**Pulmonary Hypertension in Systemic Sclerosis**

**Pulmonary Hypertension in Systemic Sclerosis**

DOI: 10.5772/intechopen.68535

Fleur Poelkens, Madelon C. Vonk and Annelies E. van Ede Annelies E. van Ede Additional information is available at the end of the chapter

Fleur Poelkens, Madelon C. Vonk and

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68535

### **Abstract**

The main cause of death in systemic sclerosis is interstitial lung disease, followed by pulmonary hypertension (PH). Pulmonary hypertension is the result of microvasculopathy which is caused by a disrupted healing process of endothelin damage and is featured by vasoconstriction, proliferation of arterial wall, inflammation, and fibrosis. Reclassification of pulmonary hypertension has led to five distinctive groups. In systemic sclerosis, patients may suffer from pulmonary artery hypertension (PAH, group 1), pulmonary hypertension due to interstitial lung disease (group 3), cardiac disease (group 2), and/ or thromboembolic pulmonary hypertension (group 4). Patients endure declining performance during exercise, but symptoms may be variable and nonspecific. Diagnosis is made by right heart catheterization. To select patients for this invasive procedure, several screening tools are discussed, including N-terminal pro-brain natriuretic peptide levels, uric acid levels, spirometry and diffusing capacity for carbon monoxide (DCLO), echocardiography (ECG), and the DETECT algorithm. Depending on features such as disease duration, presence of anti-centromere antibodies, and DCLO, three different flow charts for screening are presented. Based on pathophysiology, several medical treatments have been developed like prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and stimulation of the nitric oxide pathway. Combination therapy as well as lung transplantation and supportive therapy is discussed.

**Keywords:** systemic sclerosis, pulmonary hypertension, DETECT algorithm, pharmaceutical treatment (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, nitric oxide pathway)

### **1. Pulmonary hypertension**

Pulmonary hypertension (PH) is a progressive disease characterized by an elevated pulmonary arterial pressure and pulmonary vascular resistance. As a consequence of the elevated

pulmonary arterial pressure, patients are at risk of right ventricular failure and death. PH is classified in five distinctive groups with similar pathophysiology, patient characteristics, and treatment options. It can occur as a complication in patients with systemic sclerosis, and as such, it is the second main cause of death after pulmonary fibrosis in patients with systemic sclerosis. The estimated 3-year survival among patients with PH associated with systemic sclerosis is approximately 55% compared with 95% in those patients without PH [1]. The diagnosis of pulmonary arterial hypertension is defined at right heart catheterization (RHC) by a mean pulmonary arterial pressure (mPAP) of ≥ 25 mmHg. RHC should be performed in all patients in whom PH is suspected. Early diagnosis and, subsequently, treatment of PH are of utmost importance since they improves survival rates.

### **1.1. Epidemiology**

In patients with systemic sclerosis, approximately 10% develop pulmonary arterial hypertension as a complication of the disease [2, 3]. Prior to the availability of disease-specific PH therapies, the median survival for PH in patients with systemic sclerosis was 1 year following diagnosis [4]. A meta-analysis accomplished in 2013 with the inclusion of 22 studies representing 2244 patients with systemic sclerosis-associated PH showed that the current pooled survival rates after 1,2, and 3 years are respectively 81% (95% confidence interval [95% CI] 79–84%), 64% (95% CI 59–69%), and 52% (95% CI 47–58%) [5]. To note, the prognosis of PH associated with systemic sclerosis is substantially worse than patients with idiopathic pulmonary artery hypertension (PAH) [6]. PH is generally considered a late complication of the disease, but in fact, it can occur at any time following the diagnosis. In a study from Hachulla et al. [7], PH was diagnosed 6.3 ± 6.6 years after the first non-Raynaud symptom of systemic sclerosis. It was also shown that patients with early-onset PH were older at systemic sclerosis diagnosis than patients with late-onset PH (mean age, 58.0 ± 12.5 vs 46.6 ± 12.9 years), and that, early-onset PH was more severe than late-onset PH, with a lower cardiac index and greater total pulmonary resistance. Despite these differences, the mortality however was comparable between the early-onset and late-onset PH groups. In general, patients with limited cutaneous systemic sclerosis are considered to be at greater risk of PH than patients with diffuse cutaneous systemic sclerosis [8, 9]. In these studies, however, the diagnosis of PH was not always based on right heart catheterization but by Doppler echocardiography. In a retrospective cohort analysis from Nihtyanova et al. [10], it was found that the prevalence of RHC confirmed PH was similar in diffuse cutaneous systemic sclerosis (7%) and limited cutaneous systemic sclerosis (8%).

### **1.2. Classification of pulmonary hypertension**

The classification of PH went through a series of changes since the first classification was proposed in 1973 by the World Health Organization (WHO) [11]. This first meeting was organized due to the epidemic of the aminorex-induced PAH. Before this date, there was little knowledge of PH, and there were no effective drugs available resulting in a survival prognosis of several years. Despite the fact that PH was an orphan disease, significant interest from scientists with collaborative effort from the pharmaceutical industry resulted in studies focusing on pathophysiology, molecular biology, epidemiology, and clinical trials. Prompted by the attained scientific insights, the second world symposium on PH was held in Evian, France. Here, in 1998, the 'Evian' classification was proposed which consisted of five categories which shared pathophysiology, clinical patient characteristics, and pharmacological treatment options [12]. Five years after the Evian conference, the third world symposium on PH was held in Venice where several changes were made to the Evian classification. At this time, there were already three classes of drugs effective in the treatment of PH (prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors), and a specific treatment algorithm was proposed [13]. At the fourth world symposium on PH held in Dana Point, California, the Evian-Venice classification composition was refined, and a few modifications, reflecting new scientific knowledge, were added. The last world symposium on PH was held in Nice, France, in 2013. At that moment, several worldwide experts were divided into 12 task forces, each with a specific topic related to PH [14]. The task force responsible for the clinical classification proposed to include the individual categorization of the persistent PH of neonates, the addition of congenital diseases in groups 2, 3, and 5, and the shifting of PH associated with chronic hemolytic anemia from group 1 to group 5 [15]. **Table 1** shows the last updated clinical classification of pulmonary hypertension proposed in 2015 [16].

In systemic sclerosis, patients may suffer from both pulmonary artery hypertension (PAH, group 1) and from pulmonary hypertension due to interstitial lung disease (group 3), cardiac disease (group 2), and/or chronic thromboembolic pulmonary hypertension (group 4). The diagnosis and evaluation of PH is through a series of testing including pulmonary function testing, such as the measurement of DCLO, chest X-ray, high resolution computed tomography (HRCT) scan, ECG, echocardiography, cardio-pulmonary exercise test, and laboratory testing, including antinuclear antibodies, and is always confirmed by the gold standard, a right heart catheterization.

### **1.3. Pathophysiology**

pulmonary arterial pressure, patients are at risk of right ventricular failure and death. PH is classified in five distinctive groups with similar pathophysiology, patient characteristics, and treatment options. It can occur as a complication in patients with systemic sclerosis, and as such, it is the second main cause of death after pulmonary fibrosis in patients with systemic sclerosis. The estimated 3-year survival among patients with PH associated with systemic sclerosis is approximately 55% compared with 95% in those patients without PH [1]. The diagnosis of pulmonary arterial hypertension is defined at right heart catheterization (RHC) by a mean pulmonary arterial pressure (mPAP) of ≥ 25 mmHg. RHC should be performed in all patients in whom PH is suspected. Early diagnosis and, subsequently, treatment of PH are

In patients with systemic sclerosis, approximately 10% develop pulmonary arterial hypertension as a complication of the disease [2, 3]. Prior to the availability of disease-specific PH therapies, the median survival for PH in patients with systemic sclerosis was 1 year following diagnosis [4]. A meta-analysis accomplished in 2013 with the inclusion of 22 studies representing 2244 patients with systemic sclerosis-associated PH showed that the current pooled survival rates after 1,2, and 3 years are respectively 81% (95% confidence interval [95% CI] 79–84%), 64% (95% CI 59–69%), and 52% (95% CI 47–58%) [5]. To note, the prognosis of PH associated with systemic sclerosis is substantially worse than patients with idiopathic pulmonary artery hypertension (PAH) [6]. PH is generally considered a late complication of the disease, but in fact, it can occur at any time following the diagnosis. In a study from Hachulla et al. [7], PH was diagnosed 6.3 ± 6.6 years after the first non-Raynaud symptom of systemic sclerosis. It was also shown that patients with early-onset PH were older at systemic sclerosis diagnosis than patients with late-onset PH (mean age, 58.0 ± 12.5 vs 46.6 ± 12.9 years), and that, early-onset PH was more severe than late-onset PH, with a lower cardiac index and greater total pulmonary resistance. Despite these differences, the mortality however was comparable between the early-onset and late-onset PH groups. In general, patients with limited cutaneous systemic sclerosis are considered to be at greater risk of PH than patients with diffuse cutaneous systemic sclerosis [8, 9]. In these studies, however, the diagnosis of PH was not always based on right heart catheterization but by Doppler echocardiography. In a retrospective cohort analysis from Nihtyanova et al. [10], it was found that the prevalence of RHC confirmed PH was similar in diffuse cutaneous systemic sclerosis (7%) and limited cutaneous

The classification of PH went through a series of changes since the first classification was proposed in 1973 by the World Health Organization (WHO) [11]. This first meeting was organized due to the epidemic of the aminorex-induced PAH. Before this date, there was little knowledge of PH, and there were no effective drugs available resulting in a survival prognosis of several years. Despite the fact that PH was an orphan disease, significant interest from scientists with collaborative effort from the pharmaceutical industry resulted in studies focusing on pathophysiology, molecular biology, epidemiology, and clinical trials.

of utmost importance since they improves survival rates.

**1.1. Epidemiology**

2 Systemic Sclerosis

systemic sclerosis (8%).

**1.2. Classification of pulmonary hypertension**

PH is a hemodynamic abnormality of the pulmonary vasculature most often found in patients with heart and lung diseases. PH is also present in approximately 10% of the patients with systemic sclerosis [2, 3]. The consensus definition of PH, an mean pulmonary arterial pressure (mPAP) of ≥25 mm Hg, originates from the fifth world symposium on PH [17]. The normal physiological upper limit for mPAP is considered 20 mm Hg. The significance and prognosis is unknown so far in patients with a mildly elevated mPAP, that is a resting mPAP between 21 and 24 mmHg. In patients with systemic sclerosis for 3 years and 5 years after diagnosis of systemic sclerosis, respectively, 18.5% (95% CI 8.3–28.7) and 27.1% (95% CI 13.9–40.3) developed PH [18]. This implies that these patients should be carefully monitored.

PH may be due to abnormalities confined to the pulmonary arterial blood vessels (pre-capillary PH), to elevation of pulmonary venous pressure (post-capillary PH), to elevated resistance in the pulmonary capillary bed, to elevated cardiac output, or to a combination of these factors. Pre-capillary pulmonary hypertension is also called pulmonary arterial hypertension (PAH) and is considered one of the major clinical PH subtypes. In PAH, the hemodynamic hallmark states a normal pulmonary venous pressure measured as a pulmonary capillary wedge pressure (PCWP) of 15 mmHg or less and a high mPAP. As a consequence, the transpulmonary

### **1. Pulmonary arterial hypertension**

	- **1.3**. Drug- and toxin-induced

### **1.4**. Associated with


#### **1.5**. **Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH)**

	- *1.5.3*. Drugs, toxins, and radiation induced
	- *1.5.4*. Associated with:

#### **1.6**. **Persistent pulmonary hypertension of the newborn (PPHN)**

#### **2. Pulmonary hypertension due to left heart disease**


#### **3. Pulmonary hypertension owing to lung disease and/or hypoxia**


**3.5**. Alveolar hypoventilation disorders

**3.6**. Chronic exposure to high altitude

**3.7**. Developmental abnormalities

#### **4. Chronic thromboembolic pulmonary hypertension (CTEPH)**

**4.1**. Chronic thromboembolic pulmonary hypertension

**4.2**. Other pulmonary artery obstructions

*4.2.1*. Angiosarcoma

*4.2.2.* Other intravascular tumors

*4.2.3*. Arteritis

**1. Pulmonary arterial hypertension**

**1.3**. Drug- and toxin-induced

*1.4.1*. Connective tissue disease

*1.4.6*. Chronic hemolytic anemia

 *1.5.2.1*. EIF2AK mutation *1.5.2.2*. Other mutations

*1.5.4*. Associated with:

*1.5.4.2*. HIV infection

**2.3**. Valvular disease

**3.2**. Interstitial lung disease

**3.4**. Sleep-disordered breathing

*1.5.3*. Drugs, toxins, and radiation induced

**2. Pulmonary hypertension due to left heart disease**

**2.5**. Congenital/acquired pulmonary veins stenosis

**3.1**. Chronic obstructive pulmonary disease

**3. Pulmonary hypertension owing to lung disease and/or hypoxia**

**3.3**. Other pulmonary diseases with mixed restrictive and obstructive pattern

**2.1**. Left ventricular systolic dysfunction **2.2**. Left ventricular diastolic dysfunction

**1.6**. **Persistent pulmonary hypertension of the newborn (PPHN)**

*1.5.4.1*. Connective tissue disease

**1.5**. **Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH)**

**2.4**. Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

*1.2.2*. ALK1, ENG, SMAD9, CAV1, KCNK3

**1.1**. Idiopathic PAH **1.2** Heritable PAH *1.2.1*. BMPR2

4 Systemic Sclerosis

*1.2.3*. Unknown

**1.4**. Associated with

 *1.4.2*. HIV infection *1.4.3*. Portal hypertension *1.4.4*. Congenital heart disease

*1.4.5*. Schistosomiasis

*1.5.1*. Idiopathic *1.5.2*. Heritable

*4.2.4*. Congenital pulmonary arteries stenosis

*4.2.5*. Parasites (hydatidosis)

### **5. Pulmonary hypertension with unclear multifactorial mechanisms**

**5.1**. Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

**5.2**. Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis

**5.3**. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

**5.4**. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

**Table 1.** Updated clinical classification of pulmonary hypertension in 2015.

gradient is elevated as is the pulmonary vascular resistance. In post-capillary PH, also called pulmonary venous hypertension, the elevated PH is a consequence of an increased resistance to blood flow anywhere downstream from the pulmonary capillaries such as the pulmonary veins, left heart of even the systemic vasculature. This results in an elevated PCWP and most often normal transpulmonary gradient. The presence of solely a high cardiac output rarely results in marked PH since a healthy pulmonary vasculature is highly compliant. So the presence of PH in a situation with high cardiac output always suggests a pulmonary vascular defect.

In patients with systemic sclerosis, each of the PH subtypes may be present to different degrees. **Figure 1** provides a schematic view of the pulmonary vasculature and shows the anatomical location of the clinical subtypes of PH in patients with systemic sclerosis.

It is important to quantify each subtype in a patient, since it provides a prognosis for possible treatment effects. For example, PH associated with interstitial lung disease (ILD) has a worse prognosis compared to PAH in patients with systemic sclerosis [19–21]. A high mPAP in patients with systemic sclerosis can be due to proliferative pulmonary vasculopathy (PAH) featured by pulmonary artery vasoconstriction, proliferation of adventitia and intima wall, inflammation, and, ultimately, fibrosis. The PH may also be a consequence of the associated lung fibrosis due to prominent parenchymal destruction. The differentiation between PAH and pulmonary fibrosis-associated PH is sometimes difficult. In general, lung volumes

**Figure 1.** A schematic view of the pulmonary vasculature. RA: right atrium, RV: right ventricle, PAH: pulmonary arterial hypertension, ILD: interstitial lung disease, PVOD: pulmonary veno-occlusive disease, LV: left ventricle, LAP: left atrial pressure, and A: aorta.

(forced vital capacity (FVC) and/or total lung capacity (TLC)) below 60% of the predicted value indicate that PH is more likely to be associated with pulmonary fibrosis. When lung volumes (FVC and/or TLC) are above 70% of the predicted value, the PH is considered more likely to be due to PAH. For lung volumes between 60–70% of the predicted value, the cause is uncertain. Another cause of a high mPAP in patients with systemic sclerosis is pulmonary veno-occlusive disease (PVOD) [22]. This is thought to be the result of a more diffuse nature of the vascular lesions associated with systemic sclerosis and is located in the small venules of the vascular bed. Patients with PVOD often have more severe hypoxemia and a severe decrease in pulmonary diffusion capacity for carbon monoxide (DCLO). Indications for PVOD are typical radiological signs (lymph node enlargement, centrolobular ground glass opacities, and septal lines [23], hemoptysis, and severe hypoxemia). The diagnosis of PVOD is important since it may be harmful to prescribe pulmonary vasodilators since these vasodilators increase the risk for developing pulmonary edema. Also, post-capillary PH is seen in patients with systemic sclerosis, merely as a result of left ventricle diastolic dysfunction due to cardiomyopathy as indicated by an elevated PCWP > 15 mmHg [24, 25].

### **2. Diagnosis of pulmonary hypertension**

### **2.1. Physical signs and symptoms**

The first signs and symptoms of pulmonary hypertension are generally vague and nonspecific. Patients experience tiredness, fatigue, and shortness of breath when performing physical exercise or activities of daily living such as climbing stairs. These symptoms are often ascribed to having a low physical fitness. More severe symptoms such as feeling light headed during exercise, angina, syncope, and/or ankle edema only occur after extensive pulmonary vasculopathy have been developed. Also with physical examination, there are no specific abnormalities detected in patients with mild PH. Only when there is extensive pulmonary vasculopathy resulting in right heart failure, there may be physical signs including a loud P2 cardiac sound, a right ventricle third sound, a murmur of tricuspid regurgitation, raised central venous pressure, and other signs of right heart failure such as an enlarged liver and ankle edema. The lack of symptoms until the PH is already advanced often results in a striking patient and doctor's delay for diagnosis and consecutively effective treatment. As a consequence, the majority of patients at diagnosis are in functional New York Heart Association/ World Health Organization (NYHA/WHO) class III or IV (**Table 2**) [2, 26]. This is extraordinarily unfortunate since the prognosis is much worse in NYHA/WHO functional class III–IV compared to class I–II [27].

### **2.2. Screening for pulmonary hypertension**

(forced vital capacity (FVC) and/or total lung capacity (TLC)) below 60% of the predicted value indicate that PH is more likely to be associated with pulmonary fibrosis. When lung volumes (FVC and/or TLC) are above 70% of the predicted value, the PH is considered more likely to be due to PAH. For lung volumes between 60–70% of the predicted value, the cause is uncertain. Another cause of a high mPAP in patients with systemic sclerosis is pulmonary veno-occlusive disease (PVOD) [22]. This is thought to be the result of a more diffuse nature of the vascular lesions associated with systemic sclerosis and is located in the small venules of the vascular bed. Patients with PVOD often have more severe hypoxemia and a severe decrease in pulmonary diffusion capacity for carbon monoxide (DCLO). Indications for PVOD are typical radiological signs (lymph node enlargement, centrolobular ground glass opacities, and septal lines [23], hemoptysis, and severe hypoxemia). The diagnosis of PVOD is important since it may be harmful to prescribe pulmonary vasodilators since these vasodilators increase the risk for developing pulmonary edema. Also, post-capillary PH is seen in patients with systemic sclerosis, merely as a result of left ventricle diastolic dysfunction due

**Figure 1.** A schematic view of the pulmonary vasculature. RA: right atrium, RV: right ventricle, PAH: pulmonary arterial hypertension, ILD: interstitial lung disease, PVOD: pulmonary veno-occlusive disease, LV: left ventricle, LAP: left atrial

The first signs and symptoms of pulmonary hypertension are generally vague and nonspecific. Patients experience tiredness, fatigue, and shortness of breath when performing physical exercise or activities of daily living such as climbing stairs. These symptoms are often ascribed to having a low physical fitness. More severe symptoms such as feeling light headed during exercise, angina, syncope, and/or ankle edema only occur after extensive pulmonary vasculopathy have been developed. Also with physical examination, there are no specific abnormalities detected in patients with mild PH. Only when there is extensive pulmonary

to cardiomyopathy as indicated by an elevated PCWP > 15 mmHg [24, 25].

**2. Diagnosis of pulmonary hypertension**

**2.1. Physical signs and symptoms**

pressure, and A: aorta.

6 Systemic Sclerosis

Patients with systemic sclerosis are at risk of developing pulmonary hypertension. Since the first signs and symptoms of PH are nonspecific and the prognosis of patients diagnosed and treated in less advanced stages is better than those diagnosed late, in recent years, several screening programs have been developed to detect PH as early as possible. Depending on features such as disease duration, results from pulmonary function tests, and echocardiography, three different flow charts will be discussed.

In all newly diagnosed patients with systemic sclerosis, it is advised to perform a yearly screening for PH. After performing a thorough history and physical examination, patients should undergo a series of tests including pulmonary function test (including FVC, TLC, and diffusion capacity for carbon monoxide (DCLO)), chest X-ray, HRCT scan, ECG, echocardiography, and laboratory testing including antinuclear antibodies and N-terminal pro-Brain Natriuretic Peptide (N-terminal pro-BNP). Since the gold standard for diagnosing PH is right heart catheterization (RHC) an algorithm is used to indicate which patients should subsequently undergo the invasive procedure of an RHC [2, 28]. An RHC is recommended for those patients with an FVC/DCLO higher than 1.6 and/or DCLO below 60% of predicted values for those who experience shortness of breath or have a N-terminal pro-BNP more than twice the upper limit of normal (**Figure 2A**). For the patients where the echocardiography shows right atrial or right ventricle enlargement, a tricuspid regurgitant jet velocity (TRJ) higher than 2.8 m/s or a TRJ between 2.5 and 2.8 m/s with shortness of breath, it is also strongly advised to perform an RHC (**Figure 2B**).

For those patients with systemic sclerosis and a disease duration of more than 3 years and a pulmonary DCLO below 60% of the predicted value, the DETECT algorithm as described in

Class III: Marked limitations in activity due to symptoms even during a less-than-ordinary activity, for example, walking short distances (20–100 m). Comfortable only at rest.

Class IV: Severe limitations. Experiences symptoms even while *at rest*. Mostly bedbound patients.

**Table 2.** New York Heart Association/WHO functional class.

Class I: PH but no symptoms and no limitations in ordinary physical activity, for example, no shortness of breath when walking, climbing the stairs, and so on.

Class II: Mild symptoms (mild shortness of breath and/or angina) and slight limitations during ordinary activity.

**Figure 2.** Recommendations when to perform a right-heart catheterization are shown. FVC: forced vital capacity, DCLO: diffusion capacity for carbon monoxide, NT-pro-BNP N-terminal pro brain natriuretic peptide, TRJ: tricuspid regurgitation jet, RA: right atrium, RV: right ventricle, PH: pulmonary hypertension, and RHC: right heart catheterization.

**Figure 3** is advised to be conducted yearly [29]. The objective of the DETECT study was to develop the first evidence-based detection algorithm for systemic sclerosis–associated PH. This algorithm would minimize the number of missed PH diagnoses while optimizing the use of diagnostic RHC by determining those patients with systemic sclerosis that will not benefit from catheterization. In the first step of the DETECT algorithm, six relatively simple assessments are used to determine which patients should be referred for an echocardiography. These assessments are a percentage of predicted FVC divided by the percentage of predicted DCLO, the presence of telangiectasia, the presence of anti-centromere antibodies, the serum level of N-terminal pro-BNP, the serum level of urate, and whether there are signs of right-axis deviation on ECG. The total risk score can be calculated at: http://detect-pah.com. In step 2, the step 1 prediction score and two echocardiographic variables, right atrium enlargement and TRJ velocity, determine which patients should subsequently be referred for an RHC. The results from the DETECT study showed that the algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, when the European Society of Cardiology/European Respiratory Society guidelines were applied to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40% [29].

**Figure 3.** DETECT algorithm in patients with systemic sclerosis with more than 3 years of disease duration and DCLO<60%.

For those patients with systemic sclerosis with a disease duration of more than 3 years and a pulmonary diffusion capacity for carbon monoxide (DCLO) above 60% of the predicted value, a yearly screening for PH is recommended by means of a pulmonary function test, including DCLO and, serum level of N-terminal pro-BNP [28–31]. **Figure 4** displays the flow chart and recommends an echocardiography when there is a decline of more than 20% in DCLO within 1 year, a FVC/DCLO ratio below 1.6, or a N-terminal pro-BNP serum level more than twice above the upper limit of normal. Depending on the results of the echocardiography, an RHC is

**Figure 3** is advised to be conducted yearly [29]. The objective of the DETECT study was to develop the first evidence-based detection algorithm for systemic sclerosis–associated PH. This algorithm would minimize the number of missed PH diagnoses while optimizing the use of diagnostic RHC by determining those patients with systemic sclerosis that will not benefit from catheterization. In the first step of the DETECT algorithm, six relatively simple assessments are used to determine which patients should be referred for an echocardiography. These assessments are a percentage of predicted FVC divided by the percentage of predicted DCLO, the presence of telangiectasia, the presence of anti-centromere antibodies, the serum level of N-terminal pro-BNP, the serum level of urate, and whether there are signs of right-axis deviation on ECG. The total risk score can be calculated at: http://detect-pah.com. In step 2, the step 1 prediction score and two echocardiographic variables, right atrium enlargement and TRJ velocity, determine which patients should subsequently be referred for an RHC. The results from the DETECT study showed that the algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, when the European Society of Cardiology/European Respiratory Society guidelines were applied to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40% [29].

**Figure 2.** Recommendations when to perform a right-heart catheterization are shown. FVC: forced vital capacity, DCLO: diffusion capacity for carbon monoxide, NT-pro-BNP N-terminal pro brain natriuretic peptide, TRJ: tricuspid regurgitation jet, RA: right atrium, RV: right ventricle, PH: pulmonary hypertension, and RHC: right heart catheterization.

8 Systemic Sclerosis

**Figure 4.** A flow chart for screening PH in patients with systemic sclerosis with more than 3 years of disease duration and DCLO > 60%.

recommended (**Figure 2B**). When there are signs of cardiac failure without a known etiology, signs of pericardial effusion, or a strong suspicion of PH (despite a normal or slightly elevated N-terminal pro-BNP and DCLO above 60% of predicted value), an echocardiography is recommended.

### **3. Treatment of pulmonary hypertension**

The treatment of PH in patients with systemic sclerosis is a complex strategy which consists of a thorough evaluation of the severity of PH and the subsequent response to treatment. The treatment should be done by a team of experts in the field of rheumatology, cardiology, and pulmonary medicine and, in most countries, is restricted to highly specialized hospitals. Before treatment can be initiated, the NYHA/WHO group of PH should be defined in each patient. Vasoactive treatment is only indicated and reimbursed for NYHA/WHO group 1, PAH and NYHA/WHO group 4, and chronic thromboembolic pulmonary hypertension. The treatment strategy for PH can be divided into three main steps [16]. The first consists of general measures, supportive therapy, and referral to a specialized center. The second step includes the initiation of drugs approved for the treatment of PH. The final third step is related to the response to the initial treatment strategy and, in case of an inadequate response, the role of drug-combination therapy and lung transplantation. To note, the initial drug therapy, whether drug mono-therapy or drug-combination therapy for PH, depends on the NYHA/WHO functional class (**Table 2**). In patients with a severe disease (WHO functional class ≥ III), there is a high-estimated 1-year mortality and consequently the urge for a more aggressive treatment strategy [27].

In the first treatment step, general measures should be discussed with patients with systemic sclerosis–associated PH. This includes the encouragement to be physically active within symptom limits and to avoid excessive physical activity that leads to distressing symptoms [32, 33]. The exercise training programs should be conducted in centers which have experience in the care for PH patients. Since PH patients are at risk to develop pneumonia [34], vaccination against influenza and pneumococcal pneumonia is recommended. Patients should also be instructed that when (elective) surgery is necessary, the anesthesiologist is familiar with their PH and when possible local anesthesia or an epidural is preferable [35]. Furthermore, pregnancy should be avoided. As PH has a severe impact on daily living and may be life threatening, psychological, social, and emotional support is advocated [36]. One of the recommendations for supportive therapy for PH in patients with systemic sclerosis is the use of diuretics in those patients who show signs of right heart failure and fluid retention [37]. Although there are no RCTs on the use of diuretics in PH, clinical experience of experts show clear benefits. Continuous long-term oxygen (O<sup>2</sup> ) therapy is only recommended in PH patients when arterial blood O<sup>2</sup> pressure is consistently below 8 kPa [38], as in patients with chronic obstructive pulmonary disease (COPD). There are no scientific data which suggest that long-term oxygen therapy is beneficial. The evidence for the use of oral anticoagulants in patients with PH is not proven [39] despite the high prevalence of vascular thrombotic events [40] and risk factors such as heart failure, immobility, and coagulation abnormalities [41]. The final recommendation for supportive therapy is iron substitution in those patients with systemic sclerosis–associated PH with known iron deficiencies [42].

The second step in the treatment of PH consists of treatment of the underlying cause or initiating vasoactive therapy if appropriate. In patients with NYHA/WHO group 2 PH, it is due to left heart disease, optimization of cardiac function, and/or valvular disease. In patients with PH associated with lung disease, NYHA/WHO group 3, specific treatment of the cause of this disease is mandatory. PH treatment includes the initiation of drug therapy according to the evidence-based treatment algorithm [16]. In 2012, Nickel et al. [43] showed that goal-orientated therapy, a treatment strategy that uses known prognostic indicators (NYHA/ WHO functional class, N-terminal pro-BNP, cardiac index) as treatment targets resulted in better prognosis in the patients achieving these goals. Changes in these established prognostic indicators during the course of the disease provide important prognostic information. In contrast to other causes of PH, such as idiopathic PAH, there is no long-term favorable response to calcium-channel blockers in patients with systemic sclerosis associated-PH [44]. The three pathogenetic pathways targeted by drug therapy in patients with systemic sclerosis–associated PH are the endothelin pathway, the nitric oxide pathway, and the prostacyclin pathway as depicted in **Figure 5** [45].

recommended (**Figure 2B**). When there are signs of cardiac failure without a known etiology, signs of pericardial effusion, or a strong suspicion of PH (despite a normal or slightly elevated N-terminal pro-BNP and DCLO above 60% of predicted value), an echocardiography

The treatment of PH in patients with systemic sclerosis is a complex strategy which consists of a thorough evaluation of the severity of PH and the subsequent response to treatment. The treatment should be done by a team of experts in the field of rheumatology, cardiology, and pulmonary medicine and, in most countries, is restricted to highly specialized hospitals. Before treatment can be initiated, the NYHA/WHO group of PH should be defined in each patient. Vasoactive treatment is only indicated and reimbursed for NYHA/WHO group 1, PAH and NYHA/WHO group 4, and chronic thromboembolic pulmonary hypertension. The treatment strategy for PH can be divided into three main steps [16]. The first consists of general measures, supportive therapy, and referral to a specialized center. The second step includes the initiation of drugs approved for the treatment of PH. The final third step is related to the response to the initial treatment strategy and, in case of an inadequate response, the role of drug-combination therapy and lung transplantation. To note, the initial drug therapy, whether drug mono-therapy or drug-combination therapy for PH, depends on the NYHA/WHO functional class (**Table 2**). In patients with a severe disease (WHO functional class ≥ III), there is a high-estimated 1-year

mortality and consequently the urge for a more aggressive treatment strategy [27].

In the first treatment step, general measures should be discussed with patients with systemic sclerosis–associated PH. This includes the encouragement to be physically active within symptom limits and to avoid excessive physical activity that leads to distressing symptoms [32, 33]. The exercise training programs should be conducted in centers which have experience in the care for PH patients. Since PH patients are at risk to develop pneumonia [34], vaccination against influenza and pneumococcal pneumonia is recommended. Patients should also be instructed that when (elective) surgery is necessary, the anesthesiologist is familiar with their PH and when possible local anesthesia or an epidural is preferable [35]. Furthermore, pregnancy should be avoided. As PH has a severe impact on daily living and may be life threatening, psychological, social, and emotional support is advocated [36]. One of the recommendations for supportive therapy for PH in patients with systemic sclerosis is the use of diuretics in those patients who show signs of right heart failure and fluid retention [37]. Although there are no RCTs on the use of diuretics in PH, clinical experience of experts show clear benefits.

) therapy is only recommended in PH patients when arte-

pressure is consistently below 8 kPa [38], as in patients with chronic obstructive

pulmonary disease (COPD). There are no scientific data which suggest that long-term oxygen therapy is beneficial. The evidence for the use of oral anticoagulants in patients with PH is not proven [39] despite the high prevalence of vascular thrombotic events [40] and risk factors such as heart failure, immobility, and coagulation abnormalities [41]. The final recommendation for supportive therapy is iron substitution in those patients with systemic sclerosis–associated PH

is recommended.

10 Systemic Sclerosis

**3. Treatment of pulmonary hypertension**

Continuous long-term oxygen (O<sup>2</sup>

with known iron deficiencies [42].

rial blood O<sup>2</sup>

Endothelin (ET-1) is a peptide produced by endothelial cells which have vasoconstrictive and proliferative effects and is a mediator of vascular hypertrophy and fibrosis. In patients with PH, ET-1 concentrations are elevated and correlated with indices of disease severity [46]. There are two distinct receptor isoforms in the pulmonary vascular smooth muscle cells, the so-called endothelin receptor type A and B. Blocking of these ET-1 receptors by endothelin receptor antagonists (ERAs) has shown to exert beneficial effects on WHO functional class, improved hemodynamics, and an increased time to clinical worsening [47–50]. There are no head-to-head studies comparing the three available ERAs (ambrisentan, bosentan, and

**Figure 5.** Targeted medical therapy for pulmonary arterial hypertension based on the endothelin pathway, nitric oxide pathway, and prostacyclin pathway. Adapted from Humbert et al. [45]. ERA: endothelin receptor antagonist, PDE<sup>5</sup> -I: phosphodiesterase type 5 inhibitor, NO: nitric oxide, and PGI<sup>2</sup> : prostacyclin derivates.

macitentan), and they are considered to have similar efficacy. The most serious side effect of ambricentan and bosentan, but not Macitentan, is liver toxicity which was found to be dose dependent and reversible. Monthly liver function assessment is therefore recommended.

The second pathway targeted by drug therapy in patients with systemic sclerosis associated-PH is the nitric oxide (NO) pathway. NO stimulates guanylate cyclase in vascular smooth muscle cells to convert guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), which ultimately decreases intracellular calcium levels and thereby promotes vascular smooth muscle relaxation [51, 52]. As such, NO is considered a powerful vasodilator. In the pulmonary vasculature, phosphodiesterase type 5 (PDE<sup>5</sup> ) degrades cGMP. As a consequence, inhibition of PDE<sup>5</sup> by PDE<sup>5</sup> inhibitors (PDE<sup>5</sup> -i) results in vasodilation through the NO/cGMP pathway. At the moment, there are two registered PDE<sup>5</sup> -i for PH called sildenafil and tadalafil. Both sildenafil [53, 54] and tadalafil [55] have shown beneficial effects such as an improved exercise capacity and prolonged time to clinical worsening in RCTs after 12 weeks of treatment. The soluble guanylate cyclase stimulator, called riociguat, enhances cGMP production and has also shown favorable results on exercise capacity, hemodynamics, NYHA/WHO functional class, and, time to clinical worsening in patients with PH [56].

The final possible targeted pathway in the treatment of PH is the prostacyclin pathway. Prostacyclin is mainly produced by vascular endothelial cells and induces vasodilation of the vascular bed [57] and is a powerful inhibitor of platelet aggregation [58]. Prostacyclin exerts its effects by ultimately increasing the production of intracellular cyclic adenosine monophosphate (cAMP). Unfortunately, it has a very short half-life time of about 3 min. The introduction of stable analogues of prostacyclin with different pharmacokinetic properties but similar pharmacodynamic properties extended the clinical use of prostacyclins. Epoprostenol, a synthetic prostacyclin, has a short half-life time and requires cooling and continuous administration by means of an infusion pump and tunneled venous catheter. In an unblinded Randomized Controlled Trial (RCT), the effects of epoprostenol on 111 patients with PH secondary to the scleroderma spectrum of disease showed an improvement in exercise capacity, cardiopulmonary hemodynamics, and a decrease in mPAP [59]. Serious side effects such as venous catheter infections, sepsis, and pump malfunction have been described and may lead to death. Iloprost is a chemically more stable prostacyclin analogue and can be administered intravenously or via inhalation. Both inhaled iloprost [60] and intravenous iloprost [61] have shown to improve exercise capacity and clinical symptoms. Treprostenil is an analogue of epoprostenol with sufficient chemical stability to be administered without cooling. Both the subcutaneous administration and inhalation of treprostenil have shown beneficial effects in patients with PH [62, 63]. Recently, the first oral selective IP-prostacyclin receptor agonist selexipag was approved. In an event-driven study in 1156 patients, a 40% reduction of mortality and PH-associated complications were found in the selexipag-treated patients [64].

**Figure 6** shows the current treatment algorithm for systemic sclerosis associated-PH [16]. Initial drug therapy, whether drug monotherapy or drug-combination therapy for PH, depends on the NYHA/WHO functional class combined with determinants of a worse prognosis such as clinical signs of heart failure, syncope, N-terminal pro-BNP plasma levels above

**Figure 6.** A treatment algorithm for systemic sclerosis associated-PH. ERA: endothelin receptor antagonist, PDE<sup>5</sup> -I: phosphodiesterase type 5 inhibitor, and PGI<sup>2</sup> : prostacyclin derivates.

300ng/l, echocardiographic signs of right atrial enlargement, 6-min walking distance, and/or low physical fitness levels (VO2, peak oxygen consumption < 15 ml/min/kg).

### **3.1. Combination therapy**

macitentan), and they are considered to have similar efficacy. The most serious side effect of ambricentan and bosentan, but not Macitentan, is liver toxicity which was found to be dose dependent and reversible. Monthly liver function assessment is therefore recommended.

The second pathway targeted by drug therapy in patients with systemic sclerosis associated-PH is the nitric oxide (NO) pathway. NO stimulates guanylate cyclase in vascular smooth muscle cells to convert guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), which ultimately decreases intracellular calcium levels and thereby promotes vascular smooth muscle relaxation [51, 52]. As such, NO is considered a power-

by PDE<sup>5</sup>

inhibitors (PDE<sup>5</sup>

) degrades



ful vasodilator. In the pulmonary vasculature, phosphodiesterase type 5 (PDE<sup>5</sup>

tion through the NO/cGMP pathway. At the moment, there are two registered PDE<sup>5</sup>

PH called sildenafil and tadalafil. Both sildenafil [53, 54] and tadalafil [55] have shown beneficial effects such as an improved exercise capacity and prolonged time to clinical worsening in RCTs after 12 weeks of treatment. The soluble guanylate cyclase stimulator, called riociguat, enhances cGMP production and has also shown favorable results on exercise capacity, hemodynamics, NYHA/WHO functional class, and, time to clinical worsening in

The final possible targeted pathway in the treatment of PH is the prostacyclin pathway. Prostacyclin is mainly produced by vascular endothelial cells and induces vasodilation of the vascular bed [57] and is a powerful inhibitor of platelet aggregation [58]. Prostacyclin exerts its effects by ultimately increasing the production of intracellular cyclic adenosine monophosphate (cAMP). Unfortunately, it has a very short half-life time of about 3 min. The introduction of stable analogues of prostacyclin with different pharmacokinetic properties but similar pharmacodynamic properties extended the clinical use of prostacyclins. Epoprostenol, a synthetic prostacyclin, has a short half-life time and requires cooling and continuous administration by means of an infusion pump and tunneled venous catheter. In an unblinded Randomized Controlled Trial (RCT), the effects of epoprostenol on 111 patients with PH secondary to the scleroderma spectrum of disease showed an improvement in exercise capacity, cardiopulmonary hemodynamics, and a decrease in mPAP [59]. Serious side effects such as venous catheter infections, sepsis, and pump malfunction have been described and may lead to death. Iloprost is a chemically more stable prostacyclin analogue and can be administered intravenously or via inhalation. Both inhaled iloprost [60] and intravenous iloprost [61] have shown to improve exercise capacity and clinical symptoms. Treprostenil is an analogue of epoprostenol with sufficient chemical stability to be administered without cooling. Both the subcutaneous administration and inhalation of treprostenil have shown beneficial effects in patients with PH [62, 63]. Recently, the first oral selective IP-prostacyclin receptor agonist selexipag was approved. In an event-driven study in 1156 patients, a 40% reduction of mortality and PH-associated complications were found in the selexipag-treated patients [64].

**Figure 6** shows the current treatment algorithm for systemic sclerosis associated-PH [16]. Initial drug therapy, whether drug monotherapy or drug-combination therapy for PH, depends on the NYHA/WHO functional class combined with determinants of a worse prognosis such as clinical signs of heart failure, syncope, N-terminal pro-BNP plasma levels above

cGMP. As a consequence, inhibition of PDE<sup>5</sup>

patients with PH [56].

12 Systemic Sclerosis

When initial drug monotherapy in PH patients with WHO functional class I–II fails or when patients with systemic sclerosis associated-PH at first diagnoses are already in WHO functional class II–IV, combination therapy can be applied. Because of the three possible targeted pathways (ET-1-, NO-, and prostacyclin pathway), this was thought to be an attractive option [65]. Combination therapy can be applied sequentially or upfront. Sequential therapy was the most widely used strategy; in case of an inadequate response to monotherapy, a second and subsequently a third drug can be added. Several trials have been conducted which evaluated the efficacy of drug combination therapy compared to monotherapy. A recent meta-analysis on 15 RCTs, with combination of PAH-specific therapies (upfront and sequential add-ons) compared with PAH-specific monotherapy, showed a risk reduction for clinical worsening of 17 versus 28%, respectively [66]. A similar outcome was observed by a meta-analyses from Fox et al. [67] on 18 RCTs. Combination therapy was associated with a reduction in non-fatal end points, an improved 6-min walking distance, improved functional class, and pulmonary hemodynamics. So far, the strongest scientific evidence has been found for the combination therapy of ambrisentan and tadalafil in PH patients with NYHA/WHO functional class II and III [68]. Only recently, the effects of initial triple upfront combination therapy in patients diagnosed with PH has been evaluated [69]. Nineteen newly diagnosed NYHA/WHO functional class III/IV PAH patients initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan, and sildenafil) were collected retrospectively. After 4 months' triple combination therapy, 18 patients significantly improved their 6-min walking distance and hemodynamics. Seventeen patients had improved to NYHA/WHO functional class I or II but most striking was the overall estimated survival of 100% after 1, 2, and 3 years [69].

### **3.2. Lung transplantation**

When patients decline despite aggressive drug therapy and other interventions, lung transplantation can be considered. The first lung transplantation for pulmonary vascular disease was performed in 1982 at Stanford University by Dr. Reitz and colleagues [70]. The timing of transplantation is crucial and depends on several factors, including the cause of PH, stage of the disease, co-morbidities and suitability for operation, possible alternative treatments, and of course, availability of donors. Patients with systemic sclerosis were initially often denied transplantation because of concerns about the short- and long-term outcomes related to the extra-pulmonary manifestations of systemic sclerosis [71]. A systematic review performed by Khan et al. [72] addressed this issue and evaluated the survival of systemic sclerosis patients after lung transplantation. He identified seven observational studies reporting the results of approximately 185 patients with systemic sclerosis who underwent singlelung, double-lung, or heart-lung transplantation. The indication for lung transplantation was both ILD and/or PAH related. The results showed that post-transplantation survival ranged 69–91% at 30 days, 69–85% at 6 months, 59–93% at 1 year, 49–80% at 2 years, and 46–79% at 3 years. He concluded that the short-term and intermediate-term survival after lung transplantation were similar to patients with idiopathic forms of PAH and other causes of ILD requiring lung transplantation. So nowadays, systemic sclerosis is a widely accepted diagnosis for the potential necessary lung transplantation. Remarkable was the considerable variability in survival estimates. This is probably due to different selection criteria of patients and may also be related to survival differences across systemic sclerosis patients with PAH, ILD, or a combination of PAH and ILD. Future work should aim to prospectively study adults with systemic sclerosis as they are evaluated for lung transplantation in order to identify potentially modifiable risk factors that can improve transplant outcomes in this population [73].

### **Author details**

Fleur Poelkens, Madelon C. Vonk and Annelies E. van Ede\* \*Address all correspondence to: annelies.vanede@radboudumc.nl Radboud University Medical Center, Nijmegen, the Netherlands

### **References**

patients with NYHA/WHO functional class II and III [68]. Only recently, the effects of initial triple upfront combination therapy in patients diagnosed with PH has been evaluated [69]. Nineteen newly diagnosed NYHA/WHO functional class III/IV PAH patients initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan, and sildenafil) were collected retrospectively. After 4 months' triple combination therapy, 18 patients significantly improved their 6-min walking distance and hemodynamics. Seventeen patients had improved to NYHA/WHO functional class I or II but most striking was the overall

When patients decline despite aggressive drug therapy and other interventions, lung transplantation can be considered. The first lung transplantation for pulmonary vascular disease was performed in 1982 at Stanford University by Dr. Reitz and colleagues [70]. The timing of transplantation is crucial and depends on several factors, including the cause of PH, stage of the disease, co-morbidities and suitability for operation, possible alternative treatments, and of course, availability of donors. Patients with systemic sclerosis were initially often denied transplantation because of concerns about the short- and long-term outcomes related to the extra-pulmonary manifestations of systemic sclerosis [71]. A systematic review performed by Khan et al. [72] addressed this issue and evaluated the survival of systemic sclerosis patients after lung transplantation. He identified seven observational studies reporting the results of approximately 185 patients with systemic sclerosis who underwent singlelung, double-lung, or heart-lung transplantation. The indication for lung transplantation was both ILD and/or PAH related. The results showed that post-transplantation survival ranged 69–91% at 30 days, 69–85% at 6 months, 59–93% at 1 year, 49–80% at 2 years, and 46–79% at 3 years. He concluded that the short-term and intermediate-term survival after lung transplantation were similar to patients with idiopathic forms of PAH and other causes of ILD requiring lung transplantation. So nowadays, systemic sclerosis is a widely accepted diagnosis for the potential necessary lung transplantation. Remarkable was the considerable variability in survival estimates. This is probably due to different selection criteria of patients and may also be related to survival differences across systemic sclerosis patients with PAH, ILD, or a combination of PAH and ILD. Future work should aim to prospectively study adults with systemic sclerosis as they are evaluated for lung transplantation in order to identify potentially modifiable risk factors that can improve transplant outcomes in this

estimated survival of 100% after 1, 2, and 3 years [69].

Fleur Poelkens, Madelon C. Vonk and Annelies E. van Ede\*

\*Address all correspondence to: annelies.vanede@radboudumc.nl Radboud University Medical Center, Nijmegen, the Netherlands

**3.2. Lung transplantation**

14 Systemic Sclerosis

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**Provisional chapter**

### **Atherosclerosis and Cardiovascular Risk in Systemic Sclerosis Sclerosis**

**Atherosclerosis and Cardiovascular Risk in Systemic** 

Sabina Oreska and Michal Tomcik

Sabina Oreska and Michal Tomcik Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67495

### **Abstract**

Atherosclerosis (ATS) has been considered to be a degenerative disease affecting large and medium-sized arteries, resulting in a passive build-up of cholesterol in the artery wall. In the last decade, immune system was proved to play the key role in the pathogenesis of ATS, suggesting ATS to be more progressive and accelerated in chronic inflammatory conditions. Studies in patients with autoimmune diseases, particularly in the most prevalent ones such as rheumatoid arthritis and systemic lupus erythematosus, confirmed the significantly more serious atherosclerotic disease and increased cardiovascular (CV) risk compared to the general population, suggesting these diseases as an independent risk factor for CV diseases. There are only few studies evaluating ATS and CV risk in systemic sclerosis (SSc). Moreover, these studies present contradictory results. Furthermore, it is complicated to differentiate primary vascular affection related to the pathogenesis of SSc from the secondary vascular infliction due to ATS. Nevertheless, most of the studies to date suggest ATS and its clinical manifestations to be more prevalent in SSc. Future studies evaluating larger cohorts of patients are required to determine the relevance of ATS and CV disease and management of these comorbidities in SSc.

**Keywords:** atherosclerosis, cardiovascular risk, systemic sclerosis

### **1. Introduction**

Accelerated atherosclerosis (ATS) with increased cardiovascular (CV) morbidity and mortality is a well-known complication of many systemic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [1], resulting in higher rates of CV morbidity and mortality compared to general population [2, 3]. Therefore, ischemic heart disease secondary to coronary ATS is the leading cause of CV mortality in

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

RA patients and in late stages of SLE (while intercurrent infections are the leading cause in early disease) [4].

There is emerging data that the same process of early accelerated ATS occurs in systemic sclerosis (SSc). Epidemiological studies suggest that a cardiac cause contributes to approximately one-third of the non-SSc-related deaths. Moreover, deaths from CV causes occur in SSc more than a decade earlier than in the general population [5, 6].

In the 1960s and 1970s, the main cause of death in SSc was scleroderma renal crisis (SRC), whereas clinically manifested ATS was rare in SSc patients, and CV involvement was most likely the result of vasospasm of coronary arteries. Thanks to recent advances in the treatment of SRC and pulmonary arterial hypertension (PAH), causes of mortality in SSc have changed. The prevalence of ATS has increased according to recent studies in SSc patients [7–9].

Novel laboratory markers of ATS and non-invasive tools to evaluate subclinical coronary ATS and peripheral artery disease (PAD) have been described. Most of these are used mainly in experimental settings, because of their cost and only partially clear significance of some biomarkers [10].

### **2. Atherosclerosis**

Atherosclerosis (ATS) is a chronic multifactorial process evolving in the medium and large arteries. It figures as a leading cause of cardiac and non-cardiac-related morbidity and mortality worldwide [1]. According to the World Health Organization (WHO) definition, it is a variable combination of changes of the innermost layer of the artery—the intima and is associated with deposits of lipids (mainly cholesterol particles), polysaccharide molecules, and blood elements. The traditional view suggests that ATS results from a passive build-up of cholesterol in the artery wall [11]. In fact, it is a multifactorial disease that can be considered an immune/inflammatory response of intima to tissue damage [4].

Inflammation is a key component of ATS [12]. Even a relatively minor elevation of inflammatory markers (such as C-reactive protein, CRP) is predictive of CV events in the general population [13]. In ATS, endothelial cell dysfunction is the common pathway by which factors (such as elevated low-density lipoprotein (LDL), hypertension, diabetes mellitus, elevated plasma homocysteine, various infectious agents, and exposure to free radicals from smoking) are proposed to contribute to pathogenesis [12]. Endothelial dysfunction leads to upregulation of adhesion molecules on the endothelium and increased vessel wall permeability, which enables the accumulation of the foam cells, that is, lipid-laden monocytes and macrophages. Migration and proliferation of vascular smooth-muscle cells lead to remodeling of the vessel wall and atherosclerotic plaque formation [12].

Cardiovascular diseases (CVDs) have become the most frequent cause of death globally [14]. Myocardial infarction (MI) and ischemic stroke caused by ATS dominate the mortality and disability statistics in all regions of the world [15].

### **3. Atherosclerosis in rheumatic diseases**

RA patients and in late stages of SLE (while intercurrent infections are the leading cause

There is emerging data that the same process of early accelerated ATS occurs in systemic sclerosis (SSc). Epidemiological studies suggest that a cardiac cause contributes to approximately one-third of the non-SSc-related deaths. Moreover, deaths from CV causes occur in SSc more

In the 1960s and 1970s, the main cause of death in SSc was scleroderma renal crisis (SRC), whereas clinically manifested ATS was rare in SSc patients, and CV involvement was most likely the result of vasospasm of coronary arteries. Thanks to recent advances in the treatment of SRC and pulmonary arterial hypertension (PAH), causes of mortality in SSc have changed. The prevalence of ATS has increased according to recent studies in SSc

Novel laboratory markers of ATS and non-invasive tools to evaluate subclinical coronary ATS and peripheral artery disease (PAD) have been described. Most of these are used mainly in experimental settings, because of their cost and only partially clear significance of some bio-

Atherosclerosis (ATS) is a chronic multifactorial process evolving in the medium and large arteries. It figures as a leading cause of cardiac and non-cardiac-related morbidity and mortality worldwide [1]. According to the World Health Organization (WHO) definition, it is a variable combination of changes of the innermost layer of the artery—the intima and is associated with deposits of lipids (mainly cholesterol particles), polysaccharide molecules, and blood elements. The traditional view suggests that ATS results from a passive build-up of cholesterol in the artery wall [11]. In fact, it is a multifactorial disease that can be considered

Inflammation is a key component of ATS [12]. Even a relatively minor elevation of inflammatory markers (such as C-reactive protein, CRP) is predictive of CV events in the general population [13]. In ATS, endothelial cell dysfunction is the common pathway by which factors (such as elevated low-density lipoprotein (LDL), hypertension, diabetes mellitus, elevated plasma homocysteine, various infectious agents, and exposure to free radicals from smoking) are proposed to contribute to pathogenesis [12]. Endothelial dysfunction leads to upregulation of adhesion molecules on the endothelium and increased vessel wall permeability, which enables the accumulation of the foam cells, that is, lipid-laden monocytes and macrophages. Migration and proliferation of vascular smooth-muscle cells lead to remodeling of the vessel

Cardiovascular diseases (CVDs) have become the most frequent cause of death globally [14]. Myocardial infarction (MI) and ischemic stroke caused by ATS dominate the mortality and

an immune/inflammatory response of intima to tissue damage [4].

wall and atherosclerotic plaque formation [12].

disability statistics in all regions of the world [15].

than a decade earlier than in the general population [5, 6].

in early disease) [4].

24 Systemic Sclerosis

patients [7–9].

markers [10].

**2. Atherosclerosis**

Early ATS associated with autoimmune diseases is not fully explained by traditional risk factors such as obesity, smoking, or hyperlipidaemia [16–19]. The acceleration of ATS may be attributed (beside the traditional CV risk factors) also to systemic inflammation and use of proatherogenic drugs (**Table 1**) [2]. In addition, various cellular and cytokine pathways have been implicated in the pathogenesis of ATS, as an immuno-inflammatory disease [2, 12, 20–25]. The hyperactivation of the immune system leads to premature ATS, contributes to the formation of atherosclerotic plaque [3], and earlier occurrence of ATS clinical manifestations [4].

There is heterogeneity with respect to autoimmune-inflammatory risk factors. Cytokines, such as tumor necrosis factor alpha (TNF-α), and immune complexes are primarily involved in arthritis, such as RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA), as well as in SLE. On the other hand, autoantibodies including anti-oxidized low-density lipoproteins (anti-oxLDL), anti-cardiolipin (anti-CL), and anti-beta-2-glycoprotein I (antiβ2GPI) are rather involved in SLE and antiphospholipid syndrome (APS)-associated vascular conditions [26].

Autoimmune rheumatic diseases characterized by systemic inflammation and accelerated ATS are associated with various types of vasculopathies [12, 20, 27]. The characteristics of vasculopathies may significantly differ depending on the underlying disease. While classical accelerated ATS has


*Acronyms*: RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; CRP, C-reactive protein; APL, antiphospholipid antibodies; anti-oxLDL, anti- oxidized low-density lipoprotein antibodies; anti-Hsp, anti-heat shock protein antibodies; TNF-α, tumour necrosis factor α; IL-1, interleukin-1; IL-6, interleukin-6; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1.

Adapted from: Soltész et al. [26].

**Table 1.** Risk factors for atherosclerosis and cardiovascular diseases.

been associated with RA and SLE, obliterative vasculopathy may be characteristic for SSc. All of these diseases greatly differ in vascular pathomorphology and function (**Table 2**) [24, 28–56].


*Acronyms*: RA, rheumatoid arthritis; SpA, spondyloarthritis; SLE, systemic lupus erythematosus; APS, anti-phospholipid syndrome; SSc, systemic sclerosis; MCTD, mixed connective tissue disease Adapted from: Soltész et al. [26].

**Table 2.** Different vascular pathogenesis in autoimmune rheumatic diseases.

### **4. Atherosclersis in SSc**

Systemic sclerosis (SSc) is a multi-system autoimmune disease characterized by immune dysregulation, vasculopathy, and fibrosis. In the pathogenesis, three hallmarks have been proposed to play the key role: (1) vasculopathy with the pathognomonic microvascular involvement; (2) fibrosis of skin and visceral organs; (3) systemic inflammation characterized by the presence of circulating autoantibodies and pro-inflammatory cytokines [57, 58].

The etiology of ATS in SSc is unknown. It may be secondary to concomitant multiple factors, including traditional CV risk factors, increased endothelial damage, and disease-specific immunologic and autoimmune factors, which may contribute to both induction and progression of ATS [2, 8, 53, 59–61].

Numerous inflammatory mediators implicated in the pathogenesis of ATS, including TNF-α, interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), have been demonstrated to be increased in patients with SSc compared with controls [62]. The relationship between these mediators and CVD in SSc is unclear. However, chronic systemic inflammation probably promotes accelerated ATS. Nevertheless, the level of inflammation in SSc is lower than in RA and SLE, thus the atherosclerotic process may not be so aggressive and easily detectable in small-number studies [63].

Involvement of the microvasculature is one of the earliest features of SSc, preceding and potentially contributing via tissue ischemia to the widespread fibrosis characteristic of this condition. Pathological changes include disruption of the endothelium, mononuclear cell infiltration of the vessel wall, frank obliterative lesions, and progressive loss of capillaries.

Endothelial dysfunction in the capillaries and arterioles, common in SSc, results in disturbed vasomotor regulation [64].

Although macrovascular disease was not originally considered as a feature of SSc, multiple studies have revealed an increased prevalence of large-vessel disease of the upper and lower limbs in patients with SSc [65, 66]. The prevalence of coronary artery and cerebrovascular disease in SSc, however, remains to be elucidated.

### **4.1. Prevalence of atherosclerosis in SSc**

been associated with RA and SLE, obliterative vasculopathy may be characteristic for SSc. All of these diseases greatly differ in vascular pathomorphology and function (**Table 2**) [24, 28–56].

Systemic sclerosis (SSc) is a multi-system autoimmune disease characterized by immune dysregulation, vasculopathy, and fibrosis. In the pathogenesis, three hallmarks have been proposed to play the key role: (1) vasculopathy with the pathognomonic microvascular involvement; (2) fibrosis of skin and visceral organs; (3) systemic inflammation characterized by the presence of circulating autoantibodies and pro-inflammatory cytokines [57, 58].

*Acronyms*: RA, rheumatoid arthritis; SpA, spondyloarthritis; SLE, systemic lupus erythematosus; APS, anti-phospholipid

The etiology of ATS in SSc is unknown. It may be secondary to concomitant multiple factors, including traditional CV risk factors, increased endothelial damage, and disease-specific immunologic and autoimmune factors, which may contribute to both induction and progres-

Numerous inflammatory mediators implicated in the pathogenesis of ATS, including TNF-α, interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), have been demonstrated to be increased in patients with SSc compared with controls [62]. The relationship between these mediators and CVD in SSc is unclear. However, chronic systemic inflammation probably promotes accelerated ATS. Nevertheless, the level of inflammation in SSc is lower than in RA and SLE, thus the atherosclerotic process may not be so aggressive and easily detectable

Involvement of the microvasculature is one of the earliest features of SSc, preceding and potentially contributing via tissue ischemia to the widespread fibrosis characteristic of this condition. Pathological changes include disruption of the endothelium, mononuclear cell infiltration of the vessel wall, frank obliterative lesions, and progressive loss of capillaries.

Endothelial dysfunction in the capillaries and arterioles, common in SSc, results in disturbed

Although macrovascular disease was not originally considered as a feature of SSc, multiple studies have revealed an increased prevalence of large-vessel disease of the upper and lower

**4. Atherosclersis in SSc**

Adapted from: Soltész et al. [26].

26 Systemic Sclerosis

**Leading mechanisms Disease**

Autoantibody-mediated mechanisms SLE, APS, RA Proliferative obliteration SSc, MCTD

syndrome; SSc, systemic sclerosis; MCTD, mixed connective tissue disease

**Table 2.** Different vascular pathogenesis in autoimmune rheumatic diseases.

Accelerated atherosclerosis RA, SpA, SLE, APS (SSc)

sion of ATS [2, 8, 53, 59–61].

in small-number studies [63].

vasomotor regulation [64].

Mortality in SSc was described to be approximately three times increased as compared to the general population, in particular due to cardiopulmonary complications, including pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) [67]. The 10-year survival of SSc has improved significantly from 54% (1972–1981) to 66–82% (1982–1991), largely due to the early diagnosis and treatments available for PAH and scleroderma renal crisis (SRC) [68]. Emphasis has thus shifted to comorbidities in SSc, such as ATS, that may affect the long-term outcomes of SSc [68] with the substantially increased death rates due to atherosclerotic CVD or cerebrovascular disease [63]. Currently, CV-related deaths are responsible for a 20–30% mortality rate in SSc patients [63].

In particular, the 2010 survey from the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) database estimated that 26% of SSc-related causes of death were due to cardiac causes (mainly heart failure and arrhythmias) and 29% of non-SSc-related causes of death were due to ATS and CV causes [69].

There are contradictory reports regarding the prevalence of ATS in SSc [70]. According to some authors, the prevalence of ATS of the large epicardial coronary arteries is similar to that of general population [71].

The prevalence of primary cardiac involvement in SSc is variable and difficult to determine because of diversity of cardiac manifestations, presence of subclinical periods, type of applied diagnostic tools, and differences in patient populations [10].

Raynaud's phenomenon, PAH, and SRC represent the main clinical manifestations of microvascular damage (involvement) in SSc, characterized by both vasospasm and structural alterations, pathognomonic features of SSc. All these components are thought to predict macrovascular ATS over time [70, 72].

### **4.2. Risk factors for atherosclerosis in SSc**

There is limited data regarding the prevalence of traditional CV risk factors in SSc. Their prevalence has been found to be either similar [73, 74] or reduced [75–77] when compared with general population. The majority of these studies showed a similar distribution of CV risk factors between SSc patients and controls, thereby suggesting that other factors may contribute to the increased prevalence of CV disease in SSc [77].

In addition to age [75, 77], hypercholesterolaemia [75–77], male gender [77], hypertension [78], and diabetes [78], SSc appears to be an independent risk factor for coronary artery disease (CAD) after adjustment for traditional risk factors [73, 78], including the SSc-related factors: PAH [75, 77], renal involvement [76], and disease duration [75]. Moreover, particularly the disease duration, in addition to age and LDL levels, can act as an independent determinant for more severe coronary calcification [75]. Renal involvement in SSc relates to ischemic heart disease (after exclusion of the impact of age) [76].

Studies mostly failed to show an increased frequency of obesity, hyperlipidaemia, hypertension (there was no difference in blood pressure on 24-hour ambulatory blood pressure monitoring [79]), and diabetes in SSc [7, 73, 75, 79]. These findings were confirmed also in the Australian Scleroderma Cohort Study [77]. Moreover, significantly lower cholesterol levels and diastolic blood pressure were described in SSc compared to controls [75]. On the other hand, one study revealed a slight increase in blood pressure and fasting glucose and a lower BMI in SSc population [80].

Factors contributing to ATS in SSc, beside the traditional risk factors, include chronic inflammation, increased levels of CRP and homocysteine, autoantibodies, deranged lipid function and profile, corticosteroid treatment, increasing age and disease duration [40, 65, 66, 81]. Beside these factors, there is also association with the dysfunction of the coagulation and fibrinolytic system and increased production of adhesion molecules [82–86]. Specifically, corticosteroids and immunosuppression seem not to be associated with the risk of CAD [76].

Results from studies on lipids are contradictory. Lipid metabolism seems to be altered and accompanied by lower levels of high-density lipoprotein (HDL) [87] or significantly elevated lipoprotein(a) (LpA) without any significant difference in other cholesterol parameters [88]. High levels of LpA in SSc are usually associated with increased CV risk [88]. In addition, high levels of LpA adversely affect the effect of thrombosis, due to reduced fibrinolysis [88, 89]. Of interest, the presence of anti-centromere antibodies (ACA) is associated with decreased levels of HDL [87]. SSc patients may have some higher detected pro-inflammatory-HDL levels (representing an increased risk for ATS) [74]. Of note, increased IgG autoantibody against the lipoprotein lipase (anti-LPL) in SSc (detected in 24% of SSc patients) may cause elevation of triglyceride (TG) levels [90]. On the other hand, some studies have not described any alteration of the components of the lipid profile in SSc patients [88].

Some novel CV risk factors have been reported to be elevated in SSc, such as oxidized lowdensity lipoprotein (oxLDL) and endothelin [7]. In terms of pro-thrombotic state in SSc, the coagulation system can be activated, and fibrinolysis can be impaired [89].

### **4.3. Pathogenesis and risk factors specific for SSc**

Pathogenesis of SSc is characterized by inflammatory, vascular, and fibrotic events. It primarily affects the microvessels (e.g. Raynaud's phenomenon); however, macrovascular obliterative disease has also been described in SSc [40, 42, 70, 82, 83, 91].

Endothelial dysfunction, one of the earliest events in the pathogenesis of SSc and vasculopathy, is critical in the development of ATS, and represents a loss in vasodilatory function, together with increased platelet aggregation and leukocyte adhesion due to decreased nitric oxide (NO) as a key vasodilator [92]. Endothelial injury results in lumen occlusion and tissue hypoxia. The histopathological picture of scleroderma includes intima proliferation, the proliferation of endothelial and smooth muscle cells, destruction of internal elastic lamina and transmural lympho-plasmocytic infiltration of the vessel wall. Thus, vasculopathy in SSc does not represent the classical ATS but rather an obliterative vasculopathy [40, 82]. This has been documented by reports of very severe clinical cases of obliterative peripheral artery disease (PAD) despite the lack of traditional risk factors for ATS. About 15–20% of scleroderma patients exert multiple vascular abnormalities including the combination of CVD, stroke and PAD [2, 70, 82].

In addition, ischemia, oxidative stress, and oxLDL may trigger inflammation in the vessel wall. Homocysteine levels correlate with the development of macrovascular disease and PAH, and decreased vitamin B12 release in SSc [83].

Regarding vascular pathogenesis, the possible role of methylene-tetrahydrofolate reductase (MTHFR) gene C677T polymorphism was described in the development of macrovascular manifestations of SSc [83].

### **4.4. Mechanisms of endothelial damage**

Studies mostly failed to show an increased frequency of obesity, hyperlipidaemia, hypertension (there was no difference in blood pressure on 24-hour ambulatory blood pressure monitoring [79]), and diabetes in SSc [7, 73, 75, 79]. These findings were confirmed also in the Australian Scleroderma Cohort Study [77]. Moreover, significantly lower cholesterol levels and diastolic blood pressure were described in SSc compared to controls [75]. On the other hand, one study revealed a slight increase in blood pressure and fasting glucose and a lower

Factors contributing to ATS in SSc, beside the traditional risk factors, include chronic inflammation, increased levels of CRP and homocysteine, autoantibodies, deranged lipid function and profile, corticosteroid treatment, increasing age and disease duration [40, 65, 66, 81]. Beside these factors, there is also association with the dysfunction of the coagulation and fibrinolytic system and increased production of adhesion molecules [82–86]. Specifically, corticosteroids and immunosuppression seem not to be associated with the risk of CAD [76].

Results from studies on lipids are contradictory. Lipid metabolism seems to be altered and accompanied by lower levels of high-density lipoprotein (HDL) [87] or significantly elevated lipoprotein(a) (LpA) without any significant difference in other cholesterol parameters [88]. High levels of LpA in SSc are usually associated with increased CV risk [88]. In addition, high levels of LpA adversely affect the effect of thrombosis, due to reduced fibrinolysis [88, 89]. Of interest, the presence of anti-centromere antibodies (ACA) is associated with decreased levels of HDL [87]. SSc patients may have some higher detected pro-inflammatory-HDL levels (representing an increased risk for ATS) [74]. Of note, increased IgG autoantibody against the lipoprotein lipase (anti-LPL) in SSc (detected in 24% of SSc patients) may cause elevation of triglyceride (TG) levels [90]. On the other hand, some studies have not described any altera-

Some novel CV risk factors have been reported to be elevated in SSc, such as oxidized lowdensity lipoprotein (oxLDL) and endothelin [7]. In terms of pro-thrombotic state in SSc, the

Pathogenesis of SSc is characterized by inflammatory, vascular, and fibrotic events. It primarily affects the microvessels (e.g. Raynaud's phenomenon); however, macrovascular oblitera-

Endothelial dysfunction, one of the earliest events in the pathogenesis of SSc and vasculopathy, is critical in the development of ATS, and represents a loss in vasodilatory function, together with increased platelet aggregation and leukocyte adhesion due to decreased nitric oxide (NO) as a key vasodilator [92]. Endothelial injury results in lumen occlusion and tissue hypoxia. The histopathological picture of scleroderma includes intima proliferation, the proliferation of endothelial and smooth muscle cells, destruction of internal elastic lamina and transmural lympho-plasmocytic infiltration of the vessel wall. Thus, vasculopathy in SSc does not represent the classical ATS but rather an obliterative vasculopathy [40, 82]. This has been documented by reports of very severe clinical cases of obliterative peripheral artery disease (PAD)

tion of the components of the lipid profile in SSc patients [88].

tive disease has also been described in SSc [40, 42, 70, 82, 83, 91].

**4.3. Pathogenesis and risk factors specific for SSc**

coagulation system can be activated, and fibrinolysis can be impaired [89].

BMI in SSc population [80].

28 Systemic Sclerosis

Vascular endothelium as a functionally remarkable organ regulates coagulation, fibrinolysis, permeability, vasomotion, and inflammation. Clinical and pathological features of vascular damage and endothelial cell activation represent an important hallmark of SSc vasculopathy, even in the absence of other concomitant risk factors [10]. Endothelial dysfunction is a component of the pathophysiology of both SSc and ATS. In SSc, the initiating injury is unknown [72].

Endothelial cell damage leads to enhanced expression of adhesion molecules and elevated levels of circulating soluble adhesion molecules, such as soluble E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), which are all significantly increased in SSc, reflecting endothelial activation [93]. This results into adhesion of inflammatory cells, trans-migration across the vessel wall, and infiltration of the extracellular matrix.

Different mechanisms may induce and perpetuate endothelial dysfunction, which contributes to the pathogenesis of atherosclerotic risk, and progressive vasculopathy in SSc. The main pathogenic mechanisms underlying endothelial damage have been proposed: (1) dysregulation of vascular tone, as a consequence of an imbalance between vasoconstrictor and vasodilator mediators; (2) defective angiogenesis; (3) injury/activation elicited by the activation of innate and adaptive immune response; and (4) functional defects of endothelial progenitor cells (EPCs) [94, 95].


contributes to the development of fibrosis in both inflammatory and non-inflammatory stages of the disease [101].


### **5. Components involved in the atherogenesis in SSc**

### **5.1. Endothelial progenitor cells**

The elevation of endothelial progenitor cells (EPCs) in early disease is followed by its decrease during the disease duration [103], suggesting a probable exhaustion of the precursor endothelial pool during disease course. A decreased number of EPCs in the peripheral circulation has been shown to be predictive of recurrent acute coronary artery events [104]. Moreover, a low number of circulating EPCs seems to characterize a more active disease phenotype, identified by a higher risk of digital vascular lesions and higher severity score. Scleroderma circulating EPCs are characterized by a defective functional phenotype with consequent defective migratory activity and impaired recruitment to ischemic damaged tissue [100, 105–107].

The true significance of EPCs as a potential biomarker of both CV risk and SSc disease activity is not determined. It is not clear whether the cells are true progenitor cells [99] that incorporate into new blood vessels or rather cells of hematopoietic lineage, which have a paracrine effect on blood vessel formation [108]. Assessment of EPCs levels in SSc may be conflicting mainly because of the different methods of detection [109, 110].

### **5.2. Circulating endothelial cells**

Circulating endothelial cells (CECs) are released into the systemic circulation after detachment of cells from basement membrane in response to endothelial injury. Increased number of CECs, a novel marker of endothelial damage, has been demonstrated not only in patients with myocardial infarction (MI), unstable angina, peripheral vascular disease (PAD), but also in SSc, suggesting their role as a marker of chronic endothelial damage [111, 112].

### **5.3. Antibodies against the anti-oxidized low-density lipoproteins (anti-oxLDL)**

Patients with diffuse cutaneous SSc (dcSSc) were found to have higher levels of anti-oxidized LDL (oxLDL) antibodies [113], the titer of which correlates with the severity of ATS as well as with CV complications [114]. In addition, higher levels of circulating complexes of anti-beta-2-glycoprotein I (anti-oxLDL/β2GPI), considered as pro-atherogenic, were demonstrated in SSc as well [115, 116].

### **5.4. Antiphospholipid antibodies**

contributes to the development of fibrosis in both inflammatory and non-inflammatory

3) In the early stage of scleroderma, the endothelial cell layer of microcirculation is activated and/or injured by unknown and various mechanisms, including infection-induced apoptosis, immune mediated cytotoxicity, anti-endothelial antibodies, or ischemia-reperfusion

4) In particular, new blood vessels may form as a consequence of endothelial sprouting from pre-existing endothelial cells (angiogenesis) or as peripheral recruitment of bone marrowderived circulating EPCs. EPCs contribute, at least in the early stage of the disease, to

The elevation of endothelial progenitor cells (EPCs) in early disease is followed by its decrease during the disease duration [103], suggesting a probable exhaustion of the precursor endothelial pool during disease course. A decreased number of EPCs in the peripheral circulation has been shown to be predictive of recurrent acute coronary artery events [104]. Moreover, a low number of circulating EPCs seems to characterize a more active disease phenotype, identified by a higher risk of digital vascular lesions and higher severity score. Scleroderma circulating EPCs are characterized by a defective functional phenotype with consequent defective migra-

The true significance of EPCs as a potential biomarker of both CV risk and SSc disease activity is not determined. It is not clear whether the cells are true progenitor cells [99] that incorporate into new blood vessels or rather cells of hematopoietic lineage, which have a paracrine effect on blood vessel formation [108]. Assessment of EPCs levels in SSc may be conflicting

Circulating endothelial cells (CECs) are released into the systemic circulation after detachment of cells from basement membrane in response to endothelial injury. Increased number of CECs, a novel marker of endothelial damage, has been demonstrated not only in patients with myocardial infarction (MI), unstable angina, peripheral vascular disease (PAD), but also

Patients with diffuse cutaneous SSc (dcSSc) were found to have higher levels of anti-oxidized LDL (oxLDL) antibodies [113], the titer of which correlates with the severity of ATS as well as

in SSc, suggesting their role as a marker of chronic endothelial damage [111, 112].

**5.3. Antibodies against the anti-oxidized low-density lipoproteins (anti-oxLDL)**

tory activity and impaired recruitment to ischemic damaged tissue [100, 105–107].

vascular healing by homing in the damaged endothelium [102].

**5. Components involved in the atherogenesis in SSc**

mainly because of the different methods of detection [109, 110].

stages of the disease [101].

**5.1. Endothelial progenitor cells**

**5.2. Circulating endothelial cells**

injury [96].

30 Systemic Sclerosis

Anti-β2-glycoprotein I (anti-β2GPI) in the presence of anticardiolipin (aCL) antibodies could be independently predictive of incident ischemic stroke and MI over 20 years of follow-up [117]. The prevalence of aCL and anti-β2GPI antibodies occurring in the absence of typical clinical manifestations of antiphospholipid syndrome (APS) has been demonstrated to be increased in patients with SSc compared to controls [118]. Anti-β2GPI is associated with both higher mortality and vascular disease, including digital ischemia and PAH, in SSc [119].

### **5.5. Anti-endothelial cell antibodies**

Elevated anti-endothelial cell antibodies (AECA) correlate with increased subclinical ATS in non-rheumatic patients [120], SLE patients [121], and may contribute to an increased risk of early ATS in SSc, similarly as elevated levels of ICAM-1 [122]. However, in general the levels of AECA do not always have to be increased in all cases of chest pain and atherosclerotic involvement of the coronary arteries (compared with patients with chest pain and normal coronary angiography) [123]. The presence of circulating antibodies with anti-endothelial activity in scleroderma patients may be considered as an adjunctive mechanism associated with chronic endothelial damage [109, 110].

### **5.6. Angiotensin converting enzyme gene polymorphism**

Polymorphism (insertion or deletion, I/D) of the angiotensin converting enzyme (ACE) gene can be another factor possibly influencing ATS. The highest levels of plasma ACE are associated with the DD genotype and the lowest levels are associated with the II genotype [124]. The D allele of the ACE gene, associated with ATS severity [125], has an increased frequency in SSc [2]. The risk of MI in patients with the DD genotype is higher compared with those with either the II or ID genotype [126, 127]. The presence of a D allele in SSc correlates with increased carotid intima-media thickness (CIMT) [128].

### **5.7. Microparticles**

Microparticles (MPs), small circulating membrane-coated vesicles, are important mediators of intercellular signaling arising from a variety of cell types. MPs contribute to the immunopathogenesis of various thrombotic and rheumatic diseases via their role in the regulation of inflammation, thrombosis, and angiogenesis. MPs have been suggested as a biomarker of CAD. High levels result in severe endothelial dysfunction by selectively impairing the production of NO and are found in patients with acute MI [129].

MPs levels are also elevated in patients with SSc and correlate with the presence of ILD [130].

## **6. Types of damage**

The main clinical features of atherosclerotic disease in SSc patients are represented by an involvement of peripheral, cerebrovascular, carotid, and coronary arteries with consequent high risk of peripheral vascular disease, stroke, and coronary heart disease, in particular in late disease [131]. SSc is associated with about a twofold increased risk of developing MI and stroke, and a fourfold increased risk for peripheral vascular disease, even after adjustment for CV risk factors (BMI, smoking, hypertension, diabetes, and hyperlipidaemia). This fact suggests that the increased risk of CV events in SSc may depend on both ATS and non-atherosclerotic factors, such as vasospasm, SSc specific vasculopathy, vasculitis, and thrombosis [73].

Presence of plaques and ischemic arterial events positively correlates with the positivity of ACA, while anti-topoisomerase I antibodies (ATA) positivity in SSc is rather associated with fewer ischemic events. The antibody profile and different disease subsets are supposed to contribute to macrovascular involvement [76].

### **6.1. Coronary arteries**

Even though cardiac disease is a major cause of death in SSc patients, clinical signs of cardiac disease are apparent in only 10% [71], mostly appearing late in the course of disease [132], and predicting an adverse prognosis [133]. Up to 80% of postmortem evaluation of SSc patients' hearts may reveal a form of cardiac involvement [134].

The prevalence of ATS involving coronary vessels and its clinical manifestation, including angina, MI, and sudden death, is difficult to evaluate in SSc, because of the primary cardiac involvement possibly depending on myocardial damage secondary to microvascular alterations, myocardial fibrosis, arrhythmias resulting from the conduction system involvement, and last but not least, pericardial and valvular disease [135]. Myocardial fibrosis in SSc patients is considered a hallmark cardiac manifestation [133]. Foci of fibrosis not corresponding to coronary artery distribution were reported in 50% of autopsies conducted on SSc patients [136].

Moreover, secondary heart disease due to renal vasculopathy, ILD, and PAH could adversely influence cardiac function. Thus, symptoms of cardiac complications could be nonspecific, and could overlap with those of other comorbidities. Furthermore, hypertension, obesity, diabetes, and other comorbidities may contribute to adverse influence on cardiac function, mainly in older SSc patients [135].

The risk of acute MI may be 2.45x greater in SSc than in population of the same age, sex, and comorbidities [78]. In addition, the impact of SSc on acute MI risk may be even greater than that of hypertension (increasing the risk 2.08x), and diabetes (2.14x), while immunosuppressant drugs probably do not reduce this risk of MI [78].

Of note, MI has been described in SSc patients with unaffected coronary arteries. In this setting, microvascular disease leading to ischemic events and contraction band necrosis, resulting from both occlusive vascular disease and intermittent vasospasm (the so called "myocardial Raynaud's phenomenon"), has been demonstrated to be the main mechanism associated with myocardial ischemic events in these patients [136]. In addition, epicardial coronary arteries in SSc patients have been reported to be free of significant lesions even in the setting of MI, congestive heart failure, and sudden cardiac death [137].

On the other hand, while the frequency of epicardial coronary vessel ATS appeared to be similar in SSc and general population (48% *vs*. 43%), the atherosclerotic lesions of the small coronary arteries or arterioles occurred significantly more often in SSc patients, compared with controls [138].

The coronary vessel involvement was ascertained invasively by coronarography with the conclusion, that the prevalence of CAD in SSc patients with suspected CAD was similar to that detected in controls [71]. Angiographic abnormalities may be higher than previously thought in asymptomatic patients with SSc, including significant coronary artery stenosis, coronary artery ectasia, slow flow, tortuosity, calcification, and spasm, and must not be related to traditional CV risk factors [132]. These abnormalities (demonstrated in asymptomatic female SSc patients free from CV risk factors) suggest that coronary artery vasculopathy is common even in the absence of classic CV risk factors, supporting the role of SSc as a relevant risk factor for CAD [132].

The presence of coronary calcified plaques in SSc patients asymptomatic for angina evaluated by computed tomography (CT) coronary angiography confirms the subclinical ATS as a common one in SSc [139]. In addition, SSc seems to be an independent risk factor for increased coronary artery calcium deposition [75].

### **6.2. Peripheral macrovascular abnormalities in SSc**

**6. Types of damage**

32 Systemic Sclerosis

**6.1. Coronary arteries**

patients [136].

contribute to macrovascular involvement [76].

hearts may reveal a form of cardiac involvement [134].

cardiac function, mainly in older SSc patients [135].

sant drugs probably do not reduce this risk of MI [78].

The main clinical features of atherosclerotic disease in SSc patients are represented by an involvement of peripheral, cerebrovascular, carotid, and coronary arteries with consequent high risk of peripheral vascular disease, stroke, and coronary heart disease, in particular in late disease [131]. SSc is associated with about a twofold increased risk of developing MI and stroke, and a fourfold increased risk for peripheral vascular disease, even after adjustment for CV risk factors (BMI, smoking, hypertension, diabetes, and hyperlipidaemia). This fact suggests that the increased risk of CV events in SSc may depend on both ATS and non-atherosclerotic factors, such as vasospasm, SSc specific vasculopathy, vasculitis, and thrombosis [73].

Presence of plaques and ischemic arterial events positively correlates with the positivity of ACA, while anti-topoisomerase I antibodies (ATA) positivity in SSc is rather associated with fewer ischemic events. The antibody profile and different disease subsets are supposed to

Even though cardiac disease is a major cause of death in SSc patients, clinical signs of cardiac disease are apparent in only 10% [71], mostly appearing late in the course of disease [132], and predicting an adverse prognosis [133]. Up to 80% of postmortem evaluation of SSc patients'

The prevalence of ATS involving coronary vessels and its clinical manifestation, including angina, MI, and sudden death, is difficult to evaluate in SSc, because of the primary cardiac involvement possibly depending on myocardial damage secondary to microvascular alterations, myocardial fibrosis, arrhythmias resulting from the conduction system involvement, and last but not least, pericardial and valvular disease [135]. Myocardial fibrosis in SSc patients is considered a hallmark cardiac manifestation [133]. Foci of fibrosis not corresponding to coronary artery distribution were reported in 50% of autopsies conducted on SSc

Moreover, secondary heart disease due to renal vasculopathy, ILD, and PAH could adversely influence cardiac function. Thus, symptoms of cardiac complications could be nonspecific, and could overlap with those of other comorbidities. Furthermore, hypertension, obesity, diabetes, and other comorbidities may contribute to adverse influence on

The risk of acute MI may be 2.45x greater in SSc than in population of the same age, sex, and comorbidities [78]. In addition, the impact of SSc on acute MI risk may be even greater than that of hypertension (increasing the risk 2.08x), and diabetes (2.14x), while immunosuppres-

Of note, MI has been described in SSc patients with unaffected coronary arteries. In this setting, microvascular disease leading to ischemic events and contraction band necrosis, resulting from both occlusive vascular disease and intermittent vasospasm (the so called "myocardial Macrovascular complications (involving the arms and legs) may be detected even in SSc patients with minimal underlying CV risk factors [140]. Peripheral vascular disease (PAD) in patients with SSc has been reported to be significantly increased, with use of techniques such as the ankle brachial pressure index (ABPI), lower-limb Doppler ultrasound, and angiography [140–143]. Similarly, evaluation of the PAD using the WHO questionnaire for intermittent claudication may reveal more frequent impairment in SSc (almost 22%) than in general population (4.5%) [65]. PAD diagnosed by the ABPI may reach 17% of patients with SSc (in contrast to no healthy control), while there is no difference in the traditional CV risk factor profile [66].

Studies have showed a six times increased prevalence of PAD, detected by angiography, Doppler ultrasound, or physical examination in patients with limited cutaneous SSc (lcSSc) compared to healthy controls [141], and almost five times greater presence of intermittent lower limb claudication in SSc, detected by Edinburgh Claudication questionnaire, than the prevalence of symptomatic PAD in the general population, as reported by a similar WHO claudication questionnaire [65]. According to one study, approximately 4.2% of SSc patients (including the ones treated with vasodilators) suffer from clinical intermittent claudication, and even may develop ischemic stroke [143]. However, other studies failed to prove the increased prevalence of stroke in SSc [7].

The traditional CV risk factors seem to contribute to proximal, but not distal, vascular disease in the lower limb, as demonstrated in angiograms performed in a single SSc cohort [142]. In at least some cases, peripheral vascular disease in SSc is not atherosclerotic but related to the vasculopathy of SSc itself, which is supported by finding of chronic obliterative thromboangiitis on histological examination of an amputated limb [141]. Involvement of the vasa vasorum has been suggested as a potential cause of macrovascular disease in SSc [144].

Macrovascular disease, defined as an involvement of blood vessels with an internal diameter >100 microns, is probably associated with the more distal small vessel pathology [96]. Morphology and blood flow of the proper palmar digital arteries correlate with nailfold capillary morphology, and progression of microvascular disease (detected by capillaroscopy from early capillaroscopy pattern to an active and late capillaroscopy pattern) is linked to macrovascular disease. ATA may represent an independent predictive factor for macrovascular damage [145].

### **6.3. Cerebrovascular disease**

Literature data aimed to estimate the prevalence of cerebrovascular disease in SSc and the relationship between disease and risk of ischemic stroke is inconclusive [146]. Several studies suggested that cerebral disease may be underestimated [147–149]. The prevalence of cerebrovascular disease (transient ischemic attack, stroke, carotid or vertebral artery bruits, Doppler evidence of carotid or vertebral artery disease, or angiographic evidence of carotid artery stenosis) in SSc patients was found to be 1.3-times higher compared to controls [141].

The increased ischemic stroke risk in SSc may be due to different pathogenic mechanisms such as vascular injury, chronic inflammation, and vasospasm [146]. SSc may be independently associated with a 43% increase in ischemic stroke risk compared to healthy controls [73]. This risk is not even modified by commonly employed medications (such as calcium channel blockers, angiotensin converting enzyme inhibitors, oral corticosteroids, or immunosuppressant drugs) [146].

Cerebral vascular involvement may be caused by endothelial dysfunction, as well as by ATS [150]. The role of inflammatory or immune mechanisms can be declared by the apparent efficacy of immunosuppressive drugs in stroke treatment [151]. Finally, cerebral vasospasm ("Raynaud's phenomenon-like") may be associated with transient ischemic attacks or focal neurological defects and it is evidenced by reversibility of arterial lesions and absence of specific histologic findings [152].

Stenosis of carotid arteries, a predictive factor of stroke, is more often found in SSc patients with respect to general population with no difference in the traditional CV risk factor profile, supporting the increased risk of stroke in SSc [66]. Moreover, intracerebral vascular calcifications, an independent risk factor of ischemic stroke in the general population [153], are significantly more prevalent in asymptomatic SSc patients compared to the controls investigated by noncontrast CT scan [154]. Similarly, white matter hyperintensities on brain magnetic resonance imaging (MRI), a known risk factor for future symptomatic stroke [155], are more common in asymptomatic SSc patients than in population without autoimmune diseases [156, 157].

Another tool for examining cerebral artery involvement, a single photon emission computed tomography (SPECT), showed focal or diffuse hypoperfusion in mainly neurologically asymptomatic SSc patients, probably caused by the microangiopathic damage of brain vessels [158].

Of note, central nervous system may be affected by microvascular damage as a complication of systemic involvement [159]. A higher risk for developing neurological complications is associated with circulating anti-U1 RNP (ribonucleoprotein) and ATA [160].

### **6.4. Carotid arteries**

The traditional CV risk factors seem to contribute to proximal, but not distal, vascular disease in the lower limb, as demonstrated in angiograms performed in a single SSc cohort [142]. In at least some cases, peripheral vascular disease in SSc is not atherosclerotic but related to the vasculopathy of SSc itself, which is supported by finding of chronic obliterative thromboangiitis on histological examination of an amputated limb [141]. Involvement of the vasa vasorum

Macrovascular disease, defined as an involvement of blood vessels with an internal diameter >100 microns, is probably associated with the more distal small vessel pathology [96]. Morphology and blood flow of the proper palmar digital arteries correlate with nailfold capillary morphology, and progression of microvascular disease (detected by capillaroscopy from early capillaroscopy pattern to an active and late capillaroscopy pattern) is linked to macrovascular disease. ATA may represent an independent predictive factor for macrovas-

Literature data aimed to estimate the prevalence of cerebrovascular disease in SSc and the relationship between disease and risk of ischemic stroke is inconclusive [146]. Several studies suggested that cerebral disease may be underestimated [147–149]. The prevalence of cerebrovascular disease (transient ischemic attack, stroke, carotid or vertebral artery bruits, Doppler evidence of carotid or vertebral artery disease, or angiographic evidence of carotid artery

The increased ischemic stroke risk in SSc may be due to different pathogenic mechanisms such as vascular injury, chronic inflammation, and vasospasm [146]. SSc may be independently associated with a 43% increase in ischemic stroke risk compared to healthy controls [73]. This risk is not even modified by commonly employed medications (such as calcium channel blockers, angiotensin converting enzyme inhibitors, oral corticosteroids, or immuno-

Cerebral vascular involvement may be caused by endothelial dysfunction, as well as by ATS [150]. The role of inflammatory or immune mechanisms can be declared by the apparent efficacy of immunosuppressive drugs in stroke treatment [151]. Finally, cerebral vasospasm ("Raynaud's phenomenon-like") may be associated with transient ischemic attacks or focal neurological defects and it is evidenced by reversibility of arterial lesions and absence of spe-

Stenosis of carotid arteries, a predictive factor of stroke, is more often found in SSc patients with respect to general population with no difference in the traditional CV risk factor profile, supporting the increased risk of stroke in SSc [66]. Moreover, intracerebral vascular calcifications, an independent risk factor of ischemic stroke in the general population [153], are significantly more prevalent in asymptomatic SSc patients compared to the controls investigated by noncontrast CT scan [154]. Similarly, white matter hyperintensities on brain magnetic resonance imaging (MRI), a known risk factor for future symptomatic stroke [155], are more common in

asymptomatic SSc patients than in population without autoimmune diseases [156, 157].

stenosis) in SSc patients was found to be 1.3-times higher compared to controls [141].

has been suggested as a potential cause of macrovascular disease in SSc [144].

cular damage [145].

34 Systemic Sclerosis

**6.3. Cerebrovascular disease**

suppressant drugs) [146].

cific histologic findings [152].

Regarding vascular morphology and function, carotid ATS has been detected in more than 60% of scleroderma patients [40, 64, 161–163]. In line with this finding, the prevalence of carotid plaque, carotid wall thickening, and carotid artery stenosis has been showed to be significantly higher in SSc compared to the general population of the same age and gender [66].

Some studies found no difference in CIMT values between scleroderma patients and controls [161, 164, 165], while others depicted increased CIMT in SSc patients [64, 166]. Nevertheless, significantly higher CIMT values in SSc demonstrating increased risk of ATS were found in less than half of the studies [8, 167]. The data interpretation may be hampered by small size of the cohorts enrolled and by variability of CIMT ultrasonographic measurement among studies [7].

CIMT values seem to directly correlate with disease duration, similarly to the observations in patients with RA, diabetes mellitus, or familial hypercholesterolemia [8]. High CIMT was variably associated with age, oxLDL [166], corticosteroid treatment [168], ACE gene polymorphism, and antibodies against human heat shock protein (HSP)-60, and mycobacterial HSP-65 [166]. Increase in CIMT (≥0.10 mm) correlates with age- and sex-adjusted relative risk of 1.15 for MI, and 1.18 for stroke [131].

SSc patients with plaques are characterized by increased concentration of serum proteins implicated in both vasculopathy, and fibrosis in comparison to patients without plaques [169].

### **7. Methods of detection**

To elucidate the prevalence of PAD in SSc, several techniques, beside the physical examination (history of claudication or absence of pulses), have been employed. In particular, surrogate markers of atherosclerotic damage have been demonstrated to be useful indicators of atherosclerotic wall damage. These include ankle brachial pressure index (ABPI) for arterial involvement of the lower extremities, blood pressure interarm difference (systolic/diastolic interarm difference) for proximal arterial disease of the upper extremities, and pulse wave velocity (PWV) and pulse wave analysis (PWA) to evaluate arterial stiffness. A novel noninvasive tool to evaluate subclinical coronary ATS, a multidetector CT, generates a coronary calcium score, a surrogate marker for coronary ATS [170, 171].

### **7.1. Intima-media thickness in SSc**

Vessel intima-media thickness (IMT) is calculated by measuring the average thickness of the intima-media complex, the distance between the first and the second echogenic lines from the lumen [40, 64]. Carotid intima-media thickness (CIMT) as measured by high-resolution ultrasound is a well-validated marker of subclinical ATS. Increased CIMT has been shown to correlate with traditional CV risk factors, and to independently predict future vascular events in general population [64, 131].

A meta-analysis of CIMT in rheumatic diseases, including RA, SLE, and SSc, found significantly increased values of CIMT in this population compared with healthy, age- and sexmatched controls [167]. The pooled result of the SSc studies demonstrated a greater CIMT in SSc than in controls, suggesting an increased prevalence of subclinical ATS in both dcSSc and lcSSc [166, 172, 173]. The effect size seen in SSc was also greater than those in RA and SLE. Higher CIMT values are associated with increased age, but probably not with disease type, duration, or clinical characteristics [166].

In contrast to these findings, a number of individual studies have found no increase in CIMT in patients with SSc [40, 79, 161, 164, 165, 174]. Interestingly, there is also an anecdotal report of significantly lower CIMT in 10 SSc patients than in an age- and sex-matched control group without coronary risk factors [175].

### **7.2. Ultrasonographic evaluation and duplex scanning**

SSc patients may have more severe, as well as more frequent, carotid disease (evaluating common carotid and its branches as well as the vertebral arteries) than the general population with similar rates of CV risk factors [66]. Carotid plaques are present in SSc, but probably not significantly more when compared to controls [161]. Evaluating other arteries using the ultrasonographic examination, the most impaired arteries in SSc are ulnar arteries, which are significantly narrower than those of the healthy controls. Other arteries are not significantly altered [176].

### **7.3. Flow-mediated dilation**

Flow-mediated vasodilation (FMD) is usually evaluated by ultrasonographic measurement of artery diameter at baseline and maximal vasodilation following periodic ischemia, achieved by external cuff inflation [64]. FMD is calculated as a change in percentage following cuff release divided by baseline diameter [64]. The dilation is dependent on the endothelium function following the release of endogenous substance from endothelial cells, such as NO [70, 163, 177]. Endothelial dysfunction (as reflected by abnormally lower FMD values) is a key mechanism in predicting ATS involvement [63, 74].

Impaired FMD is associated with the presence of traditional CV risk factors [178], and is independently predictive of incident CV events [179].

Many, but not all, studies have found FMD to be decreased in SSc compared with controls [8, 40, 64, 162, 163, 165, 172, 177, 180–182]. The results were independent of SSc type, disease duration, clinical findings, and traditional CV risk factors [64]. On the other hand, unchanged FMD in SSc patients was reported as well [163].

It was suggested that increased levels of LpA in SSc patients cause impaired FMD, since LpA is capable of inhibiting inducible NO synthase [88].

### **7.4. Nitroglycerin-mediated dilation in SSc**

**7.1. Intima-media thickness in SSc**

36 Systemic Sclerosis

in general population [64, 131].

duration, or clinical characteristics [166].

without coronary risk factors [175].

altered [176].

**7.3. Flow-mediated dilation**

predicting ATS involvement [63, 74].

pendently predictive of incident CV events [179].

**7.2. Ultrasonographic evaluation and duplex scanning**

Vessel intima-media thickness (IMT) is calculated by measuring the average thickness of the intima-media complex, the distance between the first and the second echogenic lines from the lumen [40, 64]. Carotid intima-media thickness (CIMT) as measured by high-resolution ultrasound is a well-validated marker of subclinical ATS. Increased CIMT has been shown to correlate with traditional CV risk factors, and to independently predict future vascular events

A meta-analysis of CIMT in rheumatic diseases, including RA, SLE, and SSc, found significantly increased values of CIMT in this population compared with healthy, age- and sexmatched controls [167]. The pooled result of the SSc studies demonstrated a greater CIMT in SSc than in controls, suggesting an increased prevalence of subclinical ATS in both dcSSc and lcSSc [166, 172, 173]. The effect size seen in SSc was also greater than those in RA and SLE. Higher CIMT values are associated with increased age, but probably not with disease type,

In contrast to these findings, a number of individual studies have found no increase in CIMT in patients with SSc [40, 79, 161, 164, 165, 174]. Interestingly, there is also an anecdotal report of significantly lower CIMT in 10 SSc patients than in an age- and sex-matched control group

SSc patients may have more severe, as well as more frequent, carotid disease (evaluating common carotid and its branches as well as the vertebral arteries) than the general population with similar rates of CV risk factors [66]. Carotid plaques are present in SSc, but probably not significantly more when compared to controls [161]. Evaluating other arteries using the ultrasonographic examination, the most impaired arteries in SSc are ulnar arteries, which are significantly narrower than those of the healthy controls. Other arteries are not significantly

Flow-mediated vasodilation (FMD) is usually evaluated by ultrasonographic measurement of artery diameter at baseline and maximal vasodilation following periodic ischemia, achieved by external cuff inflation [64]. FMD is calculated as a change in percentage following cuff release divided by baseline diameter [64]. The dilation is dependent on the endothelium function following the release of endogenous substance from endothelial cells, such as NO [70, 163, 177]. Endothelial dysfunction (as reflected by abnormally lower FMD values) is a key mechanism in

Impaired FMD is associated with the presence of traditional CV risk factors [178], and is inde-

Many, but not all, studies have found FMD to be decreased in SSc compared with controls [8, 40, 64, 162, 163, 165, 172, 177, 180–182]. The results were independent of SSc type, disease Nitroglycerin-mediated dilation (NMD) is measured by evaluating the percentage of change of the arterial diameter from baseline following administration of 25–400 μg of sublingual nitroglycerin [40, 162]. Unlike FMD, the NMD value is independent of endothelium function [163].

Several studies have reported abnormally low NMD values in SSc patients. However, an impaired FMD was also demonstrated in SSc, while NMD was preserved [40, 70].

NMD values appear to be reduced in dsSSc with Raynaud's phenomenon compared to controls [172, 180]. However, some studies did not find abnormal NMD in SSc patients [40, 163, 165, 183].

Impaired NMD was found to correlate with increased age in SSc patients [40]. Reduced nitrate-mediated dilation [172, 180, 184] could suggest a coexisting functional or structural abnormality of arterial smooth muscle, adventitia, or both.

### **7.5. Ankle Brachial Pressure Index in SSc**

Ankle Brachial Pressure Index (ABPI) is a validated diagnostic tool for PAD of the lower extremity. It is calculated by dividing the posterior tibial artery systolic pressure by the brachial systolic pressure (both in mmHg) [66]. Normally ABPI equals 1.0, whereas abnormal ABPI is defined as a continuous variable less than 0.90 (American College of Cardiologist/ American Heart Association Practice Guidelines for Management of Patients with PAD). Increasingly lower values reflect an increased rate of arterial disease [66, 80]. According to the American Diabetes Association consensus paper, values lower than 0.9 are only mildly abnormal, and a ratio lower than 0.4 reflects a severe disease [185].

Several studies found that ABPI was more commonly abnormal in SSc patients.

Values of ABPI of 0.9–1.0 are described in about 60% of SSc patients, compared to 0–10% of general population with the same rate of CV risk factors [66]. When comparing the subsets of SSc, dcSSc may rather tend to have altered ABPI than lcSSc [143]. ABPI values remain stable in most SSc patients over time [186].

### **7.6. Arterial stiffness**

Arterial stiffness is increased in the presence of CV risk factors [187], and is an independent predictor of CV events and CV and all-cause mortality across a wide range of patient populations [188]. This parameter performs as a well-validated surrogate marker of subclinical ATS, and an independent predictor of CV events and mortality [188].

Arterial stiffness has been examined in SSc but with varying results [122, 162–165, 177, 189]. This parameter is measured by the techniques of pulse wave analysis (PWA), and pulse wave velocity (PWV). Carotid-femoral PWV is considered the current "gold-standard" measurement of arterial stiffness [190]. PWA, expressed as the augmentation index (AI), reflects the stiffness of the aorta, whereas carotid-femoral PWV reflects the velocity of the pulse wave along the aortic and aortoiliac pathways. Increased arterial stiffness results in premature return of reflected waves in late systole, causing increased load on the left ventricle and increased myocardial oxygen demand [72].

Elevated values of PWA and PWV have been described in patients with dcSSc [162] and even more increased in patients with lcSSc. Moreover, PWV correlates positively with disease duration. Thus, it could be postulated that PWV may be a better measure of arterial stiffness than AI in SSc [122].

Arterial stiffness elevated in patients with SSc may correlate with elevated levels of soluble markers of endothelial activation, including plasma nitrate, soluble E-selectin, and soluble VCAM-1 [163].

However, microvascular disease or myocardial dysfunction may also contribute to the observed abnormality in AI [191]. SSc patients free from CVD were demonstrated to have higher AI, with respect to healthy controls. PWV, however, was not significantly increased. Interestingly, there was a paradoxical association between calcium channel blocker therapy and higher AI. This correlation may reflect generalized vasculopathy rather than atherosclerotic disease [192].

Significantly increased stiffness parameters (evaluating the macrovascular disease and subclinical ATS) may correlate positively with ATA serum levels and inversely with ACA [193].

### **7.7. Angiography examination**

Angiographic findings of the lower and upper extremity in SSc patients showed a correlation between CV risk factors and proximal, but not distal, PAD. The microvasculopathy related to disease pathogenesis may be considered the leading mechanism of peripheral vascular abnormalities in SSc according to a retrospective study of angiograms, when compared to atherosclerotic damage [142].

Taken together, these data suggest that SSc patients are more likely to develop PAD and scleroderma may be considered a risk factor of PAD.

### **8. Cardiac evaluation in SSc**

### **8.1. Coronary artery evaluation**

Angiographic evaluating of SSc patients with suspected coronary artery disease can reveal coronary artery disease, which seems to affect 22% of SSc patients. However, comparing the findings with the calculated standardized prevalence ratios according to Diamond and Forrester's probability analysis, the prevalence of coronary artery disease in SSc patients seems not to be larger than expected in patients without SSc [71].

A novel method of assessing coronary artery disease is the coronary calcium score, as determined by multidetector computed tomography. This technique measures coronary artery calcification that occurs in atherosclerotic plaque and has a good negative predictive value for CAD in the general population [194]. There is an evidence of higher presence of coronary calcification and higher coronary calcium score in patients with SSc compared to the healthy controls. Nevertheless, the correlation of coronary calcification with the angiographic findings in SSc is unknown [74].

Coronary artery calcifications may represent the same process as the process of subcutaneous calcinosis in SSc. However, in SSc patients, who did not have any subcutaneous calcinosis, coronary artery calcifications can be often detected as well [74]. Hence, subcutaneous calcinosis in SSc does not necessarily need to be associated with increased risk of coronary artery calcification.

### **8.2. Coronary flow reserve in SSc**

Arterial stiffness has been examined in SSc but with varying results [122, 162–165, 177, 189]. This parameter is measured by the techniques of pulse wave analysis (PWA), and pulse wave velocity (PWV). Carotid-femoral PWV is considered the current "gold-standard" measurement of arterial stiffness [190]. PWA, expressed as the augmentation index (AI), reflects the stiffness of the aorta, whereas carotid-femoral PWV reflects the velocity of the pulse wave along the aortic and aortoiliac pathways. Increased arterial stiffness results in premature return of reflected waves in late systole, causing increased load on the left ventricle and

Elevated values of PWA and PWV have been described in patients with dcSSc [162] and even more increased in patients with lcSSc. Moreover, PWV correlates positively with disease duration. Thus, it could be postulated that PWV may be a better measure of arterial stiffness

Arterial stiffness elevated in patients with SSc may correlate with elevated levels of soluble markers of endothelial activation, including plasma nitrate, soluble E-selectin, and soluble

However, microvascular disease or myocardial dysfunction may also contribute to the observed abnormality in AI [191]. SSc patients free from CVD were demonstrated to have higher AI, with respect to healthy controls. PWV, however, was not significantly increased. Interestingly, there was a paradoxical association between calcium channel blocker therapy and higher AI. This correlation may reflect generalized vasculopathy rather than atherosclerotic disease [192].

Significantly increased stiffness parameters (evaluating the macrovascular disease and subclinical ATS) may correlate positively with ATA serum levels and inversely with ACA [193].

Angiographic findings of the lower and upper extremity in SSc patients showed a correlation between CV risk factors and proximal, but not distal, PAD. The microvasculopathy related to disease pathogenesis may be considered the leading mechanism of peripheral vascular abnormalities in SSc according to a retrospective study of angiograms, when compared to

Taken together, these data suggest that SSc patients are more likely to develop PAD and

Angiographic evaluating of SSc patients with suspected coronary artery disease can reveal coronary artery disease, which seems to affect 22% of SSc patients. However, comparing the findings with the calculated standardized prevalence ratios according to Diamond and

increased myocardial oxygen demand [72].

than AI in SSc [122].

**7.7. Angiography examination**

atherosclerotic damage [142].

**8. Cardiac evaluation in SSc**

**8.1. Coronary artery evaluation**

scleroderma may be considered a risk factor of PAD.

VCAM-1 [163].

38 Systemic Sclerosis

Coronary flow reserve (CFR) is calculated by dividing the peak diastolic velocity during adenosine infusion, with the peak diastolic velocity at rest, and with a resting velocity time integral [195]. Abnormal CFR may reflect coronary artery disease or the incapability of microcirculation to supply the heart in cases of increased demand [134].

Several reports have found abnormal CFR in SSc patients. Reduced CFR alone cannot differentiate vasospasm from anatomic arterial stenosis. Therefore, abnormal CFR in SSc does not necessarily imply the presence of atherosclerotic plaque [134]. Examination by myocardial multidetector CT may elucidate the relationship between CFR and coronary anatomy [196].

Assessing CFR in the left anterior descending coronary artery using contrast enhanced transthoracic Doppler during adenosine infusion, even severe reduction can be detected in 50% of SSc patients, who have no heart disease symptoms [134, 195, 197].

Patients with dcSSc seem to have more severe reduction of CFR than lcSSc. Even younger dcSSc than lsSSc may suffer from worse damage of coronary arteries [195, 197].

### **8.3. Assessment of myocardial perfusion in SSc patients**

Using 99m-Tc sestamibi gated myocardial perfusion SPECT with a stress-rest protocol reveals perfusion defects reported in 38% of SSc patients, which are probably not associated with age, sex, SSc subset or duration of Raynaud's phenomenon [198]. On the other hand, this perfusion defects may be associated with severe skin thickness, digital ulcers, and esophageal involvement [198].

Stress perfusion defects in cardiac MRI are common in asymptomatic SSc patients. There can be a non-segmental perfusion defect too, not corresponding to epicardial coronary artery distribution, which suggests microvascular impairment [199]. Most of SSc patients have at least one segmental MRI perfusion defect (e.g. reduced signal intensity or delayed wash-in) at baseline [200]. Nifedipine can cause a significant increase in myocardial perfusion, according to an increased MRI perfusion index [200].

### **9. Prevention, management, and treatment of ATS in SSc**

In general, early CV screening is mandatory in order to prevent and early treat vascular disease. A European League Against Rheumatism (EULAR) task force has published recommendations for screening, prevention and treatment of CVD in arthritis [47]. Similar recommendations regarding SLE and scleroderma are to follow soon [26]. According to the EULAR recommendations for inflammatory arthritis, CV risk assessment should follow the national guidelines, or in case of absence of such guidelines, Systemic Coronary Risk Evaluation (SCORE) function mode should be used [47]. Detection of CV risk includes laboratory screening, physical examination (blood pressure, body composition, and body mass index), and non-invasive imaging methods [171].

### **9.1. Laboratory markers**

Laboratory markers include: (1) the parameters of lipid metabolism: total cholesterol (TC), LDL, HDL, TC/HDL ratio, TG or LpA and oxLDL, both associated with ATS in autoimmune diseases [171]; (2) glucose metabolism alteration and insulin resistance: fasting glucose or oral glucose tolerance test [171, 201]; (3) acute phase reactants, hsCRP, and erythrocyte sedimentation rate (ESR), which are associated with the presence of subclinical ATS, CV events, and CV mortality [202–204].

The association of specific biomarkers of endothelial activation, markers of inflammatory pathways, and specific genes with ATS and increased CV risk have been described, for example: cytokines (TNF superfamily and receptors for TNF, interferon gamma (IFNγ), interleukin 6 (IL-6), IL-1, transforming growth factor beta 1 (TGF-β1)), chemokines, and adipokines [205].

Biologic markers of possible cardiac dysfunction such as brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) are often elevated in patients with SSc [133]. Troponin has not been found to be elevated in SSc, so its elevated levels are suspected from non-scleroderma CVD or myopericarditis [206].

### **9.2. Non-invasive imaging methods**

Screening non-invasive and imaging techniques include a broad spectrum of methods for detection of ATS: US of peripheral arteries, and especially of common carotid arteries to provide CIMT measurement and plaque detection, assessment of subclinical ATS (using ABPI, FMD, NMD, PWA, PVW, AI), assessment of cardiac disease (using coronary calcium score detected by CT, SPECT or PET, MRI, etc.), all of which were mentioned above [170].

### **9.3. Therapy**

Beside the administration of vasculoprotective pharmacological agents, such as aspirin, statins, ACE inhibitors, and angiotensin II receptor blockers [47, 207–209], tight control over the disease activity and inflammatory activity is needed, using low-dose corticosteroids, immunosuppressive agents, or biologics [43, 207, 208, 210, 211].

baseline [200]. Nifedipine can cause a significant increase in myocardial perfusion, according

In general, early CV screening is mandatory in order to prevent and early treat vascular disease. A European League Against Rheumatism (EULAR) task force has published recommendations for screening, prevention and treatment of CVD in arthritis [47]. Similar recommendations regarding SLE and scleroderma are to follow soon [26]. According to the EULAR recommendations for inflammatory arthritis, CV risk assessment should follow the national guidelines, or in case of absence of such guidelines, Systemic Coronary Risk Evaluation (SCORE) function mode should be used [47]. Detection of CV risk includes laboratory screening, physical examination (blood pressure, body composition, and body mass

Laboratory markers include: (1) the parameters of lipid metabolism: total cholesterol (TC), LDL, HDL, TC/HDL ratio, TG or LpA and oxLDL, both associated with ATS in autoimmune diseases [171]; (2) glucose metabolism alteration and insulin resistance: fasting glucose or oral glucose tolerance test [171, 201]; (3) acute phase reactants, hsCRP, and erythrocyte sedimentation rate (ESR), which are associated with the presence of subclinical ATS, CV events, and CV

The association of specific biomarkers of endothelial activation, markers of inflammatory pathways, and specific genes with ATS and increased CV risk have been described, for example: cytokines (TNF superfamily and receptors for TNF, interferon gamma (IFNγ), interleukin 6 (IL-6), IL-1, transforming growth factor beta 1 (TGF-β1)), chemokines, and adipokines [205]. Biologic markers of possible cardiac dysfunction such as brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) are often elevated in patients with SSc [133]. Troponin has not been found to be elevated in SSc, so its elevated levels are suspected from non-sclero-

Screening non-invasive and imaging techniques include a broad spectrum of methods for detection of ATS: US of peripheral arteries, and especially of common carotid arteries to provide CIMT measurement and plaque detection, assessment of subclinical ATS (using ABPI, FMD, NMD, PWA, PVW, AI), assessment of cardiac disease (using coronary calcium score

Beside the administration of vasculoprotective pharmacological agents, such as aspirin, statins, ACE inhibitors, and angiotensin II receptor blockers [47, 207–209], tight control over

detected by CT, SPECT or PET, MRI, etc.), all of which were mentioned above [170].

**9. Prevention, management, and treatment of ATS in SSc**

to an increased MRI perfusion index [200].

40 Systemic Sclerosis

index), and non-invasive imaging methods [171].

**9.1. Laboratory markers**

mortality [202–204].

**9.3. Therapy**

derma CVD or myopericarditis [206].

**9.2. Non-invasive imaging methods**

There are no specific recommendations for management of traditional risk factors, such as dyslipidemia, diabetes mellitus, or smoking in SSc patients. Their treatment mostly follows the national guidelines. According to the EULAR recommendations, statins, ACE inhibitors, and angiotensin II (AT-II) blockers are considered as preferred treatment options [47, 212].

Statins significantly reduce the risk of CV disease by lipid lowering effect and modulation of inflammatory pathways [213, 214]. Aspirin is used in general population to prevent the risk of CVD. Glitazones (peroxisome proliferator-activated receptor gamma, PPARγ agonists) are preferred in treatment of insulin resistance because of their potential vasculoprotective and anti-inflammatory effects [215].

The most severe complications (e.g. PAH and SRC) are treated according to the EULAR recommendations for SSc, with use of calcium channel blockers in case of PAH, and ACE inhibitors in case of SRC [216]. Both of them, similarly as endothelin receptor antagonist (ERA) bosentan [217], have been demonstrated to have beneficial effects on myocardial perfusion, and on limiting further progression of life-threatening complications [200, 218, 219].

Nonsteroidal anti-inflammatory drugs (NSAIDs), administrated in pericarditis in SSc [216], are not recommended for long-term use with respect to the CV perspective [220].

To control the disease activity and inflammation, proper anti-inflammatory therapy should be administered. Corticosteroids and disease modifying antirheumatic drugs (DMARDs), used in some SSc manifestations according to the EULAR recommendation [216], may influence the CV risk.

Corticosteroids (used e.g. for treatment of myocarditis) may reduce vascular risk by effectively suppressing systemic inflammation [47]. On the other hand, they are pro-atherogenic and lead to dyslipidaemia, diabetes and hypertension [220, 221]. A daily threshold dose of 8 mg of prednisone was established, above which the number of deaths increases in a dosedependent manner [222]. Corticosteroids should be used at the lowest doses possible for the shortest period of time possible [47].

Methotrexate (MTX), recommended particularly to treat the skin manifestations, exerts bimodal effects on the vasculature. It increases the production of pro-atherogenic homocysteine, which can promote endothelial injury, and increases LDL oxidation [223, 224]. On the other hand, hyperhomocysteinemia can be reversed by folate supplementation [225]. However, MTX may also be atheroprotective by inhibiting foam cell formation and modifying reverse cholesterol transport [226]. In the EULAR cardiovascular recommendations for inflammatory arthritis, administration of MTX to the adequate control of disease activity is preferred to the possible negative CV effects of treatment [47].

Cyclophosphamide (CPA), used in treatment of ILD, induces cardiac damage and heart failure by its influence on the myocardial cells metabolism and induction of apoptosis [227]. According to experimental studies, CPA may influence the lipid metabolism [228], for example, via the cholesterol transfer activity enhancement [229].

Regarding the biologics, studies in CV effects are almost exclusively in RA, and these drugs are not commonly used in patients with SSc. Numerous recent studies concluded, that infliximab, etanercept, adalimumab and rituximab may improve endothelial function and decrease CIMT and arterial stiffness in arthritis patients [208, 210, 211].

There may be differences among anti-TNF agents in terms of their effects on CV risk. There are controversial results on the effects of TNF blockers on lipid profiles, while infliximab may worsen the atherogenic index [211, 230]. On the other hand, biologics may also improve insulin sensitivity, decrease resistin, and increase adiponectin production [211, 231]. Rituximab may also exert vasculoprotective effects [232–234].

### **10. Conclusion**

Systemic sclerosis is a chronic, progressive, potentially lethal rheumatic disease. The management and treatment of life-threating disease manifestations, such as pulmonary arterial hypertension or scleroderma renal crisis, have improved over the last decades. Other causes, which increase the morbidity and mortality, have arisen, including the cardiovascular diseases in the first place. Similar to other rheumatic diseases, and based on many above-mentioned studies on pathogenesis of atherosclerosis in autoimmune conditions, cardiovascular risk in scleroderma is believed to be increased compared to the general population. The rate of this risk is not clear to date. Angiographic, sonographic, and computed tomography studies have provided conflicting data regarding the presence of macrovascular coronary lesions and accelerated atherosclerosis in scleroderma. Screening for subclinical cardiac involvement provides an opportunity for early diagnosis and treatment, which is crucial for positive outcome and prognosis. Thus, patients with systemic sclerosis should be closely observed, followed, and modifiable risk factors should be treated in the early stage. Moreover, future studies assessing larger cohorts of patients using standardized tools are needed to elucidate the cardiovascular risk in scleroderma patients.

### **Acknowledgements**

This chapter was supported by grant projects AZV 16-33542A, AZV 16-33574A, SVV 260263, PRVOUK, and the Ministry of Health of the Czech Republic [Research Project No. 00023728].

### **Author details**

Sabina Oreska and Michal Tomcik\*

\*Address all correspondence to: michaltomcik@yahoo.com

Department of Rheumatology, First Faculty of Medicine, Institute of Rheumatology, Prague, Czech Republic

### **References**

Regarding the biologics, studies in CV effects are almost exclusively in RA, and these drugs are not commonly used in patients with SSc. Numerous recent studies concluded, that infliximab, etanercept, adalimumab and rituximab may improve endothelial function and decrease

There may be differences among anti-TNF agents in terms of their effects on CV risk. There are controversial results on the effects of TNF blockers on lipid profiles, while infliximab may worsen the atherogenic index [211, 230]. On the other hand, biologics may also improve insulin sensitivity, decrease resistin, and increase adiponectin production [211, 231]. Rituximab

Systemic sclerosis is a chronic, progressive, potentially lethal rheumatic disease. The management and treatment of life-threating disease manifestations, such as pulmonary arterial hypertension or scleroderma renal crisis, have improved over the last decades. Other causes, which increase the morbidity and mortality, have arisen, including the cardiovascular diseases in the first place. Similar to other rheumatic diseases, and based on many above-mentioned studies on pathogenesis of atherosclerosis in autoimmune conditions, cardiovascular risk in scleroderma is believed to be increased compared to the general population. The rate of this risk is not clear to date. Angiographic, sonographic, and computed tomography studies have provided conflicting data regarding the presence of macrovascular coronary lesions and accelerated atherosclerosis in scleroderma. Screening for subclinical cardiac involvement provides an opportunity for early diagnosis and treatment, which is crucial for positive outcome and prognosis. Thus, patients with systemic sclerosis should be closely observed, followed, and modifiable risk factors should be treated in the early stage. Moreover, future studies assessing larger cohorts of patients using standardized tools are needed to elucidate the cardiovascular risk in scleroderma patients.

This chapter was supported by grant projects AZV 16-33542A, AZV 16-33574A, SVV 260263, PRVOUK, and the Ministry of Health of the Czech Republic [Research Project No. 00023728].

Department of Rheumatology, First Faculty of Medicine, Institute of Rheumatology, Prague,

CIMT and arterial stiffness in arthritis patients [208, 210, 211].

may also exert vasculoprotective effects [232–234].

**10. Conclusion**

42 Systemic Sclerosis

**Acknowledgements**

**Author details**

Czech Republic

Sabina Oreska and Michal Tomcik\*

\*Address all correspondence to: michaltomcik@yahoo.com


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**Provisional chapter**

## **Survival, Mortality, Causes of Death and Risk Factors of Poor Outcome Poor Outcome**

**Survival, Mortality, Causes of Death and Risk Factors of** 

DOI: 110.5772/intechopen.68549

Manuel Rubio-Rivas Additional information is available at the end of the chapter

Manuel Rubio-Rivas

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60 Systemic Sclerosis

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Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68549

### **Abstract**

Systemic sclerosis is a rare autoimmune disorder with a historically bad prognosis. Survival has been improving over time and we can currently estimate a 1-year survival, 94.9; a 5-year survival, 84.4; a 10-year survival, 70.9 and a 20-year survival, 44.9%, from the time of diagnosis. Accordingly, mortality has been decreasing over time, being the overall standardized mortality ratio (SMR) 2.72 (1.90–3.83), SMR 2.4 after 1990. Among the SSc-related causes of death, the lung death is the most important cause and its relative percentage is increasing over time since the introduction of ACE inhibitors for the treatment of scleroderma renal crisis (SRC) in early 1990s. Among the SSc-non-related causes of death, cancer, infection and cardiovascular disorders are the leading causes of death. Risk factor predictors of poor outcomes are an elder age at diagnosis, the male gender, diffuse subset, visceral involvement and non-Raynaud's phenomenon onset.

**Keywords:** systemic sclerosis, survival, mortality, death, prognosis

### **1. Introduction**

Systemic sclerosis (SSc) represents one of the autoimmune systemic diseases with worse prognosis. It was actually a devastating scenario until it became well advanced in the twentieth century in terms of survival and mortality, but since late 1980s, the knowledge and course of scleroderma have been progressively improving. Nowadays, more risk factors are recognized and allow physicians to focus on patients with worse prognosis. As traditional SSc-related involvements improved, secondary involvements or SSc-non-related diseases have gained prominence.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **2. Survival**

Scleroderma was a devastating disease for ages. Physicians were short of proper tools to change significantly the prognosis of the disease since late 1980s–early 1990s due to the introduction of new therapies, firstly angiotensin converting enzyme (ACE) inhibitors for the treatment of the scleroderma renal crisis (SRC) and, in late 1990s-early 2000s, due to the implementation of pulmonary arterial hypertension (PAH) treatment with new drugs such as phosphodiesterase five (PDE5) inhibitors and antagonists of the receptor of endothelin (AREs). Survival has improved over time, measured at any time of the follow-up, from onset (in most studies described in the form of Raynaud's phenomenon) as well as from diagnosis and what is more important is that it keeps improving. This is true that survival in all stages has improved but especially 1-year and 5-year survival. Since late death is related the most to SSc-non-related causes, it might be reflecting the fact that physicians are improving significantly the prognosis of SSc-related involvements but not that much in other SSc-non-related diseases. Thus, just like in other autoimmune diseases, scleroderma is becoming step-by-step a chronic disease and not a terminal and deleterious diagnosis.

Prior to the assessment of survival of any cohort, we must pay attention to the methodology of the study because there is a huge variability among them, sometimes assessing survival from diagnosis and sometimes from the onset of disease. These last data are obviously a more imprecise data but certainly more real. Several survival and mortality studies from single cohorts and reviews have been published from the last mid-century, reporting data about cumulative survival at different times of follow-up and measured sometimes from the onset of disease and sometimes from the time of diagnosis (**Table 1**) [1–42].

We show data previously released in Seminars in Arthritis and Rheumatism in the last and more precise meta-analysis, so that we can currently predict at the time of diagnosis: a 1-year survival, 94.9; a 5-year survival, 84.4; a 10-year survival, 70.9 and a 20-year survival, 44.9% (**Table 2** and **Figure 1**) [43].



**Study Country Years (mid-**

(**Table 2** and **Figure 1**) [43].

**2. Survival**

62 Systemic Sclerosis

**cohort)**

a chronic disease and not a terminal and deleterious diagnosis.

of disease and sometimes from the time of diagnosis (**Table 1**) [1–42].

**1-year survival**

Scleroderma was a devastating disease for ages. Physicians were short of proper tools to change significantly the prognosis of the disease since late 1980s–early 1990s due to the introduction of new therapies, firstly angiotensin converting enzyme (ACE) inhibitors for the treatment of the scleroderma renal crisis (SRC) and, in late 1990s-early 2000s, due to the implementation of pulmonary arterial hypertension (PAH) treatment with new drugs such as phosphodiesterase five (PDE5) inhibitors and antagonists of the receptor of endothelin (AREs). Survival has improved over time, measured at any time of the follow-up, from onset (in most studies described in the form of Raynaud's phenomenon) as well as from diagnosis and what is more important is that it keeps improving. This is true that survival in all stages has improved but especially 1-year and 5-year survival. Since late death is related the most to SSc-non-related causes, it might be reflecting the fact that physicians are improving significantly the prognosis of SSc-related involvements but not that much in other SSc-non-related diseases. Thus, just like in other autoimmune diseases, scleroderma is becoming step-by-step

Prior to the assessment of survival of any cohort, we must pay attention to the methodology of the study because there is a huge variability among them, sometimes assessing survival from diagnosis and sometimes from the onset of disease. These last data are obviously a more imprecise data but certainly more real. Several survival and mortality studies from single cohorts and reviews have been published from the last mid-century, reporting data about cumulative survival at different times of follow-up and measured sometimes from the onset

We show data previously released in Seminars in Arthritis and Rheumatism in the last and more precise meta-analysis, so that we can currently predict at the time of diagnosis: a 1-year survival, 94.9; a 5-year survival, 84.4; a 10-year survival, 70.9 and a 20-year survival, 44.9%

Tuffanelli [1] The USA 1935–1958(46) NA 70.3% 69% NA Diagnosis Farmer [2] The USA 1945–1952(48) NA 53% NA NA Diagnosis Bennet [3] The UK 1947–1970(58) 94% 73% 50% NA Diagnosis Medsger [4] The USA 1955–1970(62) 78% 48% NA NA Diagnosis Zarafonetis [5] The USA 1948–1980(64) NA 81.4% 69.4% NA Diagnosis Medsger [6] The USA 1963–1970(66) 70% 44% NA NA Diagnosis Rowell [7] The UK 1960–1975(67) NA NA 74% NA Onset (first

Barnett [8] AUS 1953–1983(68) NA 83.6% 59.3% 27.1% Onset (first

Gouet [9] FR 1960–1984(72) 88% 62.5% 50.5% NA Diagnosis

**5-year survival** **10-year survival** **20-year survival** **From onset/ diagnosis**

Raynaud)

Raynaud)


**Table 1.** Survival studies on scleroderma [43].



T-test for independent groups among studies before and after 1990 (mid-cohort year). NA: non-available. Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

**Table 2.** Survival studies on scleroderma [43].

**Study Country Years (mid-**

64 Systemic Sclerosis

**cohort)**

**1-year survival**

Nihtyanova [32] The UK 1990–1993(91) NA 84.2% NA NA Diagnosis

Joven [33] SPA 1980–2006(93) 95% 85% 75% 55% Onset

Ruangjutipopan [34] THAI 1987–2001(94) NA 73% 67.4% NA Onset (no

Czirják [35] HUN 1983–2005(94) NA 84% 72.6% NA Diagnosis Arias-Núñez [36] SPA 1988–2006(97) NA 83.9% 64.9% NA Diagnosis Alba [37] SPA 1986–2010(98) NA 90.7% NA NA Diagnosis Al-Dhaher [38] CAN 1994–2004(99) NA 90% 82% NA Diagnosis Sampaio-Barros [39] BRA 1991–2010(00) NA 90% 84% NA Onset (no

Hoffmann-Vold [40] NOR 1999–2009(04) NA 95% 86% NA Onset

Vettori [41] ITA 2000–2008(04) NA 94.8 NA NA Onset (first

Kuo [42] TAIW 2002–2007(05) 94.9% 83.2% NA NA Diagnosis

**p Before 1990 (four studies)**

840 1693 846 802 4365 3476

**Survival from onset (first non-Raynaud's symptom)**

– – – 92 (NA) 95 (NA) – 85.3(9.5) 94.9(NA) 0.384

85.1(10.4) 92.8(2.9) 0.385 79.7 (8.2) 90 (5.0) 0.118 70.6(14.3) 84.4(3.8) 0.001

71.5(9.5) 88(NA) 0.189 72.1 (2.5) 80.5 (7.8) 0.358 58.8(14.8) 70.9(10.1) 0.086

**After 1990 (three studies)**

**p Before 1990 (18 studies)**

NA: non-available. Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

**Table 1.** Survival studies on scleroderma [43].

**Raynaud)**

Number of patients

1-year survival% mean (SD)

5-year survival% mean (SD)

10-year survival% mean

(SD)

**Before 1990 (five studies)**

**Survival from onset (first** 

**After 1990 (three studies)**

**5-year survival**

2000–2003(01) NA 89.9% NA NA Onset

**10-year survival** **20-year survival** **From onset/ diagnosis**

(first non-Raynaud's symptom)

(first non-Raynaud's symptom)

definition)

definition)

(first non-Raynaud's symptom)

Raynaud)

**Survival from diagnosis**

**After 1990 (eight studies)**

**p**

**Figure 1.** Survival evolution over time. Meta-regression. Five-year survival (coefficient b = 0.308 and p = 0.402) and 10-year survival (coefficient b = 0.595 and p = 0.237) from the onset (first Raynaud). Five-year survival (coefficient b = 0.612 and p = 0.113) and 10-year survival (coefficient b = 0.590 and p = 0.037) from the onset (first non-Raynaud's symptom). Fiveyear survival (coefficient b = 0.595 and p < 0.001) and 10-year survival (coefficient b = 0.536 and p = 0.025) from diagnosis. Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

### **3. Mortality**

SSc is an autoimmune disease with a broad spectrum of severity, ranging from a mild disease to a devastating one. The most valuable parameter in order to compare mortality (instead of a crude mortality rate) is the assessment of the SMR, a fundamental tool in the only five mortality metaanalyses reported so far in SSc (**Table 3**). The SMR is the ratio between observed mortality and expected mortality in sex- and age-matched general population. These five meta-analyses are based on the assessment of the SMR: Elhai et al. {nine studies, overall SMR is 3.53 (3.03–4.11)} [45], Loannidis et al. {seven studies} [44], Toledano et al. {seven studies, overall SMR 3.51 (2.74–4.50)} [46], Komócsi et al. {10 studies, overall SMR 3.24} [47] and Rubio-Rivas et al. {17 studies, overall SMR 2.72 (1.90–3.83)} [43]. In base of this last study based on 17 studies, we could state that mortality is over 2.7-fold compared to the general population (**Table 4** and **Figure 2**) [5, 17, 24, 26, 29, 30, 31, 33, 37, 40, 42, 48–53]. Mortality has been decreasing over time and notoriously after 1990, being more reasonable to accept nowadays an SMR over 2.4-fold in a patient diagnosed today (**Figure 2**). Obviously, prognosis should be individualized since different risk factors present at diagnosis or during the follow-up can modify this predicted SMR. For instance, SMR in males and dcSSc subset is expected to be worse compared to SMR in females or lcSSc subset (**Figure 3**).


**Table 3.** Meta-analyses on scleroderma and mortality.



NA: non-available, SMR: standardized mortality ratio, dcSSc: diffuse cutaneous systemic sclerosis and lcSSc: limited cutaneous systemic sclerosis. Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

**Table 4.** Studies included in the SMR meta-analysis by Rubio-Rivas et al [43].

**3. Mortality**

66 Systemic Sclerosis

NA: non-available.

Abu-Shakra [48]

Hesselstrand [26]

Hashimoto [29]

**Table 3.** Meta-analyses on scleroderma and mortality.

**cohort year)**

(64)

(78)

(85)

(87)

SWE 1983–1995 (89)

JAP 1973–1908 (90)

CAN 1976–1990 (83)

**Study Country Years (mid-**

Zarafonetis [5] US 1948–1980

Jacobsen [17] DEN 1960–1996

Walsh [49] US 1981–1990

Bryan [24] UK 1982–1992

SSc is an autoimmune disease with a broad spectrum of severity, ranging from a mild disease to a devastating one. The most valuable parameter in order to compare mortality (instead of a crude mortality rate) is the assessment of the SMR, a fundamental tool in the only five mortality metaanalyses reported so far in SSc (**Table 3**). The SMR is the ratio between observed mortality and expected mortality in sex- and age-matched general population. These five meta-analyses are based on the assessment of the SMR: Elhai et al. {nine studies, overall SMR is 3.53 (3.03–4.11)} [45], Loannidis et al. {seven studies} [44], Toledano et al. {seven studies, overall SMR 3.51 (2.74–4.50)} [46], Komócsi et al. {10 studies, overall SMR 3.24} [47] and Rubio-Rivas et al. {17 studies, overall SMR 2.72 (1.90–3.83)} [43]. In base of this last study based on 17 studies, we could state that mortality is over 2.7-fold compared to the general population (**Table 4** and **Figure 2**) [5, 17, 24, 26, 29, 30, 31, 33, 37, 40, 42, 48–53]. Mortality has been decreasing over time and notoriously after 1990, being more reasonable to accept nowadays an SMR over 2.4-fold in a patient diagnosed today (**Figure 2**). Obviously, prognosis should be individualized since different risk factors present at diagnosis or during the follow-up can modify this predicted SMR. For instance, SMR in males and dcSSc subset is expected to be worse compared to SMR in females or lcSSc subset (**Figure 3**).

**Study Year of publication Number of studies included SMR (95% CI)**

Elhai et al. [45] 2012 9 3.53 (3.03–4.11) Toledano et al. [46] 2012 7 3.51 (2.74–4.50) Komócsi et al. [47] 2012 10 3.24 (NA) Rubio-Rivas et al. [43] 2014 17 2.72 (1.93–3.83)

> **Death Overall SMR (95%CI)**

> > (3.17-7.63)

(2.50-3.40)

(3.73-5.65)

(1.01-1.1)

(3.03-5.22)

(3.48-6.07)

(2.18-3.35)

142 5.40

160 2.90

61 4.69

2123 1.05

55 4.05

49 4.59

86 2.76

**dcSSc SMR (95%CI)**

4.50 (3.50-5.70)

6.18 (4.17-8.81)

6.06 (4.09-9.02)

5.90 (4.20-7.61) **lcSSc SMR (95%CI)**

2.30 (1.80-2.80)

3.80 (2.58-5.39)

NA NA 3.22

3.72 (2.41-532)

1.71 (1.18-2.24)

NA NA NA NA

NA NA NA NA

**Male SMR (95%CI)**

3.70 (2.70-5.10)

4.18 (2.09-7.48)

(1.85-4.97)

4.77 (3.21-7.09)

3.31 (1.15-5.47) **Female SMR (95%CI)**

2.70 (2.30-3.30)

4.81 (3.65-6.44)

4.59 (3.22-6.19)

4.44 (2.87-6.34)

2.71 (2.10-3.32)

Ioannidis et al. [44] 2005 7 –

**Figure 2.** SMR meta-analysis. The overall SMR (discontinuous points) is 2.71 (1.95–3.75). SMR before 1990 (continuous line) is 3.33 (1.64–6.75). SMR after 1990 (discontinuous lines) is 2.42 (1.89–3.11). Forest plot. Meta-regression of change in SMR (lnSMR) with mid-cohort year (Coefficient b = –0.055 and p = 0.064). Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

**Figure 3.** SMR meta-analysis. For the male gender, overall SMR is 3.18 (2.62–3.85) and for the female gender, overall SMR is 2.81 (2.25–3.50); for dcSSc subtype, the overall SMR is 4.73 (3.69–6.07) and for lcSSc subtype, overall SMR is 2.04 (1.55–2.68). Forest plot. Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

### **4. Causes of death**

As in other autoimmune diseases, the pattern of mortality has been changing over time since the autoimmune disease by itself has been the main cause of death in these patients for ages but the more physicians control the disease, the more likely it is to die due to other causes not directly related to SSc [43, 54–56].

### **4.1. SSc-related causes of death**

Among the SSc-related causes, there are four major organs potentially involved: the lungs, heart, kidneys and gastrointestinal tract. Among them, lung and renal involvement were the most important as a cause of death during the twentieth century (**Table 5**) [2, 3, 7, 8, 11–13, 15, 17–19, 21–24, 26, 29, 31, 33–42, 48, 50–53, 56, 57, 59–62].

### *4.1.1. Lung involvement*

In the case of lung involvement, death can be due to the progression towards respiratory failure due to PAH or interstitial lung disease (ILD).

In the case of PAH, evidence suggests that SSc-PAH patients have a worse response to therapy when compared to idiopathic PAH. New therapies (phosphodiesterase type 5 inhibitors and endothelin receptor antagonists) have improved its prognosis but not that much and thus, this is still a severe manifestation of the disease and a frequent cause of death. An early combination schedule of treatment has been suggested to be better in terms of prognosis. However, more studies are required to demonstrate and standardize this strategy of treatment [63].

Interstitial lung disease constitutes the most severe manifestation of the disease and is in fact the first cause of death in these patients (**Figure 4**). Therefore, it is crucial to perform a regular screening of this involvement and an early treatment when diagnosed. Patients showing the following criteria would warrant an immunosuppressive treatment: (1) either an extent of lung disease >20% on High-resolution computed tomography (HRCT) or an indeterminate extent (disease extent not readily classifiable as minimal or severe; HRCT extent is 10–30%) of disease plus an FVC < 70%, (2) patients experiencing a significant decrease in pulmonary functional assessment during the follow-up (FVC > 10% or DLco >15% or both, whatever the extent of lung involvement is for 12 months). Currently, the management of SSc–ILD is largely confined to immunomodulvation. Non-selective immunosuppressants such as cyclophosphamide followed by mycophenolate mofetil and azathioprine are still the most widely used medications in SSc-ILD. Several alternative approaches may be considered, including B cell depletion therapies (rituximab), anti-TGF-β antibody, tyrosine kinase inhibitors (imatinib, dasatinib), anti-IL-6 antibody, anti-IL-13 antibody, pirfenidone and haematopoietic stem cell transplantation (HSCT). Finally, lung transplantation may be limited to those patients, with severe SSc-ILD, unresponsive to pharmacologic therapy [64]. It is important to remember that, although often used, during the first stages of treatment, prednisone doses over 15 mg a day can be dangerous in order to trigger a scleroderma renal crisis.

### *4.1.2. Renal involvement*

**4. Causes of death**

68 Systemic Sclerosis

directly related to SSc [43, 54–56].

**4.1. SSc-related causes of death**

17–19, 21–24, 26, 29, 31, 33–42, 48, 50–53, 56, 57, 59–62].

As in other autoimmune diseases, the pattern of mortality has been changing over time since the autoimmune disease by itself has been the main cause of death in these patients for ages but the more physicians control the disease, the more likely it is to die due to other causes not

**Figure 3.** SMR meta-analysis. For the male gender, overall SMR is 3.18 (2.62–3.85) and for the female gender, overall SMR is 2.81 (2.25–3.50); for dcSSc subtype, the overall SMR is 4.73 (3.69–6.07) and for lcSSc subtype, overall SMR is 2.04

(1.55–2.68). Forest plot. Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

Among the SSc-related causes, there are four major organs potentially involved: the lungs, heart, kidneys and gastrointestinal tract. Among them, lung and renal involvement were the most important as a cause of death during the twentieth century (**Table 5**) [2, 3, 7, 8, 11–13, 15, Scleroderma renal crisis occurs during the rapid progression of skin thickening in the early stages of dcSSc (<5 years after disease onset). Several case series published during the past 20 years and a 2013 systematic literature review has estimated that SRC develops in 5–15 and 15% of patients with dcSSc, respectively. Interestingly, the incidence and prevalence of SRC seem to be decreasing over time, possibly as a result of early recognition and management of SRC risk factors and early signs and symptoms in patients with dcSSc [65]. The introduction of ACE inhibitors (captopril) reduced dramatically its frequency as the cause of death since early 1990s of the past century (**Figure 4**). Besides, its incidence is decreasing but due to unknown reasons. The extended use of ACE inhibitors prescribed for other reasons (i.e. arterial hypertension or heart failure) has not been found as the cause of this decreasing incidence.



Lung, heart, kidney and GI are deaths related to SSc. NA: non-available; GI: gastrointestinal. Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

**Table 5.** SSc-related causes of death in medical literature [43].

**Country Years (mid-**

(48)

(58)

(67)

(68)

(75)

(75)

(75)

(77)

(78)

(78)

(80)

(82)

(83)

(84)

(84)

(86)

(87)

(87)

(88)

(89)

(89)

Farmer [2] US 1945–1952

70 Systemic Sclerosis

Bennet [3] UK 1947–1970

Rowell [7] UK 1960–1975

Barnett [8] AUS 1953–1983

Altman [11] US 1973–1977

Eason [12] NZ 1970–1980

Wynn [13] US 1970–1980

Ferri [15] ITA 1955–1999

Lally [16] US 1972–1984

Jacobsen [17] DEN 1960–1996

Kuwana [18] JAP 1971–1990

Geirsson [19] ICE 1975–1990

Abu-Shakra [48] CAN 1976–1990

Nishioka [21] JAP 1974–1994

Steen [56] US 1972–1996

Simeón [22] SPA 1976–1996

Bulpitt [23] US 1982–1992

Bryan [24] UK 1982–1992

Geirsson [57] SWE 1982–1995

Hesselstrand [26] SWE 1983–1995

Bond [58] AUS 1983–1996

**cohort year)**

**Deads/n SSc-related death**

115/271 (49%)

26/67 (38.8%)

22/84 (26.2%)

86/177 (48.6%)

131/264 (49.6%)

24/47 (51%)

25/64 (39.1%)

17/91 (18.7%)

160/344 (46.5%)

51/275 (18.5%)

5/23 (21.7%)

61/237 (25.7%)

90/496 (18.1%)

364/1508 (24.1%)

12/79 (15.2%)

15/48 (31.3%)

55/283 (19.4%)

30/100 (30%)

49/249 (19.7%)

123/123 (100%)

279/1012 (27.6%)

**Lung death**

17 (14.8%) 5 (29.4%) 6

42 (48.8%) 8 (19%) 10

18 (75%) 7 (38.9%) 4

17 (68%) 7 (41.2%) 6

14 (82.4%) 0 (0%) 8

(31.7%)

(71.9%)

(29.5%)

(68.8%)

9 (60%) 4 (44.4%) 1

(44.1%)

(66.7%)

(30.2%)

41 (25.6%) 13

32 (62.7%) 23

44 (77.1%) 13

64 (71.1%) 44

34 (61.8%) 15

15 (30.6%) 10

43 (35%) 13

(21.3%)

89 (68%) 19

**Heart death**

(35.3%)

(11.6%)

(22.2%)

(35.3%)

(57.1%)

61 (35.9%) NA NA NA NA

4 (12.5%)

2 (40%) 0 (0%) 1 (50%) 1 (50%) 0 (0%)

5 (11.4%)

31 (48.4%)

182 (50%) NA NA NA NA

11 (91.7%) 4 (36.4%) 0 (0%) 7 (63.6%) 0 (0%)

(11.1%)

5 (14.7%)

10 (33.3%) 5 (50%) 4 (40%) 1 (10%) 0 (0%)

14 (32.6%)

19 (21.3%)

1 (9.1%) 0 (0%) 1 (9.1%) 0 (0%) 0 (0%)

NA NA NA NA NA

**Kidney death**

1 (5.9%) 1 (5.9%)

16 (38.1%) 8 (9.3%)

35 (39.3%) 13 (14.6%)

5 (27.8%) 2 (11.1%)

4 (23.5%) 0 (0%)

6 (42.9%) 0 (0%)

5 (15.6%) 0 (0%)

5 (11.4%) 0 (0%)

4 (44.4%) 0 (0%)

5 (14.7%) 3 (8.8%)

1 (6.7%) 1 (6.7%) 3 (20%)

6 (14%) NA

12 (18.8%) 13 (20.3%)

1 (2.4%) 17 (41.5%) 9 (22%)

**GI death**

**Figure 4.** Meta-regression of deaths due to lung over time (coefficient b = 0.935 and p = 0.005) and renal (coefficient b=−0.206 and p = 0.352). Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

### *4.1.3. Heart involvement*

Despite the fact that definite SSc for cardiac involvement does not exist, we could categorize its involvement in five major groups: pericarditis with or without cardiac tamponade, ischemic cardiopathy (documented myocardial infarction, angina, ischemic alterations in myocardial perfusion SPECT or requirement of coronary revascularization, surgical or percutaneous), pacemaker bearing regardless of the time of arrhythmia, sudden death and congestive heart failure [66]. As it is more recognized nowadays, its ratio is increasing, but the real challenge in the years to come shall be to distinguish the real scleroderma involvement from a cardiac SSc-non-related involvement. Anyway, we can hypothesize today that this is related to SSc in younger patients without classical cardiovascular risk factors.

### *4.1.4. Gastrointestinal involvement*

The gastrointestinal tract is the most affected organ after the skin and can be affected from the oral cavity to the anus. About 90% of all patients will be affected during follow-up. This involvement can result in a decreased quality of life more often than a direct cause of death. In fact, it has been a rare cause of death over time. The few fatal cases have been related to those with severe intestinal involvement leading to malabsorption and secondary starvation. We cannot forget the possible role of the oesophageal involvement in the development of interstitial lung disease [67].

### **4.2. SSc-non-related causes of death**

Among SSc-non-related causes of death, we can find three major diseases: cancer, infections and cardiovascular diseases (**Table 6**) [2, 3, 7, 8, 11–13, 15, 17–19, 21–24, 26, 29, 31, 33–42, 48, 50–53, 56, 57, 59–62].


**Figure 4.** Meta-regression of deaths due to lung over time (coefficient b = 0.935 and p = 0.005) and renal (coefficient

Despite the fact that definite SSc for cardiac involvement does not exist, we could categorize its involvement in five major groups: pericarditis with or without cardiac tamponade, ischemic cardiopathy (documented myocardial infarction, angina, ischemic alterations in myocardial perfusion SPECT or requirement of coronary revascularization, surgical or percutaneous), pacemaker bearing regardless of the time of arrhythmia, sudden death and congestive heart failure [66]. As it is more recognized nowadays, its ratio is increasing, but the real challenge in the years to come shall be to distinguish the real scleroderma involvement from a cardiac SSc-non-related involvement. Anyway, we can hypothesize today that this is related to SSc in

The gastrointestinal tract is the most affected organ after the skin and can be affected from the oral cavity to the anus. About 90% of all patients will be affected during follow-up. This involvement can result in a decreased quality of life more often than a direct cause of death. In fact, it has been a rare cause of death over time. The few fatal cases have been related to those with severe intestinal involvement leading to malabsorption and secondary starvation. We cannot forget the possible role of the oesophageal involvement in the development of

Among SSc-non-related causes of death, we can find three major diseases: cancer, infections and cardiovascular diseases (**Table 6**) [2, 3, 7, 8, 11–13, 15, 17–19, 21–24, 26, 29, 31, 33–42, 48,

b=−0.206 and p = 0.352). Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

younger patients without classical cardiovascular risk factors.

*4.1.3. Heart involvement*

72 Systemic Sclerosis

*4.1.4. Gastrointestinal involvement*

interstitial lung disease [67].

50–53, 56, 57, 59–62].

**4.2. SSc-non-related causes of death**


**Table 6.** SSc-non-related causes of death in medical literature [43].

### *4.2.1. Cancer*

A higher standardized incidence ratio (SIR) of cancer in these patients not only compared to the general population that could be related to immunosuppressive treatment but also to the self-nature of the disease has been described [68]. In fact, those cancers diagnosed within the first 3 years after the diagnosis of scleroderma have been suggested to be classified as SSc-related causes. Cancer among SSc patients with RNA polymerase III antibodies has been reported to be in a close temporal relationship to the onset of SSc (first 36 months after the onset of SSc), which supports the paraneoplastic phenomenon in this subset of patients [69]. Thus, it is recommended to rule out this possibility at the time of the diagnosis, although protocol for this purpose has not been standardized so far. Cancers most frequently found in SSc patients are those from breast, blood, lung, gastrointestinal tract, genitourinary tract and skin and, out of these, those most related to the presence of RNAp III antibodies were breast cancer, skin cancer and genitourinary cancer [69].

### *4.2.2. Infections*

Risk factors associated with infections in patients diagnosed with scleroderma include oesophageal (increased risk for aspiration pneumonia) and interstitial lung disease (increased risk for pneumonia), severe Raynaud's phenomenon or calcinosis (risk for localized superinfections) and the use of specific treatments for the management of the disease. Bacterial infections due to Gram-positive bacilli have been described, especially in patients with severe Raynaud or calcinosis. In patients receiving immunosuppressive treatment, especially corticosteroids, *Nocardia* sp. and *Mycobacteria* sp. must be taken into account. A few viruses such as *Epstein-Barr virus* and *CMV* have been described as triggering the onset of scleroderma, and *Parvovirus B19* DNA has been detected in patients who have scleroderma, but the clinical correlate of this finding is unclear. Finally, among fungi, *Pneumocystis jirovecii* pneumonia has been reported in some patients who have scleroderma [70]. *Aspergillus* sp. has been rarely reported in scleroderma, but in any patient under cellular immunosuppression has to be taken into account as well [71].

### *4.2.3. Cardiovascular disease*

**Country Years (midcohort)**

Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

**Table 6.** SSc-non-related causes of death in medical literature [43].

cancer, skin cancer and genitourinary cancer [69].

be taken into account as well [71].

*4.2.1. Cancer*

74 Systemic Sclerosis

*4.2.2. Infections*

Assassi [61] US 1998–2008 (03) 52/250 (20.8%) NA NA NA Mok [52] CHI 1999–2008 (03) 110/449 (24.5%) 11 (10%) 19 (17.3%) NA Hoffmann-Vold [40] NOR 1999–2009 (04) 43/312 (13.8%) 13 (54.2%) 6 (14%) 4 (9.3%) Vettori [41] ITA 2000–2008 (04) 20/251 (8%) 2 (10%) 1 (5%) 2 (10%) Hachulla [63] FR 2002–2006 (04) 47/546 (8.6%) 8 (17%) 4 (8.5%) 2 (4.3%) Strickland [53] UK 1999–2010 (04) 53/204 (26%) 10 (18.9%) 13(24.5%) 12 (22.6%) Kuo [42] TAIW 2002–2007 (05) 204/1479 (13.8%) 30 (14.7%) 12 (5.9%) 29 (14.2%)

A higher standardized incidence ratio (SIR) of cancer in these patients not only compared to the general population that could be related to immunosuppressive treatment but also to the self-nature of the disease has been described [68]. In fact, those cancers diagnosed within the first 3 years after the diagnosis of scleroderma have been suggested to be classified as SSc-related causes. Cancer among SSc patients with RNA polymerase III antibodies has been reported to be in a close temporal relationship to the onset of SSc (first 36 months after the onset of SSc), which supports the paraneoplastic phenomenon in this subset of patients [69]. Thus, it is recommended to rule out this possibility at the time of the diagnosis, although protocol for this purpose has not been standardized so far. Cancers most frequently found in SSc patients are those from breast, blood, lung, gastrointestinal tract, genitourinary tract and skin and, out of these, those most related to the presence of RNAp III antibodies were breast

Risk factors associated with infections in patients diagnosed with scleroderma include oesophageal (increased risk for aspiration pneumonia) and interstitial lung disease (increased risk for pneumonia), severe Raynaud's phenomenon or calcinosis (risk for localized superinfections) and the use of specific treatments for the management of the disease. Bacterial infections due to Gram-positive bacilli have been described, especially in patients with severe Raynaud or calcinosis. In patients receiving immunosuppressive treatment, especially corticosteroids, *Nocardia* sp. and *Mycobacteria* sp. must be taken into account. A few viruses such as *Epstein-Barr virus* and *CMV* have been described as triggering the onset of scleroderma, and *Parvovirus B19* DNA has been detected in patients who have scleroderma, but the clinical correlate of this finding is unclear. Finally, among fungi, *Pneumocystis jirovecii* pneumonia has been reported in some patients who have scleroderma [70]. *Aspergillus* sp. has been rarely reported in scleroderma, but in any patient under cellular immunosuppression has to

**Deads/n Cancer death Infection** 

**death**

**Atherosclerosis death**

Scleroderma, as other autoimmune diseases, shows up as an inflammatory background that leads to the fibroblast activation. This background is more visual in the first stages of the skin or lung involvement, but it is thought to happen elsewhere. Thus, scleroderma itself can be understood as a new cardiovascular risk factor not only involved in the development of microvascular disease but also of macrovascular disease [72]. Atherosclerosis has been found to be increased in patients with SSc in all territories: coronary arteries, carotid arteries, cerebrovascular vessels and peripheral arteries [72]. This is the most controversial group of diseases in terms of classification since it is a challenge to differentiate whether it is an SSc-related or a SSc-non-related event. Although sometimes undistinguishable, currently, the clinical context has been hypothesized to aid for this purpose. Thus, in young patients without other classical cardiovascular risk factors (smoking behaviour, diabetes mellitus, arterial hypertension, hyperlipidaemia, obesity), we state that a particular event should be classified as SSc-related.

According to the latest studies [43], the big picture when talking about causes of death should be that SSc-related death is estimated nowadays in 56.7% of all deaths. Among them, representing lung death 57%, heart death 28.2%, renal death 11.7% and gastrointestinal death 6.4% (**Table 7**). In contrast, SSc-non-related death is estimated in 43.3% of all patients and among them being cancer, infections and cardiovascular disease the leading cause of SSc-non-related death.

### **4.3. A temporary pattern of SSc-related causes of death**

In general, we could state that early death within the first years after the diagnosis of scleroderma is primarily due to the autoimmune disease itself, and late death is due to SSc-non directly related causes. Besides, this progression is currently even more notorious since data from the Spanish Registry show the fact that beyond 10 years after diagnosis, 83% of all deaths are due to SSc-non-related causes, supporting the idea that by struggling with the disease in the first years could save quite a few deaths due to the self-disease [54, 55].


T-test for independent groups among studies before and after 1990 (mid-cohort year). GI: gastrointestinal. Reprinted from Rubio-Rivas et al. [43], with permission from Elsevier.

**Table 7.** SSc-related causes of death [43].

Among these SSc-related causes, pulmonary death (due to ILD or PAH) has been and still currently is the leading SSc-related cause of death in all stages of the disease. In contrast, renal death was the second cause of the death in the past and most of all in the dcSSc subset and within the first 5 years after SSc diagnosis, but, in the last years, we have been witnesses of an important decrease of renal death rate. Heart death is at first sight more present nowadays and within the early stages of the disease but possibly due to a better understanding and knowledge of this involvement. Gastrointestinal death has been the cause of death only inisolated cases over time (**Table 8**).

Thus, it is expected to see an increasing rate of SSc-non-related causes in the years to come, mainly cancer and cardiovascular causes. Among the SSc-related causes, cardiovascular causes will be the cornerstone and the challenge will be to distinguish SSc-related and SScnon-related cardiovascular events.


Early (first 5 years after diagnosis), intermediate (5–10 years after diagnosis) and late death ( >10 years after diagnosis) from the Spanish Scleroderma Network. Reprinted from Rubio-Rivas [54].

**Table 8.** SSc-non-related and SSc-related (lung, heart, renal and gastrointestinal) causes of death. In bold, p-values reaching statistical significance or close to significance.

### **5. Risk factors of poor outcome**

To date, several risk factors have been identified related to poor prognosis, sometimes reported as a result of univariate analysis and sometimes as a result of multivariate analysis [43].

Taking into account the number of citations from the different studies (**Figure 5**), more cited risk factors would be an older age at diagnosis, dcSSc subset, male gender and visceral involvement (most of all lung, heart and renal involvement).

Among these SSc-related causes, pulmonary death (due to ILD or PAH) has been and still currently is the leading SSc-related cause of death in all stages of the disease. In contrast, renal death was the second cause of the death in the past and most of all in the dcSSc subset and within the first 5 years after SSc diagnosis, but, in the last years, we have been witnesses of an important decrease of renal death rate. Heart death is at first sight more present nowadays and within the early stages of the disease but possibly due to a better understanding and knowledge of this involvement. Gastrointestinal death has been the cause of death only

Thus, it is expected to see an increasing rate of SSc-non-related causes in the years to come, mainly cancer and cardiovascular causes. Among the SSc-related causes, cardiovascular causes will be the cornerstone and the challenge will be to distinguish SSc-related and SSc-

**Cause of death 1990–1999 2000–2009 p**

**Pulmonary** 8 (47.1%) 16 (34.0%) 0.390 **Renal** 6 (35.3%) 1 (2.1%) **< 0.001 Cardiac** 0 (0.0%) 7 (14.9%) 0.175 **Gastrointestinal** 0 (0.0%) 0 (0.0%) –

**Pulmonary** 13 (61.9%) 6 (27.3%) **0.033 Renal** 1 (4.8%) 1 (4.5%) 1.000 **Cardiac** 2 (9.5%) 4 (18.2%) 0.664 **Gastrointestinal** 0 (0.0%) 0 (0.0%) –

**Pulmonary** 11 (40.7%) 1 (16.7%) 0.379 **Renal** 1 (3.7%) 0 (0.0%) 1.000 **Cardiac** 4 (14.8%) 0 (0.0%) 1.000 **Gastrointestinal** 1 (3.7%) 0 (0.0%) 1.000 Early (first 5 years after diagnosis), intermediate (5–10 years after diagnosis) and late death ( >10 years after diagnosis)

**Early SSc-non-related** 3 (17.6%) 23 (48.9%) **0.042**

**Intermediate SSc-non-related** 5 (23.8%) 11 (50.0%) 0.116

**Late SSc-non-related** 10 (37.0%) 5 (83.3%) **0.070**

To date, several risk factors have been identified related to poor prognosis, sometimes reported as a result of univariate analysis and sometimes as a result of multivariate analysis [43].

**Table 8.** SSc-non-related and SSc-related (lung, heart, renal and gastrointestinal) causes of death. In bold, p-values

inisolated cases over time (**Table 8**).

76 Systemic Sclerosis

non-related cardiovascular events.

**5. Risk factors of poor outcome**

reaching statistical significance or close to significance.

from the Spanish Scleroderma Network. Reprinted from Rubio-Rivas [54].

It is not easy to quantify the overall risk attributed to any of these factors since they have been described in different ways, but by meta-analysing those described homogeneously (**Figure 6**), we could state a hazard ratio for kidney involvement 4.22 (3.42–5.19), for heart involvement 3.43 (1.35–8.70), for ILD 2.89 (2.24–3.72), for high eritrosedimentation rate 2.77 (2.06–3.71), for PAH 2.62 (1.64–4.17), for dcSSc 2.28 (1.69–3.08), for male gender 1.88 (1.48–2.38) and age/year 1.05 (1.04–1.06) [43].

New risk factors are required in order to identify those patients with worse prognosis who could get some benefits in terms of a more aggressive therapy and/or closer follow-up. Recently, the mode of onset has been evaluated as a potential risk factor, finding a worse prognosis in those patients with an onset in the form of non-Raynaud's phenomenon, with the only exception of arthralgia (data not yet released).

Anyway, the risk should be individualized and accordingly lead to the decision-making for every patient. Thus, it should be our aim to create prognosis scales based on these known risk factors.

**Figure 5.** Risk factors for poor outcomes (number of citations in the different studies). Into "others" are included proteinuria, gastrointestinal and osteoarticular involvement, high BUN, hypo/hyperpigmentation, digital ulcers, HLADQA1 and HLA DRB1, low body mass index, hands deformity, low STC and low total lung compliance, myositis, anti-RNP +, S3 heart gallop, corticosteroid treatment, longer time from first Raynaud, no CREST, tobacco and alcohol uptake and hypoproteinaemia. Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

**Figure 6.** A quantitative meta-analysis of the main risk factors related to mortality. Reprinted from Rubio-Rivas et al., with permission from Elsevier [43].

### **Author details**

Manuel Rubio-Rivas

Address all correspondence to: mrubio@bellvitgehospital.cat

Autoimmune Diseases Unit, Department of Internal Medicine, Bellvitge University Hospital-IDIBELL. L'Hospitalet de Llobregat, Barcelona, Spain

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**Figure 6.** A quantitative meta-analysis of the main risk factors related to mortality. Reprinted from Rubio-Rivas et al.,

with permission from Elsevier [43].

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### **Nonpharmacological Treatment in Systemic Sclerosis** Nonpharmacological Treatment in Systemic Sclerosis

DOI: 10.5772/intechopen.68537

Maja Špiritović and Michal Tomčík Maja Špiritović and Michal Tomčík

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68537

### Abstract

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e279-291

84 Systemic Sclerosis

Arthritis Research and Therapy. 2014;**16**:R53

Clinics of North America. 2003;**29**:163-184

analysis. Arthritis & Rheumatology. 2011;**63**:2078-2090

Systemic sclerosis (SSc) is a rare, severe connective tissue disease without available universal treatment. Organ involvement increases the mortality of this disease; nevertheless, skin involvement and the involvement of muscles and joints lead to loss of function, disability, and reduced quality of life.

Our experience and data from the literature suggest that physical activity interventions are an essential and integral part of treatment of patients with SSc. The limitation on most of the small number of existing studies aimed at nonpharmacological treatment for patients with SSc includes suboptimal methodological quality, low number of patients, lack of a control group or monitoring (follow-up), and short-term intervention.

The purpose of this chapter was to introduce the few studies that have examined this issue and to show that nonpharmacological therapy for diseases such as systemic sclerosis has been the focus of some research teams in recent years—the studies of which have demonstrated safety and benefits of these approaches.

Keywords: systemic sclerosis, function, disability, rehabilitation, physiotherapy, nonpharmacological interventions

### 1. Introduction

In the last few years, increased attention has been focused on nonpharmacological interventions in rare rheumatic diseases such as systemic sclerosis (SSc). However, there is still an unmet need to ensure medical awareness of the importance of physical therapy among patients, health professionals, rheumatologists, and other specialists to implement these nonpharmacological interventions into the daily care of patients with SSc.

Currently, physical therapy is considered a process by which patients try to restore and maintain their optimal physical, mental, social, occupational, and emotional state. It is therefore a comprehensive approach to the patient, which includes physical activity, as well as the principles of secondary prevention and healthy lifestyles, which are based on the patient's collaboration, activity, and

© The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

distribution, and eproduction in any medium, provided the original work is properly cited.

compliance. It is beyond doubt that physical inactivity is a major risk factor for both cardiovascular and respiratory systems, but also for functional limitations and reduced quality of life.

To acknowledge the importance of prevention and adherence to healthy lifestyle even before the onset of the disease, we can draw inspiration from the results of a recently published study on another, less rare, rheumatic disease, rheumatoid arthritis (RA): about the influence of environmental factors (e.g., the intensity and frequency of physical activity, of smoking, and different exposures) showing that patients with regular physical activity before the onset of RA suffer from a milder form of the disease and that obesity reduces the chance of achieving a good response to standard pharmacological approaches in RA [1, 2].

### 2. Nonpharmacological interventions in patients with systemic sclerosis

Tissue fibrosis is the dominant feature of SSc and affects both the skin and internal organs especially the lungs, heart, and gastrointestinal tract [3]. While visceral involvement is responsible for increased mortality, musculoskeletal involvement (e.g., arthralgia/arthritis, flection contractures, and muscle weakness) and skin involvement (skin thickening and tethering) pose a significant burden for the patient in terms of reduction of functionality, quality of life, and ability to work or perform activities of daily living [4].

Current recommendations for the treatment of SSc include symptomatic therapy of individual organ manifestations and complications of SSc. However, to date, we have no effective treatment of tissue fibrosis, for example, skin, lung, heart, and gastrointestinal tract. Nonpharmacological management of patients with SSc with the main focus on the musculoskeletal system and the affected skin may be useful to reduce disability and improve quality of life and contribute to reducing the burden of disease on the organism. Nevertheless, the major limitations of most of the small number of existing publications focused on physical interventions in patients with SSc include the diversity of interventions, small cohorts of patients, the absence of a control group, randomization and/or a follow-up, and a short duration of intervention [3].

The most frequently investigated nonpharmacological interventions include commonly used methods such as paraffin, manual lymphatic drainage, soft tissue techniques, stretching exercises for hands and face, massage, exercises to maintain range of motion in joints, mobilization, aerobic exercise, and strength training. Other studies focus on occupational therapy, physical therapy, sleep disturbances, sexual function, and depression.

The following paragraphs will provide an overview of the results of the available publications, which are divided according to the nature of the intervention.

### 2.1. Interventions using paraffin

One of the methods frequently used in physiotherapy of rheumatic diseases is paraffin treatment. Paraffin solidifies at a temperature of 52–62C and yet gives latent heat. In order to utilize this heat, paraffin must be applied to the body in a fluid state and allowed to solidify in the course of application. There are a few studies of paraffin in SSc patients: two randomized controlled studies (RCTs), one nonrandomized controlled trial and a series of three individual case studies.

The RCT by Sandqvist et al. evaluated the difference in intervention outcomes in 17 patients with SSc who underwent therapy with paraffin in combination with exercise on one hand chosen by random, and on the other hand received only exercise. Interventions continued daily for 1 month. Hand function was assessed at the beginning of the intervention and after the first month according to hand mobility and strength, the perception of pain, stiffness and elasticity of the skin. The authors demonstrated a significant improvement in flexion and extension of the fingers, thumb abduction, plantar flexion, perceived stiffness, and elasticity of the skin in patients who underwent paraffin intervention in combination with exercise compared to baseline levels. Furthermore, significant improvement in hand function (specifically in extension deficit, perception of stiffness, and elasticity of skin) was significantly greater in the hand that was treated with paraffin in combination with exercise than in the hand treated with exercise only [5].

In another RCT study [6], 16 patients with SSc underwent 12 times paraffin wrap therapy and then were randomly assigned to the intervention and control groups. The intervention group continued with paraffin therapy for 3 months, and the control group did not. Skin thickness decreased in all patients after 12 sessions of paraffin treatment. However, at the end of 3 months therapy in the intervention group, there was no significant difference between the intervention and control group [6].

One of the first studies, a nonrandomized controlled trial by Askew et al., recruited 10 patients with SSc and examined the effectiveness of once performed interventions including paraffin, friction massage, and exercise maintaining range of motion in the joints of the wrist and hand. Compared with seven patients with SSc, who did not attend any sessions, the interventions lead to significant improvements in the articular range of motion, skin elasticity, and overall function of the hand [7].

In a series of three individual case studies [8], respondents conducted active exercises with their hands after paraffin wrap 5 times per week for 8 weeks. The authors detected clinically significant improvements in both body function/structure measurements of hand function and in their ability to participate in activities in all participants [8].

### 2.2. Orofacial exercises

compliance. It is beyond doubt that physical inactivity is a major risk factor for both cardiovascular and respiratory systems, but also for functional limitations and reduced quality of life. To acknowledge the importance of prevention and adherence to healthy lifestyle even before the onset of the disease, we can draw inspiration from the results of a recently published study on another, less rare, rheumatic disease, rheumatoid arthritis (RA): about the influence of environmental factors (e.g., the intensity and frequency of physical activity, of smoking, and different exposures) showing that patients with regular physical activity before the onset of RA suffer from a milder form of the disease and that obesity reduces the chance of achieving a

2. Nonpharmacological interventions in patients with systemic sclerosis

Tissue fibrosis is the dominant feature of SSc and affects both the skin and internal organs especially the lungs, heart, and gastrointestinal tract [3]. While visceral involvement is responsible for increased mortality, musculoskeletal involvement (e.g., arthralgia/arthritis, flection contractures, and muscle weakness) and skin involvement (skin thickening and tethering) pose a significant burden for the patient in terms of reduction of functionality, quality of life, and

Current recommendations for the treatment of SSc include symptomatic therapy of individual organ manifestations and complications of SSc. However, to date, we have no effective treatment of tissue fibrosis, for example, skin, lung, heart, and gastrointestinal tract. Nonpharmacological management of patients with SSc with the main focus on the musculoskeletal system and the affected skin may be useful to reduce disability and improve quality of life and contribute to reducing the burden of disease on the organism. Nevertheless, the major limitations of most of the small number of existing publications focused on physical interventions in patients with SSc include the diversity of interventions, small cohorts of patients, the absence of a control group, randomization and/or a follow-up, and a short duration of intervention [3]. The most frequently investigated nonpharmacological interventions include commonly used methods such as paraffin, manual lymphatic drainage, soft tissue techniques, stretching exercises for hands and face, massage, exercises to maintain range of motion in joints, mobilization, aerobic exercise, and strength training. Other studies focus on occupational therapy, physical

The following paragraphs will provide an overview of the results of the available publications,

One of the methods frequently used in physiotherapy of rheumatic diseases is paraffin treatment. Paraffin solidifies at a temperature of 52–62C and yet gives latent heat. In order to utilize this heat, paraffin must be applied to the body in a fluid state and allowed to solidify in

good response to standard pharmacological approaches in RA [1, 2].

ability to work or perform activities of daily living [4].

86 Systemic Sclerosis

therapy, sleep disturbances, sexual function, and depression.

which are divided according to the nature of the intervention.

2.1. Interventions using paraffin

Orofacial region has many functions. Primarily, it ensures food intake and contributes to breathing. Coordinated interplay of activity of facial muscles allows for expression of verbal, articulate speech. In the orofacial region, we find more than fifty facial muscles that enable people to communicate nonverbally, to express their feelings. No other part of the human body possesses such a social function as the orofacial region. Through this region we communicate, we speak to others, express our feelings, and create new relationships. In patients with SSc, tightening of the skin and muscle atrophy in orofacial region lead to loss of facial expressions and an appearance of a mask-like face. The affected orofacial region with skin thickening often contribute to inability of mechanical mouth opening, microstomia, which along with other symptoms, such as dry mouth, can lead to dental and mouth hygiene issues, and hampered alimentation.

In the RCT by Yuen Hon et al., the authors studied the effect of orofacial home exercise program to increase the orifice in adults with SSc. The study included 48 adult patients with SSc who were randomly divided into two groups and examined for oral aperture at baseline, 3-month, and 6-month intervals. The intervention group underwent a multifaceted oral health intervention including adaptive oral hygiene devices, instruction and demonstration on the use of the devices, brushing teeth for 2 min and flossing twice a day for 6 months. The control group received the usual dental care. Participants with orifices <40 mm in the intervention group underwent orofacial exercise program, which included manual mouth-stretching and oral augmentation exercises with a wooden stick, twice a day with a total of 6 minutes for 6 months. The results showed a significant increase in oral orifice in patients of the intervention group at 3 months, but not after 6 months evaluation. However, compliance with the program was low (48.9%), which could distort the results of this study [9].

An RCT by Maddali-Bongi et al. evaluated the effectiveness of an intervention program based on a combination of the Kabat's technique (proprioceptive neuromuscular facilitation, PNF), connective tissue massage, and kinesiotherapy specially developed for the face of SSc patients. Out of the 40 recruited SSc patients, 20 patients were randomly selected into the intervention group and underwent the intervention program for 9 weeks, 2 times a week for 1 h with a home exercise program. Twenty patients were randomly assigned into the control group, which underwent home exercise program only. Patients of both groups were evaluated at baseline, after 9 weeks and after 9 weeks of follow-up in terms of quality of life and health, stiffness of the facial area, opening of the mouth, and oral handicap. At the end of treatment, both groups showed improved orifice. However, in the follow-up period, improvement persisted only in the intervention group. The facial score in the intervention group improved both at the end of therapy and follow-up period, whereas in the control group, there were no changes. According to the results of quality of life and health status, no effect of therapy was detected in any group. A significant improvement was also found in oral handicap at the end of therapy in the intervention group, whereas in the control group, no changes were observed [10].

In an observational study by Poole et al., the authors investigated the improvement in oral hygiene in SSc patients who underwent a program involving structured oral hygiene and exercises for the face and hands. The authors recruited 17 patients with SSc who previously underwent basic dental checkup, including examination for decayed or missing teeth, calculus, sites that bleed upon probing, measures of oral aperture, and the patient hygiene performance index. The study also evaluated upper limb function involving strength, joint range and maneuverability. Participants underwent a structured exercise program including education on brushing and flossing techniques used, hand exercise of three series with five repetitions, once daily stretching, once daily facial exercise of five times stretching 3–5 seconds, individually adjusted dental equipment, and a 6-month supply of dental products. This program was performed one or two times a day for 6 months. At the end of the 6-month intervention, there were a significant improvement in oral hygiene and a significant decline in the number of teeth with calculus and a reduction in bleeding gums. There were no differences in any of the upper extremity measures or oral aperture [11].

and an appearance of a mask-like face. The affected orofacial region with skin thickening often contribute to inability of mechanical mouth opening, microstomia, which along with other symptoms, such as dry mouth, can lead to dental and mouth hygiene issues, and hampered

In the RCT by Yuen Hon et al., the authors studied the effect of orofacial home exercise program to increase the orifice in adults with SSc. The study included 48 adult patients with SSc who were randomly divided into two groups and examined for oral aperture at baseline, 3-month, and 6-month intervals. The intervention group underwent a multifaceted oral health intervention including adaptive oral hygiene devices, instruction and demonstration on the use of the devices, brushing teeth for 2 min and flossing twice a day for 6 months. The control group received the usual dental care. Participants with orifices <40 mm in the intervention group underwent orofacial exercise program, which included manual mouth-stretching and oral augmentation exercises with a wooden stick, twice a day with a total of 6 minutes for 6 months. The results showed a significant increase in oral orifice in patients of the intervention group at 3 months, but not after 6 months evaluation. However, compliance with the program

An RCT by Maddali-Bongi et al. evaluated the effectiveness of an intervention program based on a combination of the Kabat's technique (proprioceptive neuromuscular facilitation, PNF), connective tissue massage, and kinesiotherapy specially developed for the face of SSc patients. Out of the 40 recruited SSc patients, 20 patients were randomly selected into the intervention group and underwent the intervention program for 9 weeks, 2 times a week for 1 h with a home exercise program. Twenty patients were randomly assigned into the control group, which underwent home exercise program only. Patients of both groups were evaluated at baseline, after 9 weeks and after 9 weeks of follow-up in terms of quality of life and health, stiffness of the facial area, opening of the mouth, and oral handicap. At the end of treatment, both groups showed improved orifice. However, in the follow-up period, improvement persisted only in the intervention group. The facial score in the intervention group improved both at the end of therapy and follow-up period, whereas in the control group, there were no changes. According to the results of quality of life and health status, no effect of therapy was detected in any group. A significant improvement was also found in oral handicap at the end of therapy in the intervention group, whereas in the control group, no changes were

In an observational study by Poole et al., the authors investigated the improvement in oral hygiene in SSc patients who underwent a program involving structured oral hygiene and exercises for the face and hands. The authors recruited 17 patients with SSc who previously underwent basic dental checkup, including examination for decayed or missing teeth, calculus, sites that bleed upon probing, measures of oral aperture, and the patient hygiene performance index. The study also evaluated upper limb function involving strength, joint range and maneuverability. Participants underwent a structured exercise program including education on brushing and flossing techniques used, hand exercise of three series with five repetitions, once daily stretching, once daily facial exercise of five times stretching 3–5 seconds, individually adjusted dental equipment, and a 6-month supply of dental products. This program was

was low (48.9%), which could distort the results of this study [9].

alimentation.

88 Systemic Sclerosis

observed [10].

Another observational study by Pizzo et al. examined the effects of nonsurgical exercise program in 10 patients with severe SSc-associated microstomia (maximal mouth opening ≤ 30 mm). Patients were instructed to perform an exercise program, which included mouth stretching exercises for at least 15 minutes, twice a day, and oral augmentation exercise with a stick of soft wood daily during 18 weeks. After 18 weeks, the effect of exercise was evaluated measuring the maximal mouth opening. The exercise program improved mouth opening of all subjects. At the end of the period of 18 weeks, all patients noted that eating, speaking, and oral hygiene were easier [12].

In 2009, Maddali-Bongi et al. performed two other RCTs that examined the effect of specialized intervention programs and pointed out their safety and improvements in the hands and mouth (facial). These studies will be discussed in the following sections of this chapter.

At this point, it is worth to mention a study that can be useful for dentists treating this area in such a rare disease as SSc. Alantar et al. reviewed the literature and collected expert opinion for the design of preventive and curative treatment of oral and dental disability in patients with SSc. The authors point out that prevention of oral and dental complications is a major issue in patients with SSc. Dental treatment should be tailored to limitations in mouth opening, disease severity, and on-going treatments [13].

### 2.3. Comprehensive physical therapy for physical and/or psychological functioning

Physiotherapy is a vital part of nonpharmacological approaches, which deals with the prevention and treatment of disorders of the musculoskeletal system. Based on a comprehensive approach, physiotherapy pays special attention to the life situations, in which the person is. The aim of comprehensive physiotherapy is to find the best way to mitigate or eliminate health problems and to maintain the current effect in a long term. There are several studies available in this area of research.

In 2009, Maddali-Bongi et al. performed two RCTs that examined the effect of a specialized intervention program in the area of hands and mouth (face). The first study aimed to evaluate the effectiveness of the intervention program based on a combination of connective tissue massage and joint manipulation according to Mc Mennell specially designed for the hands of SSc patients. Of the 40 recruited SSc patients, 20 patients were randomly assigned to intervention and underwent the exercise program for 9 weeks, twice a week for one hour, and a home exercise program. Twenty patients were randomly assigned to the control group which underwent only the home exercise program. Patients of both groups were evaluated at baseline, after 9 weeks and after 9 weeks of follow-up in terms of quality of life, hand involvement, hand functional disability, and the measurements of range of motion. The intervention group demonstrated a significant improvement in all measured parameters, whereas the home exercise program in the control group improved just closing the hand into a fist at the end of therapy [14].

The aim of the second study was to evaluate the efficacy of a specific and comprehensive rehabilitation program tailored for patients with SSc. Hand involvement was treated with a combination of connective tissue massage and Mc Mennell joint manipulation. Manual lymph drainage was applied if patients had edematous hands. Face involvement was treated with a combination of Kabat's method, connective tissue massage, and kinesiotherapy. Other techniques used in the study included hydrokinesiotherapy (for patients without ulcers), landbased rehabilitation (for patients with ulcers), and respiratory rehabilitation exercises. The authors recruited twenty patients with SSc, who were randomly divided into two groups and evaluated at baseline and after 9 weeks in terms of quality of life, health, hand function, range of motion, water volumetric test, orifice, Duruoz scale, and purpose-built-questionnaire for hand and face Involvement. The intervention group was evaluated also after 9 weeks of follow-up. The intervention group 10 patients underwent a specific rehabilitation program, one or two times per week for 9 weeks. The control group underwent only educational advice and medical information for patients with SSc. At the end of treatment, patients in the intervention group improved in all measured parameters. In follow-up, orofacial function and mobility as well as general health condition were partially lost, whereas only the mobility and function of the hand were preserved. No changes in the examined parameters were observed in the control group [15].

In a controlled clinical study by Antonioli et al., the authors evaluated the effect of a specialized individual rehabilitation program that consisted of warm-up and cool-down exercises, training of motor functions, diaphragmatic breathing, controlled coughing exercises, treadmill, freewalking, finger stretching, and occupational therapy for 2 weeks of daily 30-minute sessions (10 sessions in total). Physical therapy was also prescribed to 13 patients with jointrelated problems. At-home exercise program was prescribed on days when the intervention program was terminated. Patients were reevaluated after 2 and 4 months. The control group consisted of 17 patients who did not receive any form of rehabilitation. The authors evaluated aerobic capacity, hand function, limitations in activities of daily living, quality of life, and skinrelated problems. At the end of the 4-month period, the examiners observed an improvement in the perception of quality of life, better exercise tolerance, and better mobility of hand in a significant number of patients with SSc [16].

Since patients with SSc reported great need to receive support and education regarding their disease, Kwakkenbos et al. developed a short, group-based psychoeducational program, and evaluated it in an observational study using pre- and posttest design. Participants filled out a questionnaire assessing their physical and mental condition. Subsequently, patients were asked to evaluate the program content using a questionnaire. Completely filled questionnaires were available for data analysis from 41 patients. The authors detected a high satisfaction of patients with the program, smaller helplessness after the intervention, and a higher acceptance of patients' limitations. However, no differences were observed in depressed mood or in physical function. Thus, this psychoeducational program contributed to meeting the reported needs of patients and to improving the care of patients with SSc [17].

In an RCT by Schouffoer et al., the authors compared the effectiveness of a 12-week multidisciplinary nursing program with usual outpatient care for SSc patients. The multidisciplinary nursing program included individual treatment goals once a week for 12 weeks, general exercises, hand/mouth exercises, educational sessions under supervision of a local physical therapist, and a home-based exercise program at least 6 days a week for 12 weeks. Twentyeight patients with SSc were randomly selected into the intervention group (twenty-five of them completed the treatment), and twenty-five patients were randomly assigned to the control group. The examiners evaluated the hand function, grip strength, maximal mouth opening, aerobic capacity, gait, quality of life, and health status at baseline, at the end of treatment (12 weeks), and at the end of follow up (after 24 weeks). Results showed that the 12-week daily multidisciplinary care program was more effective than regular outpatient care with regard to significant improvement in grip strength, mouth opening, gait, and quality of life after 12 weeks, whereas the results in other followed parameters showed no difference between the intervention and control group. At the end of the follow-up period, after 24 weeks, only improvement in grip strength was maintained [18].

Our own preliminary results (unpublished data) from an ongoing single-center controlled study further support the role of intensive physiotherapy in patients with SSc. Our project aimed to address some limitations of existing studies and to assess the efficacy of a long-term (24-week intervention, 24-week follow-up), intensive (1 h physiotherapy + 0.5 h occupational therapy twice weekly, and home-exercise for 0.5 h five times a week), tailored physiotherapy program on function and impairment of the hands and face, and quality of life and disability in patients with SSc. We recruited 27 SSc patients into the intervention group, which underwent the 24-week intervention, and 29 SSc patients into the control group, which received an education and textbook on home exercise at baseline only. The intervention program unit comprised several physiotherapy/occupational therapy techniques, such as warm-up with infrared lamp, manual lymphatic drainage, skin wrinkling, fascial techniques, postisometric muscle relaxation, joint mobilization, passive/active muscle stretching and exaggerated facial mimicry training, soft ball facilitation techniques, senosoric stimulation with terabeans and therapeutic plasticine. Our program not only prevented the natural course of progressive deterioration of function of hands/mouth (observed in the control group) but also led to a significant improvement in monitored parameters (e.g., delta finger to palm, hand/finger grip strength, HAMIS-Hand Mobility in Scleroderma, interincisor/lip distance), which was clinically meaningful in a substantial proportion of patients.

### 2.4. Stretching interventions

exercise program in the control group improved just closing the hand into a fist at the end of

The aim of the second study was to evaluate the efficacy of a specific and comprehensive rehabilitation program tailored for patients with SSc. Hand involvement was treated with a combination of connective tissue massage and Mc Mennell joint manipulation. Manual lymph drainage was applied if patients had edematous hands. Face involvement was treated with a combination of Kabat's method, connective tissue massage, and kinesiotherapy. Other techniques used in the study included hydrokinesiotherapy (for patients without ulcers), landbased rehabilitation (for patients with ulcers), and respiratory rehabilitation exercises. The authors recruited twenty patients with SSc, who were randomly divided into two groups and evaluated at baseline and after 9 weeks in terms of quality of life, health, hand function, range of motion, water volumetric test, orifice, Duruoz scale, and purpose-built-questionnaire for hand and face Involvement. The intervention group was evaluated also after 9 weeks of follow-up. The intervention group 10 patients underwent a specific rehabilitation program, one or two times per week for 9 weeks. The control group underwent only educational advice and medical information for patients with SSc. At the end of treatment, patients in the intervention group improved in all measured parameters. In follow-up, orofacial function and mobility as well as general health condition were partially lost, whereas only the mobility and function of the hand were preserved. No changes in the examined parameters were observed

In a controlled clinical study by Antonioli et al., the authors evaluated the effect of a specialized individual rehabilitation program that consisted of warm-up and cool-down exercises, training of motor functions, diaphragmatic breathing, controlled coughing exercises, treadmill, freewalking, finger stretching, and occupational therapy for 2 weeks of daily 30-minute sessions (10 sessions in total). Physical therapy was also prescribed to 13 patients with jointrelated problems. At-home exercise program was prescribed on days when the intervention program was terminated. Patients were reevaluated after 2 and 4 months. The control group consisted of 17 patients who did not receive any form of rehabilitation. The authors evaluated aerobic capacity, hand function, limitations in activities of daily living, quality of life, and skinrelated problems. At the end of the 4-month period, the examiners observed an improvement in the perception of quality of life, better exercise tolerance, and better mobility of hand in a

Since patients with SSc reported great need to receive support and education regarding their disease, Kwakkenbos et al. developed a short, group-based psychoeducational program, and evaluated it in an observational study using pre- and posttest design. Participants filled out a questionnaire assessing their physical and mental condition. Subsequently, patients were asked to evaluate the program content using a questionnaire. Completely filled questionnaires were available for data analysis from 41 patients. The authors detected a high satisfaction of patients with the program, smaller helplessness after the intervention, and a higher acceptance of patients' limitations. However, no differences were observed in depressed mood or in physical function. Thus, this psychoeducational program contributed to meeting the reported

needs of patients and to improving the care of patients with SSc [17].

therapy [14].

90 Systemic Sclerosis

in the control group [15].

significant number of patients with SSc [16].

Stretching includes special exercises leading to increased mobility of the body that can address a variety of health-related issues. It is a method, which can gently prepare your muscles to increased physical stress, but also to very ordinary functioning of our body during daily life activities. Stretching increases performance, maintains the elasticity of muscles and tendons, prevents muscle imbalance, improves joint mobility, and helps to maintain correct posture, proper breathing, and efficient and economical movement. Furthermore, stretching reduces muscle tone and brings overall relaxation, provides prevention from muscle- and joint-related injuries, improves response and readiness, and increases resistance to fatigue. To sum up the benefits of stretching, this technique maintains overall good physical and mental condition. For patients, most of all, it is a method/technique that maintains the elasticity of tendons, muscles, and improves joint mobility. Therefore, not only in healthy individuals but also in patients with SSc, it is the only way to recover, or aim to restore physiologic length of shortened muscles.

Mugii et al., in their observational study, compared the effect of autostretching of individual fingers in patients with SSc. Forty-five patients with SSc were instructed how to autostretch their fingers. The individual fingers were held with the other hand in the stretched position for 10 s, and this was repeated 3–10 times a day. To evaluate the effect of autostretching intervention, passive range of motion of the fingers was evaluated using a goniometer during the first visit, after 1 month and 1 year of the autostretching program. Quality of life was also assessed at the first visit and after a year using the Health Assessment Questionnaire (HAQ). The authors demonstrated a significant improvement in the overall range of passive joint motion of each finger after 1 month of autostretching, which was further improved or maintained even after 1 year. Although the range of motion of the fingers was lower in patients with diffuse cutaneous (dc) SSc than in patients with limited cutaneous (lc) SSc during the first visit, the examiners detected a significant improvement regardless of the disease duration or severity of skin sclerosis. The study team noted that stretching your fingers can improve the function of fingers, because HAQ score assessing the hand function activities, such as eating and grasping, decreased significantly [19].

An RCT by Vannajak et al. recruited 28 patients with SSc who were divided into two groups of 14 patients. Both groups received the same daily home treatment with one difference: one group with gloves and the other group without gloves. The 2-week daily home intervention included a Thai massage, stretching exercises and heating. The authors assessed the function of the hand using Hand Mobility in Scleroderma (HAMIS). Both groups showed a significant improvement in the function of the hand. Wearing gloves, however, lead to greater thumb mobility [20].

### 2.5. Aerobic training and combined endurance/resistance training

The rehabilitation of patients with impaired cardiovascular system is based on endurance, aerobic training, that is, a prolonged dynamic loading at or below the anaerobic threshold. Regular aerobic exercise improves the efficiency of the cardiovascular system (lungs, heart, and circulatory system), and regular endurance and strength training induce characteristic changes that lead to improved physical condition. These changes represent the training effect and help to achieve greater physical load with lower heart-rate responses.

Pinto et al. in their observational study focused on the effects of 12 weeks of combined resistance and aerobic training program (concurrent training) in 11 SSc patients. Supervised concurrent training session consisted of treadmill warm-up (5 min) followed by resistance training (30 min), treadmill aerobic training (20 min), and stretching exercises (5 min). Resistance training included five exercises for the main muscle groups: bench press, leg press, latissimus pull down, leg extension, and seated row. The concurrent training program was performed in one hour sessions, twice per week for 12 weeks. The study showed that concurrent 12-week training program was safe and significantly improved muscle strength, function and aerobic capacity in SSc patients [21].

The aim of a pilot study by Alexanderson et al. was to determine the effect of 8-week intense aerobic and endurance training program in four patients (three women and one man) with SSc with 50–100% of forced vital capacity (FVC). The authors detected significantly improved muscular endurance in three participants and significantly or clinically significantly improved aerobic capacity in two participants [22].

Oliveira et al., in their prospective nonrandomized controlled trial, examined whether patients with SSc have reduced exercise capacity compared to healthy individuals, and whether aerobic exercise is safe for patients with SSc and improves their aerobic capacity. In this study, 7 patients with SSc (without interstitial lung disease) and 7 healthy controls underwent an 8 week aerobic exercise program of moderate intensity. Participants were evaluated by cardiopulmonary stress test before and after 8 weeks of training, and examined for blood lactate concentration and oxygen saturation at each visit and at rest, and quality of life. Patients with SSc and healthy controls underwent 40-min training twice weekly. The first five minutes of the exercise program were reserved for the warm-up, when the speed was gradually increased until a target heart rate. The last five minutes of exercise were represented by the cool-down with slowing down the speed to a standstill. In the first session of the program, the participants underwent 15 min of aerobic exercise at their respective target heart rate. In the second session, aerobic training was increased to 20 min, in the third session to 25 min, and in all subsequent sessions to 30 min. Both groups showed a significant improvement in peak VO2 but with no significant difference between the study groups. Furthermore, both groups improved in exercise intensity which was documented by significantly increased peak lactate concentration in blood. No significant changes in SSc skin score or quality of life were detected [23].

### 2.6. Interventions on lower extremities

benefits of stretching, this technique maintains overall good physical and mental condition. For patients, most of all, it is a method/technique that maintains the elasticity of tendons, muscles, and improves joint mobility. Therefore, not only in healthy individuals but also in patients with SSc, it is the only way to recover, or aim to restore physiologic length of shortened muscles.

Mugii et al., in their observational study, compared the effect of autostretching of individual fingers in patients with SSc. Forty-five patients with SSc were instructed how to autostretch their fingers. The individual fingers were held with the other hand in the stretched position for 10 s, and this was repeated 3–10 times a day. To evaluate the effect of autostretching intervention, passive range of motion of the fingers was evaluated using a goniometer during the first visit, after 1 month and 1 year of the autostretching program. Quality of life was also assessed at the first visit and after a year using the Health Assessment Questionnaire (HAQ). The authors demonstrated a significant improvement in the overall range of passive joint motion of each finger after 1 month of autostretching, which was further improved or maintained even after 1 year. Although the range of motion of the fingers was lower in patients with diffuse cutaneous (dc) SSc than in patients with limited cutaneous (lc) SSc during the first visit, the examiners detected a significant improvement regardless of the disease duration or severity of skin sclerosis. The study team noted that stretching your fingers can improve the function of fingers, because HAQ score assessing the hand function activities, such as eating and grasping,

An RCT by Vannajak et al. recruited 28 patients with SSc who were divided into two groups of 14 patients. Both groups received the same daily home treatment with one difference: one group with gloves and the other group without gloves. The 2-week daily home intervention included a Thai massage, stretching exercises and heating. The authors assessed the function of the hand using Hand Mobility in Scleroderma (HAMIS). Both groups showed a significant improvement in the function of the hand. Wearing gloves, however, lead to greater thumb

The rehabilitation of patients with impaired cardiovascular system is based on endurance, aerobic training, that is, a prolonged dynamic loading at or below the anaerobic threshold. Regular aerobic exercise improves the efficiency of the cardiovascular system (lungs, heart, and circulatory system), and regular endurance and strength training induce characteristic changes that lead to improved physical condition. These changes represent the training effect

Pinto et al. in their observational study focused on the effects of 12 weeks of combined resistance and aerobic training program (concurrent training) in 11 SSc patients. Supervised concurrent training session consisted of treadmill warm-up (5 min) followed by resistance training (30 min), treadmill aerobic training (20 min), and stretching exercises (5 min). Resistance training included five exercises for the main muscle groups: bench press, leg press, latissimus pull down, leg extension, and seated row. The concurrent training program was performed in one hour sessions, twice per week for 12 weeks. The study showed that

2.5. Aerobic training and combined endurance/resistance training

and help to achieve greater physical load with lower heart-rate responses.

decreased significantly [19].

mobility [20].

92 Systemic Sclerosis

In SSc commonly affected area of the body is the lower limbs, especially their muscular strength and function, the loss of which has an impact on quality of life of patients with SSc. Therefore, Lima et al. in their cross-sectional study assessed peripheral and respiratory muscle strength in patients with SSc and examined their correlation with the 6-minute walk test and quality of life. Secondary aim of this study was to characterize the nutritional status, lung function, functional ability and quality of life of SSc patients compared with healthy controls. The study included 20 patients with SSc and 20 healthy control subjects. Results showed that patients with SSc have significantly reduced respiratory muscle strength, decreased strength in m. quadriceps femoris, and increased fatigability compared to healthy controls [24].

### 2.7. Self-management programs

Poole et al., in 2013 and 2014, assessed their two self-management programs and their impact on self-management for patients with SSc. The first program (2013) consisted of a workbook and a DVD (sent by postmail) that provided information on medical aspects of the disease, dysphagia, fatigue management, advocacy, activities of daily living, oral hygiene, skin and wound care, psychosocial changes, exercises, and other features of the condition. Forty-nine participants evaluated the effect of the program providing feedback through series of questions, filling out the protocol on health condition, and through their participation in the evaluation interview. The results of the study showed a decrease in depression, fatigue and pain, and an improvement in the hand function, self-efficacy for controlling pain, and selfefficacy "other." However, the only statistically significant change was in self-sufficient pain control. Moreover, the study showed that the program was easy to use and should help individuals with SSc in self-sufficiency [25].

In another pilot study (2014), Poole et al. assessed the effectiveness of internet-based selfmanagement program for patients with SSc. Participants logged on to a password-protected web site and completed the program, which consisted of 10 modules (e.g., coping and body image/appearance, fatigue and energy conservation, self-advocacy), an exercise video, learning activities, worksheets, and resources. Participants proceeded through the modules at their own pace over 10 weeks. Participants were encouraged to log on to the discussion board, participate in an interactive component of the web site, and respond to questions posted for each module. Participants completed pre- and postintervention questionnaires on perceived self-efficacy, health efficacy, ability to manage care, functional disability, depression, pain, and fatigue. They also completed an eight-question evaluation form regarding satisfaction with the web site, program content, discussion boards, and learning activities. Sixteen participants completed the study and postintervention measures. The authors demonstrated significant improvements in mean scores for ability to manage health care and efficacy, and significant decreases in fatigue and depression. Self-efficacy was improved as well, but not significantly [26].

### 2.8. Splinting interventions

Functional impairment of the hand in SSc patients is one of the major problems encountered in rehabilitation practice. Research in this area also includes splinting interventions of the hand and wrist, which aim to facilitate restoration of the lost function. In a 2-month study by Seeger et al., the authors investigated splinting effect on the secondary contractures in 19 patients with SSc. Specifically, whether dynamic splinting can improve flexion contractures in the proximal interphalangeal joints (PIP). Of the eight patients who completed the study, only one had significant improvement in range of motion as a result of PIP joint splinting, which shows that the study failed to demonstrate the use of splints as a suitable method to maintain PIP extension compared with the control hand [27].

### 2.9. Physical therapy

In addition to the abovementioned list of interventions, there are few studies that evaluate the effectiveness of some other nonpharmacological approaches in SSc including the use of physical therapy, which is the practical application of physical treatments procedures and methods on living organism.

Manual lymphatic drainage (MLD) stimulates the lymphatic system and reduces swelling. It is one of the main components of a combined physical therapy, which is used for the treatment of lymphedema [28]. It is a technique that applies a force to the interstitial fluid and proteins within the initial lymphatics, thereby shifting toward collaterals and/or normally functioning lymphatics [29]. This technique not only directly softens the tissues, but perhaps also removes excessive local fluid. Therefore, it is speculated that the MLD technique should modify the mechanical properties, such as strain, of the skin and subcutaneous tissue. Strain is defined as deformation of a solid due to stress and is considered to be one of the measures representing tissue hardness [30].

wound care, psychosocial changes, exercises, and other features of the condition. Forty-nine participants evaluated the effect of the program providing feedback through series of questions, filling out the protocol on health condition, and through their participation in the evaluation interview. The results of the study showed a decrease in depression, fatigue and pain, and an improvement in the hand function, self-efficacy for controlling pain, and selfefficacy "other." However, the only statistically significant change was in self-sufficient pain control. Moreover, the study showed that the program was easy to use and should help

In another pilot study (2014), Poole et al. assessed the effectiveness of internet-based selfmanagement program for patients with SSc. Participants logged on to a password-protected web site and completed the program, which consisted of 10 modules (e.g., coping and body image/appearance, fatigue and energy conservation, self-advocacy), an exercise video, learning activities, worksheets, and resources. Participants proceeded through the modules at their own pace over 10 weeks. Participants were encouraged to log on to the discussion board, participate in an interactive component of the web site, and respond to questions posted for each module. Participants completed pre- and postintervention questionnaires on perceived self-efficacy, health efficacy, ability to manage care, functional disability, depression, pain, and fatigue. They also completed an eight-question evaluation form regarding satisfaction with the web site, program content, discussion boards, and learning activities. Sixteen participants completed the study and postintervention measures. The authors demonstrated significant improvements in mean scores for ability to manage health care and efficacy, and significant decreases in fatigue and depression.

Functional impairment of the hand in SSc patients is one of the major problems encountered in rehabilitation practice. Research in this area also includes splinting interventions of the hand and wrist, which aim to facilitate restoration of the lost function. In a 2-month study by Seeger et al., the authors investigated splinting effect on the secondary contractures in 19 patients with SSc. Specifically, whether dynamic splinting can improve flexion contractures in the proximal interphalangeal joints (PIP). Of the eight patients who completed the study, only one had significant improvement in range of motion as a result of PIP joint splinting, which shows that the study failed to demonstrate the use of splints as a suitable method to maintain

In addition to the abovementioned list of interventions, there are few studies that evaluate the effectiveness of some other nonpharmacological approaches in SSc including the use of physical therapy, which is the practical application of physical treatments procedures and methods

Manual lymphatic drainage (MLD) stimulates the lymphatic system and reduces swelling. It is one of the main components of a combined physical therapy, which is used for the treatment of

individuals with SSc in self-sufficiency [25].

94 Systemic Sclerosis

Self-efficacy was improved as well, but not significantly [26].

PIP extension compared with the control hand [27].

2.8. Splinting interventions

2.9. Physical therapy

on living organism.

The effect of manual lymphatic drainage to reduce swelling, improve the functionality of the hand and the perceived quality of life (QoL) in patients with SSc in edematous stage of disease was assessed in an RCT by Bongi et al. The study recruited 35 patients with SSc who were in the edematous disease stage (swelling of the hands), 20 of which were randomly assigned to the intervention group, and underwent MLD 1h once a week for 5 weeks according to the Vodder procedures, and 15 of which served as a control group. The study demonstrated a reduction in the hand volume, improved hand function, and perceived swelling and pain. Reduction in the volume and improvement in hand function were also maintained at follow-up. Furthermore, the authors detected an improvement in overall disability and quality of life in patients who received therapy. In the control group, no improvement was observed. The authors concluded that the application of MLD is effective in the treatment of the hand in edematous SSc by reducing hand volume, edema, and pain, and improving hand function and perceived quality of life. A study on a larger cohort of patients and with a longer follow-up is needed to assess the effect of MLD on different disease subsets as well, and to verify whether the technique could be of help in preventing the transition from hand edema to fibrosis [31].

Beyond examining the effects of MLD, researchers also investigated the effects of other types of physical therapy in the rehabilitation of patients with SSc.

Sallam et al. evaluated the impact of 14-day transcutaneous electrical nerve stimulation (TENS) of gastrointestinal (GI) acupoints on GI symptoms and quality of life in 17 SSc patients. This treatment significantly increased sympathetic and vagal activity in comparison with the basal value, lead to normalization of sympathovagal balance, and increased physical function score, which is closely related to the change in the sympathovagal balance. This provides the potential to treat the upper GI tract symptoms; however, further studies are needed to support these results [32].

In a pilot study by Tinazzi et al., the authors investigated the effect of extracorporeal shock wave therapy on the skin of 30 patients with SSc. This study was based on a hypothesis that the treatment effect of extracorporeal shock wave may decrease damage to the endothelial cells and skin fibrosis in patients with SSc. The authors demonstrated rapid and sustained reduction in Rodnan skin scores and a reduction in visual analog scale. Furthermore, an improvement in skin structure and vascularization was recorded 90 days after treatment. The number of endothelial progenitor cells and circulating endothelial cells increased 60 and 90 days after treatment, whereas serological biomarkers showed no differences before and after treatment [33].

Results of a prospective RCT by Sporbeck et al. point out the beneficial impact of biofeedback and deep oscillation (three times a week for 4 weeks) on Raynaud's phenomenon in patients with SSc [34].

In an observational study by Uhlemann et al., the authors evaluated the effect of ultrasound applied to the hands with an intensity of 0.6 W/cm2 , for 6 minutes, 3 times a day for 6 days on the hand function and strength. Pain decreased in 18 of 24 patients. At the end of therapy, no increase in pain was observed, and the hand strength significantly improved in all patients [35].

Milačić et al. examined the change in volume of orifice before and after combined hyperbaric oxygen (HBO) therapy with facial physical therapy. Patients received HBO therapy ten times (2.0 ATA) and infrared phototherapy using Solux lamp 15 min before kinesiotherapy in front of mirrors daily for 10 days. This treatment targeted facial muscles. The results showed a statistically highly significant difference in improvement before and after treatment, and that use of HBO in the treatment of these patients has a significant role [36].

### 3. Conclusion

Chronic rheumatic diseases have a significant impact on the function, quality of life, and ability to work and represent a significant clinical and economic burden on healthcare systems. It is generally known that adequate physical activity is considered one of the adequate means to maintain or improve the quality of life, both physically and mentally. Nonpharmacological therapy plays a key role in the treatment of most rheumatic diseases. However, its effect for some of them has not been adequately studied or been little researched. A limitation of most of the small number of existing works aimed at nonpharmacological treatment for patients with SSc is low methodological quality, low number of patients, lack of a control group or monitoring (follow-up), and short-term intervention. The purpose of this chapter was to introduce the few studies that have examined this issue (Table 1) and to show that nonpharmacological therapies for diseases such as systemic sclerosis have been the focus of some research teams in recent years, the studies of which have demonstrated safety and benefits of these approaches.

Nonpharmacological therapy in patients with SSc includes, in particular, methods commonly used, for example, paraffin, manual lymphatic drainage, massage, stretching exercises to maintain range of motion in joints, mobilization, aerobic exercises, specially developed programs for the face and hands, self-management programs, splinting, and physical therapy. Other studies also investigated occupational therapy, sexual dysfunction, education, psychosocial status, and nutrition in patients with SSc.

Quality of treatment depends on the cooperation of a multidisciplinary team. A physician should properly choose the right medical treatment. A physiotherapist must select an adequate therapy to be individually tailored for a specific patient. An exercise program should be feasible even in the home environment, and patient's family or partner should get involved. Modifications to the home and work environments should be consulted with an occupational therapist. A psychologist or a psychosomatic medicine specialist can help not only the patient


Results of a prospective RCT by Sporbeck et al. point out the beneficial impact of biofeedback

In an observational study by Uhlemann et al., the authors evaluated the effect of ultrasound

the hand function and strength. Pain decreased in 18 of 24 patients. At the end of therapy, no increase in pain was observed, and the hand strength significantly improved in all patients [35].

Chronic rheumatic diseases have a significant impact on the function, quality of life, and ability to work and represent a significant clinical and economic burden on healthcare systems. It is generally known that adequate physical activity is considered one of the adequate means to maintain or improve the quality of life, both physically and mentally. Nonpharmacological therapy plays a key role in the treatment of most rheumatic diseases. However, its effect for some of them has not been adequately studied or been little researched. A limitation of most of the small number of existing works aimed at nonpharmacological treatment for patients with SSc is low methodological quality, low number of patients, lack of a control group or monitoring (follow-up), and short-term intervention. The purpose of this chapter was to introduce the few studies that have examined this issue (Table 1) and to show that nonpharmacological therapies for diseases such as systemic sclerosis have been the focus of some research teams in recent years, the studies of which have demonstrated safety and benefits of these approaches. Nonpharmacological therapy in patients with SSc includes, in particular, methods commonly used, for example, paraffin, manual lymphatic drainage, massage, stretching exercises to maintain range of motion in joints, mobilization, aerobic exercises, specially developed programs for the face and hands, self-management programs, splinting, and physical therapy. Other studies also investigated occupational therapy, sexual dysfunction, education, psycho-

Quality of treatment depends on the cooperation of a multidisciplinary team. A physician should properly choose the right medical treatment. A physiotherapist must select an adequate therapy to be individually tailored for a specific patient. An exercise program should be

Modifications to the home and work environments should be consulted with an occupational therapist. A psychologist or a psychosomatic medicine specialist can help not only the patient

2

ć et al. examined the change in volume of orifice before and after combined hyperbaric oxygen (HBO) therapy with facial physical therapy. Patients received HBO therapy ten times (2.0 ATA) and infrared phototherapy using Solux lamp 15 min before kinesiotherapy in front of mirrors daily for 10 days. This treatment targeted facial muscles. The results showed a statistically highly significant difference in improvement before and after treatment, and that

's phenomenon in patients

, for 6 minutes, 3 times a day for 6 days on

's family or partner should get involved.

and deep oscillation (three times a week for 4 weeks) on Raynaud

use of HBO in the treatment of these patients has a significant role [36].

applied to the hands with an intensity of 0.6 W/cm

social status, and nutrition in patients with SSc.

feasible even in the home environment, and patient

with SSc [34].

96 Systemic Sclerosis

3. Conclusion

Mila č i Nonpharmacological Treatment in Systemic Sclerosis http://dx.doi.org/10.5772/intechopen.68537 97



series of single case

studies [8] Effect of orofacial

YUEN, 2012

 RCT

 Orofacial

Multifaceted

 oral

Usual dental

26 SSc

22 SSc

Twice a day with a

After 3 months,

A significantly larger increase in

oral aperture for

participants

receiving the

orofacial exercise

program was

found when compared to those

in the usual care at

3 months, but not

at 6 months

evaluation.

Participants'

adherence rate to

the exercise

program was low

(48.9%)

The rehabilitation

MADDALI-BONGI,

RCT

 Orofacial

Combination

 of the

Only home

20 SSc

20 SSc

9 weeks, 2 times a

After 9 weeks and

The combination of

connective tissue

massage, Kabat's

technique,

kinesiotherapy,

home-based

exercises was more

effective than a

home exercise

program alone in

the rehabilitative

treatment of SSc facial involvement

There was a

significant

improvement

 in

 and

after 9 weeks of

follow-up

exercise

patients

patients

week for 1 hour

program

treatment

Kabat's technique,

connective tissue

massage, and

kinesiotherapy

specially developed

for the face of SSc patients with a home

exercise program

of facial

2011

involvement in systemic sclerosis:

efficacy of the

combination of connective tissue

massage, Kabat's

technique and

kinesitherapy

Oral hygiene in

POOLE, 2010

 OD

 Orofacial

Structured oral

–

17 SSc

–

6 months daily

 After 6 month

intervention

patients

treatment

hygiene and exercises

for the face and hands

scleroderma:

effectiveness

 of a

 the

 [10]

and 6 months

care

patients

patients

total of 6 minutes

for 6 months

treatment

health intervention

exercises on oral aperture in adults

with systemic

sclerosis [9]

 Author, year

 Study

Type of

Description of

Description

Number of

Number of

Duration of the

Postintervention

Results

98 Systemic Sclerosis

improve activity/

participation

involving the use of

the hands

assessment

individuals

individuals

intervention

intervention

intervention

 group

 in

of

intervention

in

in control

> in control

intervention

group

group

group

intervention

design

#### Nonpharmacological Treatment in Systemic Sclerosis http://dx.doi.org/10.5772/intechopen.68537 99

rehabilitation

therapy for

massage and Mc

weeks

follow-up

and global



program for

physical and/or

Mennell joint

medical

rehabilitative

techniques

designed and

tailored for SSc

patients improved disability, HRQoL,

hand and face disability and

functionality,

its effects partially

maintained at the

follow-up

 with

information

psychological

manipulation

 (MLD if

functioning

patients had

edematous hands.

Face involvement was

treated with a combination of Kabat's method, connective tissue

massage, and

kinesiotherapy.

Hydrokinesiotherapy

(for patients without

ulcers) or land-based

rehabilitation

patients with ulcers),

and respiratory

rehabilitation

exercises)

An

individualized

ANTONIOLI,

 2009 CCT

physical

program that

consisted of warm-up

therapy for

physical and/or

and cool-down

psychological

exercises, training of

functioning

motor functions,

diaphragmatic

breathing, controlled

coughing exercises,

treadmill,

freewalking, finger

stretching, and

occupational

(physical therapy was

also prescribed to 13

patients with articular

problems) and home

exercise program

 therapy

Comprehensive

Rehabilitation

–

16 SSc

17 SSc

2 weeks daily 30-

After 2 and 4

This study suggests

that a significant

proportion of

patients with SSc

experience an

improvement

their perception of

QoL, a better

exercise tolerance, and a better hand

mobility after a

rehabilitation

program consisting

of a 2-week period of daily individual

30-min sessions of

outpatient care,

followed by at-

home exercise

program

 in

months

patients

patients

minute sessions

(10 sessions in

total)

rehabilitation

program in

patients with

systemic sclerosis

may improve quality of life and

hand mobility [16]

 (for

systemic

sclerosis [15]

 Author, year

 Study

Type of

Description of

Description

Number of

Number of

Duration of the

Postintervention

Results

100 Systemic Sclerosis

assessment

individuals

individuals

intervention

intervention

intervention

 group

 in

of

intervention

in

in control

> in control

intervention

group

group

group

intervention

design



combination with

traditional Thai

massage, heat, and

stretching exercise

to improve hand

mobility in

scleroderma

patients [20] Efficacy and safety

PINTO, 2011

 OD

 Aerobic training

Combined resistance

–

11 SSc

–

12 weeks

 After intervention

 This study demonstrates

12-week concurrent training program is

safe and substantially

improves muscle

strength, function,

and aerobic capacity in SSc

patients

 that a

patients

and combined

and aerobic training

endurance/

program (concurrent

training)

resistance

training

of concurrent training in systemic

sclerosis [21] Intensive aerobic

ALEXANDERSON,

Pilot study Aerobic training

Intense aerobic and

–

4 SSc

–

6 weeks

Every other week

Three participants

improved

significantly in

muscular

endurance, and

two participants

improved

significantly or

clinically relevantly

in aerobic capacity. All other variables

remained

unchanged, except for a trend toward

reduced fatigue

(noninterventional

throughout the 14-

week study

baseline period)

and 8 weeks

(exercise

intervention

period 3 a week)

patients

endurance training

and combined

endurance/

program

resistance

training

and muscle

2014

endurance exercise

in patients with

systemic sclerosis:

a pilot study [22]

Aerobic exercise is

OLIVEIRA, 2009

 CCT

 Aerobic training

Aerobic exercise

Aerobic

7 SSc

7 healthy

8 weeks

Pre- and posttest

 Both groups

showed a significant

exercise

patients

volunteers

program of

program of moderate

intensity

and combined

endurance/

safe and effective in

 Author, year

 Study

Type of

Description of

Description

Number of

Number of

Duration of the

Postintervention

Results

102 Systemic Sclerosis

assessment

individuals

individuals

intervention

intervention

intervention

 group

 in

of

intervention

in

in control

> in control

intervention

group

group

Thai massage with

without

significant

improvement

hand mobility after

2 weeks of daily

home exercise

program. Wearing the glove, however,

resulted in better

thumb mobility

 in

gloves

stretching exercises

and heat with gloves

group

intervention

design



 Author, year

 Study

Type of

Description of

Description

Number of

Number of

Duration of the

Postintervention

Results

104 Systemic Sclerosis

efficacy for

controlling pain, and self-efficacy

"other" however, the only

statistically

significant change

was in self-efficacy

for pain

improved;

assessment

individuals

individuals

intervention

intervention

intervention

 group

 in

of

intervention

in

in control

> in control

intervention

group

group

management,

advocacy, activities of

daily living, oral

hygiene, skin and

wound care, psychosocial

exercises, and other

features of the

condition

The program

–

16 SSc

–

Over 10 weeks

–

There were

significant

improvements

mean scores for ability to manage

care and health,

and significant decreases in fatigue

and depression.

Self-efficacy

improved, but not

significantly

 in

patients

consisted of 10 modules (e.g. coping

and body image/

appearance, fatigue

and energy conservation,

advocacy), an exercise

video, learning activities, worksheets,

and resources

 self-

Taking charge of

POOLE, 2014

 Pilot study Selfmanagement

program

systemic sclerosis:

a pilot study to

assess the effectiveness

internet selfmanagement

program [26] Effects of splinting

SEEGER, 1987

 Pilot study Splinting interventions

the hand daily for

8 hours (could decrease proximal

interphalangeal

flexion contractures?)

 (PIP)

Dynamic splinting of

The

8 SSc

8 SSc

2 months

 After 1 and 2

Just one of eight

patients

experienced a

statistically

significant

improvement

PIP range of

motion as a result

of the splinting.

There was no evidence that the

use of the splints served to maintain PIP extension when

compared with the

control hand

 in

months

nonsplinted

patients

patients

hand

in the treatment of

hand contractures

in progressive

systemic

sclerosis [27]

 of an

 changes,

group

intervention

design



 Author, year

 Study

Type of

Description of

Description

Number of

Number of

Duration of the

Postintervention

Results

106 Systemic Sclerosis

majority of cases it

determines a rapid

improvement

skin elasticity and

skin wellness, even

if the effects tend to

reduce during the

time

Effect of

SPORBECK, 2012 RCT

 Physical

The effect of deep

No

8 SSc

10 SSc

3 times per week

After 4 and 12

Biofeedback

resulted in an improvement

as determined by

score reduction of

visual analogue scale compared with patients of the

control group,

whereas deep oscillation revealed

a tendency for

improvement.

study underlines

the beneficial role

of for the treatment of

SSc-related RP

physiotherapy

 The

 in RP

weeks

intervention

patients

patients

for 4 weeks

biofeedback

oscillation and biofeedback on RP

or therapies

with an

and 10 SSc

expected

patients—

effect

deep

oscillation

secondary to SSc

therapy

biofeedback and deep oscillation on

Raynaud's

phenomenon

secondary to

systemic sclerosis:

results of a

controlled

prospective

randomized

clinical trial [34]

Multiple daily

UHLEMANN,

 1990 OD

 Physical

Ultrasound therapy

–

24 SSc

–

3 times a day

After 6 days

 Pain decreased in 18 of 24 patients. At

the end of therapy,

no increase in pain

was observed, and

the hand strength

significantly

improved in all

patients

during 6 days

patients

therapy

of the hands with an

intensity of 0.6W/cm2,

6 minutes per region

ultrasound

treatment of patients with

progressive

systemic

scleroderma [35]

 in

assessment

individuals

individuals

intervention

intervention

intervention

 group

 in

of

intervention

in

in control

> in control

intervention

group

group

group

intervention

design

Table 1. Overview of available studies on nonpharmacological interventions in patients with systemic sclerosis.

 HBO, hyperbaric oxygenation.

motion; VO2, oxygen uptake; MLD, manual lymphatic drainage; 6MWD, 6-min walk distance; TENS,

ESWT,

extracorporeal

 shock wave therapy; RP, Raynaud's phenomenon;

transcutaneous

 electrical nerve stimulation; GI,

gastrointestinal;

 ESW,

extracorporeal

 shock wave; but also the family or a partner to solve the psychological problems that could be associated with the establishment of the diagnosis.

It is clear from the systematic literature search of available studies that nonpharmacological treatment for these patients has its positive results and has been investigated worldwide. However, since it is a rare disease, the strength of evidence of efficacy of nonpharmacological treatment is limited. The aforementioned limitations suggest that there is an unmet need for international multicentric cooperation, teamwork, and unified projects with a solid design in order to explore this area to arrive at definite conclusions and treatment recommendations. Thus, even nonpharmacological approaches could offer specific techniques that could be implemented and would effectively contribute to greater self-sufficiency, and easier selfmanagement of patients with SSc.

It is also important to carry out further studies to assess other neglected areas such as psychosocial status, depression or sexual dysfunction in order to provide a complex therapy by a team of specialist offering a versatile assistance to patients with SSc.

### Acknowledgements

This chapter was supported by grant projects AZV 16-33542A, AZV 16-33574A, SVV for FTVS UK 2017, UNCE, PRVOUK P38, GAUK 214615, and the Ministry of Health of the Czech Republic [Research Project No. 00023728].

### Author details

Maja Špiritović 1,2 and Michal Tomčík<sup>2</sup> \*

\*Address all correspondence to: michaltomcik@yahoo.com

1 Faculty of Sport and Physical Education, Department of Physiotherapy, Charles University, Prague, Czech Republic

2 Institute of Rheumatology and Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, Czech Republic

### References

[1] Sandberg ME, Bengtsson C, Kallberg H, Wesley A, Klareskog L, Alfredsson L, et al. Overweight decreases the chance of achieving good response and low disease activity in early rheumatoid arthritis. Annals of the Rheumatic Diseases. 2014;73(11):2029-2033

[2] Sandberg MEC, Wedren S, Klareskog L, Lundberg IE, Opava CH, Alfredsson L, et al. Patients with regular physical activity before onset of rheumatoid arthritis present with milder disease. Annals of the Rheumatic Diseases. 2014;73(8):1541–1544

but also the family or a partner to solve the psychological problems that could be associated

It is clear from the systematic literature search of available studies that nonpharmacological treatment for these patients has its positive results and has been investigated worldwide. However, since it is a rare disease, the strength of evidence of efficacy of nonpharmacological treatment is limited. The aforementioned limitations suggest that there is an unmet need for international multicentric cooperation, teamwork, and unified projects with a solid design in order to explore this area to arrive at definite conclusions and treatment recommendations. Thus, even nonpharmacological approaches could offer specific techniques that could be implemented and would effectively contribute to greater self-sufficiency, and easier self-

It is also important to carry out further studies to assess other neglected areas such as psychosocial status, depression or sexual dysfunction in order to provide a complex therapy by a

This chapter was supported by grant projects AZV 16-33542A, AZV 16-33574A, SVV for FTVS UK 2017, UNCE, PRVOUK P38, GAUK 214615, and the Ministry of Health of the Czech

1 Faculty of Sport and Physical Education, Department of Physiotherapy, Charles University,

2 Institute of Rheumatology and Department of Rheumatology, First Faculty of Medicine,

[1] Sandberg ME, Bengtsson C, Kallberg H, Wesley A, Klareskog L, Alfredsson L, et al. Overweight decreases the chance of achieving good response and low disease activity in early rheumatoid arthritis. Annals of the Rheumatic Diseases. 2014;73(11):2029-2033

team of specialist offering a versatile assistance to patients with SSc.

with the establishment of the diagnosis.

108 Systemic Sclerosis

management of patients with SSc.

Republic [Research Project No. 00023728].

Charles University, Prague, Czech Republic

1,2 and Michal Tomčík<sup>2</sup>

\*Address all correspondence to: michaltomcik@yahoo.com

\*

Acknowledgements

Author details

Prague, Czech Republic

Maja Špiritović

References


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**Provisional chapter**
