MMF therapy to determine whether combining an anti-fibrotic with MMF leads to an improvement in skin and lung outcomes compared with MMF alone.

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