Clinical Challenges in Rheumatoid Arthritis Patients

**67**

vessels [1].

**Chapter 4**

**Abstract**

**1. Introduction**

tory, haematologic) [1].

Vascular Involvement in

*Alexandru Caraba, Stela Iurciuc and Mircea Iurciuc*

evolution. Rheumatoid vasculitis can occur in severe forms of RA.

**Keywords:** macrovascular, microvascular involvement, rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disorder, characterized by synovitis of small- and medium-sized joints, which causes cartilage breakdown, bone erosions, and finally destruction and loss of joints function. But beside the joints involvement, RA, especially with long-term evolution and suboptimal control of the disease activity, can generate systemic involvement (cardiovascular, respira-

RA is the most common inflammatory rheumatic disease, affecting about 0.5–1% of North American and European people over 18 years. The RA incidence and prevalence have regional differences: the lowest rates are identified in Southern regions, and the highest rates are present in Northern Europe and North America. Women are more frequently affected than men (women/men ratio 3/1), this disease

RA is an autoimmune disorder; through the interaction between genetic predisposition and environmental factors, a trigger event generates an inflammatory autoimmune response, which affects primarily the synovial joint but also the blood

The interrelation between RA and vascular involvement began to be studied many years ago. In 2008, in their review, Szekanecz and Koch introduced the term "vascular rheumatology," referring to vascular impairment from inflammatory rheumatic diseases [4]. Indeed, in RA, vascular involvement comprises both macroand microvessels. Special attention requires rheumatoid vasculitis, a rare but severe complication of this disease. Histologically, vascular lesions have been found in 25% of RA patients [5]. Patients with RA are prone to early and accelerated atherosclerosis, which induces higher cardiovascular risk, independent of traditional risk factors

occurring more commonly in the 4th or the 5th decades of life [2, 3].

Rheumatoid arthritis (RA) represents the one of the most common inflammatory rheumatic diseases, which generates disability and significantly reduces the quality of life. RA can affect the vascular system, in addition to joint involvement. Vascular involvement increases the morbidity and mortality among these patients. Macrovascular disease, related to accelerated atherosclerosis, has a high prevalence among RA patients, in the form of carotid artery disease, ischemic heart disease, and peripheral arterial obstructive disease. Microvascular disease, studied in recent years by means of nailfold capillaroscopy, is present even in the early stage of RA

Rheumatoid Arthritis

### **Chapter 4**

## Vascular Involvement in Rheumatoid Arthritis

*Alexandru Caraba, Stela Iurciuc and Mircea Iurciuc*

### **Abstract**

Rheumatoid arthritis (RA) represents the one of the most common inflammatory rheumatic diseases, which generates disability and significantly reduces the quality of life. RA can affect the vascular system, in addition to joint involvement. Vascular involvement increases the morbidity and mortality among these patients. Macrovascular disease, related to accelerated atherosclerosis, has a high prevalence among RA patients, in the form of carotid artery disease, ischemic heart disease, and peripheral arterial obstructive disease. Microvascular disease, studied in recent years by means of nailfold capillaroscopy, is present even in the early stage of RA evolution. Rheumatoid vasculitis can occur in severe forms of RA.

**Keywords:** macrovascular, microvascular involvement, rheumatoid arthritis

#### **1. Introduction**

Rheumatoid arthritis (RA) is a chronic inflammatory disorder, characterized by synovitis of small- and medium-sized joints, which causes cartilage breakdown, bone erosions, and finally destruction and loss of joints function. But beside the joints involvement, RA, especially with long-term evolution and suboptimal control of the disease activity, can generate systemic involvement (cardiovascular, respiratory, haematologic) [1].

RA is the most common inflammatory rheumatic disease, affecting about 0.5–1% of North American and European people over 18 years. The RA incidence and prevalence have regional differences: the lowest rates are identified in Southern regions, and the highest rates are present in Northern Europe and North America. Women are more frequently affected than men (women/men ratio 3/1), this disease occurring more commonly in the 4th or the 5th decades of life [2, 3].

RA is an autoimmune disorder; through the interaction between genetic predisposition and environmental factors, a trigger event generates an inflammatory autoimmune response, which affects primarily the synovial joint but also the blood vessels [1].

The interrelation between RA and vascular involvement began to be studied many years ago. In 2008, in their review, Szekanecz and Koch introduced the term "vascular rheumatology," referring to vascular impairment from inflammatory rheumatic diseases [4]. Indeed, in RA, vascular involvement comprises both macroand microvessels. Special attention requires rheumatoid vasculitis, a rare but severe complication of this disease. Histologically, vascular lesions have been found in 25% of RA patients [5]. Patients with RA are prone to early and accelerated atherosclerosis, which induces higher cardiovascular risk, independent of traditional risk factors (diabetes mellitus, arterial hypertension, smoking, dyslipidemia, age, lifestyle). RA-related risk factors are identified and characterized in these patients [6, 7]. In RA patients, the cardiovascular risk is obtained by the multiplication of measured risk (SCORE, Framingham) by a factor of 1.5, if two of the three following criteria are fulfilled (RA evolution >10 years, positivity of RF or ACPA, extra-articular involvement) [8].

### **2. Risk factors for vascular involvement**

Vascular involvement in RA patients has a multifactorial model. Traditional cardiovascular risk factors together with those related to RA contribute to the development of macro- and microvascular involvement. It is known that the first step in atherogenesis development is endothelial dysfunction. Several factors associated with RA are involved in the endothelial dysfunction appearance: pro-inflammatory mediators and cells, oxidative stress, insulin resistance, physical inactivity, genetic factors, and drugs [9].

During its evolution, RA is a chronic inflammatory condition. Even in the preclinical stage, then continuing with the period when the clinical picture is complete, the chronic inflammatory environment exists in these patients. Pro-inflammatory cytokines contribute to synovial inflammation and to atherosclerosis development, through endothelial dysfunction.

Under physiological conditions, endothelium represents an active barrier between vascular wall and bloodstream, being involved in maintaining vascular muscle tone and homeostasis, controlling cell adhesion, proliferation, and coagulation balance. In pathophysiological conditions (chronic inflammatory diseases), these endothelium physiological functions are disturbed, and endothelial dysfunction occurs. During this new situation, reduced vasodilation, pro-inflammatory and prothrombotic status, and increased cell adhesion and proliferation contribute to atherosclerosis development. Endothelial dysfunction is a preclinical marker of atherosclerosis development, commonly detected in RA patients, but it is also involved in plaque progression and the occurrence of atherosclerotic complications [10, 11]. In RA patients, endothelial dysfunction occurs differentially in different vascular beds (macro- and microcirculation) [12]. Bocci et al. showed that in RA patients, the coronary microvascular involvement is identified in the absence of macrovascular disease [13].

Several factors are involved in endothelial dysfunction appearance in RA patients (**Table 1**) [9, 11].

#### **2.1 Arterial hypertension**

High blood pressure represents an independent predictor of cardiovascular events in RA patients. COMORA study reported that the prevalence of high blood pressure among RA patients was about 40% [14]. In their meta-analysis, Baghdadi et al. reported that high blood pressure was associated with a relative risk of cardiovascular morbidity of 2.24 in patients with RA [15]. On the other hand, Panoulas et al. identified that the most important determinant of target organ damage in RA patients is arterial hypertension [16]. It is known that the increase in systolic blood pressure with 20 mmHg is associated with high risk of endothelial dysfunction and cardiovascular disease. Some drugs used in RA therapy, as Leflunomide, NSAIDs, corticoids, and cyclosporine, are associated with high risk of arterial hypertension development, with consecutive endothelial dysfunction [7]. In hypertensive RA patients, ambulatory blood pressure monitoring revealed that the non-dipper and excessive dipper

**69**

plasma [8].

**2.4 Obesity**

*Vascular Involvement in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91142*

• Insulin resistance and metabolic syndrome

**Traditional risk factors** • Arterial hypertension • Dyslipidemia

• Chronic inflammatory status

*Factors involved in RA endothelial dysfunction.*

• Oxidative stress

• Obesity • Smoking **RA-related factors**

**Table 1.**

population [20–22].

**2.2 Dyslipidemia**

tocilizumab, and IL-6 receptor blocker [8].

**2.3 Insulin resistance and metabolic syndrome**

patterns were frequent among them and pulse pressure was increased, these characteristics predisposing to cardiovascular complications [17]. Most researchers wondered if high blood pressure is effectively controlled in RA patients. Panoulas et al. and Desai et al., in their studies, showed that the identification and effective control of high blood pressure is suboptimal in RA patients [18, 19]. Two studies published in 2016 and one published in 2019 showed that there were no significant differences in the diagnosis and therapy of high blood pressure in RA patients versus the general

Dyslipidemia represents a well-known traditional cardiovascular risk factor, affecting between 55 and 65% of the RA patients [23]. These patients present low levels of low density lipoprotein (LDL), high density lipoprotein (HDL), and total cholesterol, these levels being inversely correlated with markers of inflammation. But during inflammation, these molecules develop functional and structural changes, becoming atherogenic and promoting endothelial dysfunction. Some drugs used in RA treatment may increase lipid levels: DMARDs, TNF-α inhibitors,

The prevalence of insulin resistance and metabolic syndrome is increased in RA patients (40%), increasing the risk of endothelial dysfunction and cardiovascular events by twofold compared to the general population. RA with high activity increases the effect of insulin resistance/metabolic syndrome on endothelial dysfunction. The effect of the medication that decreases the RA activity (DMARDs, biologics) on insulin resistance is not to be neglected. Endothelial-dependent vasodilation, mediated by nitric oxide release, is impaired in insulin resistance individuals. They display high levels of endothelin and plasminogen activator inhibitor in

Obesity, physical inactivity, and endothelial dysfunction coexist in RA patients. Obesity is associated with other cardiovascular risk factors, as atherogenic dyslipidemia, high blood pressure, insulin resistance, and low grade inflammation, generating endothelial dysfunction. But in RA an association between low body mass

*Vascular Involvement in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91142*


#### **Table 1.**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

**2. Risk factors for vascular involvement**

involvement) [8].

factors, and drugs [9].

through endothelial dysfunction.

macrovascular disease [13].

patients (**Table 1**) [9, 11].

**2.1 Arterial hypertension**

(diabetes mellitus, arterial hypertension, smoking, dyslipidemia, age, lifestyle). RA-related risk factors are identified and characterized in these patients [6, 7]. In RA patients, the cardiovascular risk is obtained by the multiplication of measured risk (SCORE, Framingham) by a factor of 1.5, if two of the three following criteria are fulfilled (RA evolution >10 years, positivity of RF or ACPA, extra-articular

Vascular involvement in RA patients has a multifactorial model. Traditional cardiovascular risk factors together with those related to RA contribute to the development of macro- and microvascular involvement. It is known that the first step in atherogenesis development is endothelial dysfunction. Several factors associated with RA are involved in the endothelial dysfunction appearance: pro-inflammatory mediators and cells, oxidative stress, insulin resistance, physical inactivity, genetic

During its evolution, RA is a chronic inflammatory condition. Even in the preclinical stage, then continuing with the period when the clinical picture is complete, the chronic inflammatory environment exists in these patients. Pro-inflammatory cytokines contribute to synovial inflammation and to atherosclerosis development,

Under physiological conditions, endothelium represents an active barrier between vascular wall and bloodstream, being involved in maintaining vascular muscle tone and homeostasis, controlling cell adhesion, proliferation, and coagulation balance. In pathophysiological conditions (chronic inflammatory diseases), these endothelium physiological functions are disturbed, and endothelial dysfunction occurs. During this new situation, reduced vasodilation, pro-inflammatory and prothrombotic status, and increased cell adhesion and proliferation contribute to atherosclerosis development. Endothelial dysfunction is a preclinical marker of atherosclerosis development, commonly detected in RA patients, but it is also involved in plaque progression and the occurrence of atherosclerotic complications [10, 11]. In RA patients, endothelial dysfunction occurs differentially in different vascular beds (macro- and microcirculation) [12]. Bocci et al. showed that in RA patients, the coronary microvascular involvement is identified in the absence of

Several factors are involved in endothelial dysfunction appearance in RA

in RA patients. COMORA study reported that the prevalence of high blood pressure among RA patients was about 40% [14]. In their meta-analysis, Baghdadi et al. reported that high blood pressure was associated with a relative risk of cardiovascular morbidity of 2.24 in patients with RA [15]. On the other hand, Panoulas et al. identified that the most important determinant of target organ damage in RA patients is arterial hypertension [16]. It is known that the increase in systolic blood pressure with 20 mmHg is associated with high risk of endothelial dysfunction and cardiovascular disease. Some drugs used in RA therapy, as Leflunomide, NSAIDs, corticoids, and cyclosporine, are associated with high risk of arterial hypertension development, with consecutive endothelial dysfunction [7]. In hypertensive RA patients, ambulatory blood pressure monitoring revealed that the non-dipper and excessive dipper

High blood pressure represents an independent predictor of cardiovascular events

**68**

*Factors involved in RA endothelial dysfunction.*

patterns were frequent among them and pulse pressure was increased, these characteristics predisposing to cardiovascular complications [17]. Most researchers wondered if high blood pressure is effectively controlled in RA patients. Panoulas et al. and Desai et al., in their studies, showed that the identification and effective control of high blood pressure is suboptimal in RA patients [18, 19]. Two studies published in 2016 and one published in 2019 showed that there were no significant differences in the diagnosis and therapy of high blood pressure in RA patients versus the general population [20–22].

#### **2.2 Dyslipidemia**

Dyslipidemia represents a well-known traditional cardiovascular risk factor, affecting between 55 and 65% of the RA patients [23]. These patients present low levels of low density lipoprotein (LDL), high density lipoprotein (HDL), and total cholesterol, these levels being inversely correlated with markers of inflammation. But during inflammation, these molecules develop functional and structural changes, becoming atherogenic and promoting endothelial dysfunction. Some drugs used in RA treatment may increase lipid levels: DMARDs, TNF-α inhibitors, tocilizumab, and IL-6 receptor blocker [8].

#### **2.3 Insulin resistance and metabolic syndrome**

The prevalence of insulin resistance and metabolic syndrome is increased in RA patients (40%), increasing the risk of endothelial dysfunction and cardiovascular events by twofold compared to the general population. RA with high activity increases the effect of insulin resistance/metabolic syndrome on endothelial dysfunction. The effect of the medication that decreases the RA activity (DMARDs, biologics) on insulin resistance is not to be neglected. Endothelial-dependent vasodilation, mediated by nitric oxide release, is impaired in insulin resistance individuals. They display high levels of endothelin and plasminogen activator inhibitor in plasma [8].

#### **2.4 Obesity**

Obesity, physical inactivity, and endothelial dysfunction coexist in RA patients. Obesity is associated with other cardiovascular risk factors, as atherogenic dyslipidemia, high blood pressure, insulin resistance, and low grade inflammation, generating endothelial dysfunction. But in RA an association between low body mass

(secondary to high rheumatoid inflammation, generating rheumatoid cachexia) and cardiovascular events, too, is described [8].

#### **2.5 Smoking**

Another cardiovascular risk factor, smoking, is involved in RA appearance [24]. Rojas-Serrano et al. showed that the RA patients who smoked had a more severe RA evolution and positivity for rheumatoid factor and anticitrullinated protein antibodies [25]. Baghdadi et al. demonstrated that the cardiovascular risk was higher in RA patients who smoked [15].

Baghdadi et al. revealed in their meta-analysis that in RA patients the increased cardiovascular morbidity is related to the presence of high blood pressure [relative risk (RR): 2.24, 95% confidence intervals (CI): 1.42–3.06], smoking (RR: 1.5, 95% CI: 1.15–1.84), obesity (RR: 1.16, 95% CI: 1.03–1.29), insulin resistance (RR: 1.94, 95% CI: 1.58–2.30), and atherogenic dyslipidemia (RR: 1.73, 95% CI: 1.03–2.44) [15].

#### **2.6 Inflammation**

Chronic inflammation is considered to be an independent risk factor for the atherosclerosis development. Together with immune dysregulation, it contributes to endothelial dysfunction and atheroma plaque development. The cardiovascular risk begins to be evident from the early stages of RA, making the cardiovascular investigation necessary even from the first medical visit [26].

Chronic inflammation is considered to be of utmost importance in endothelial dysfunction onset. The previous studies have shown that the inflammatory processes in the rheumatoid synovium and atherosclerotic plaques are remarkably similar. TNF-alpha, interleukin-1 (IL-1), and interleukin-6 (IL-6) play an important role in RA pathogenesis, but they are involved in the development of endothelial dysfunction, too. TNF-alpha increases IL-1, IL-6, IL-8, and chemokines synthesis. On the other hand, this cytokine increases cellular infiltration in the synovium, through enhancing chemokine expression, endothelial cells activation, and neoangiogenesis. IL-1 stimulates the expression of adhesion molecules on the endothelial cells and neoangiogenesis. IL-6 contributes to endothelial cell activation; upregulates the expression of the chemokines that attract T cells, leading to enhanced cellular infiltration; and increases the concentration of VEGF with high vascular permeability appearance. VEGF induces the endothelial cell activation and differentiation, generating neoangiogenesis, too. These cytokines have metabolic effects, acting on the adipose tissue, the skeletal muscle, and the liver and contributing to the traditional cardiovascular risk factor production (insulin resistance, obesity). They contribute to the endothelial dysfunction development.

The inflammatory environment increases the effect of traditional cardiovascular risk factors on endothelial cells, generating endothelial dysfunction development. Other studies revealed that the anti-inflammatory treatment improves the endothelial dysfunction in RA patients [8, 27, 28].

#### **2.7 Reactive oxygen species**

Reactive oxygen species (ROS), generated at higher concentrations at sites of inflammation, can induce cellular injury. Vascular endothelial cells represent the main target for the ROS, increasing the endothelial permeability and promoting leukocyte adhesion. On the other hand, high levels of ROS and low levels of antioxidants in RA with high inflammatory activity generate the impairment of the HDL

**71**

therapy.

triglyceride levels are increased.

reducing endothelial dysfunction.

vascular events in RA patients [1, 8].

*Vascular Involvement in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91142*

**2.8 RA treatment and vascular dysfunction**

appearance in RA patients [7, 10].

ischemic cardiovascular disease [8, 9].

Prednisone/day), for the shortest period of time [9].

cardiovascular risk.

function. Through these effects, ROS contributes to the endothelial dysfunction

The drugs used in RA therapy may contribute to vascular dysfunction and

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent a class of drugs frequently used by these patients. The data regarding the NSAID use and cardiovascular risk in RA patients remain controversial. Data from the Danish nationwide registry revealed that the increased cardiovascular risk related to the overall use of NSAIDs in RA patients was modest and even significantly lower than in non-RA subjects. Rofecoxib and diclofenac were the exception, being associated with increased cardiovascular risk [29]. It is recommended to use NSAIDs with caution in RA patients in the presence of cardiovascular risk factors or in the presence of

Corticosteroids contribute to insulin resistance, high blood pressure, and atherogenic dyslipidemia; all these factors are associated with endothelial dysfunction and subsequently appearance of cardiovascular events. But, on the other hand, by controlling inflammation, corticoids may reduce cardiovascular risk in RA patients. EULAR recommended the corticoid use at lowest dose possible (<7.5 mg

Among disease-modifying drugs (DMARDs), methotrexate, sulfasalazine, and hydroxychloroquine are associated with the cardiovascular risk reduction. By controlling inflammation (decrease of pro-inflammatory cytokine level), methotrexate improves the endothelial function in RA patients. But this drug contributes to endothelial protection by means of induction of AMPK-regulated protective genes. Sulfasalazine interferes with platelet function. Hydroxychloroquine improves lipid profile and has antithrombotic effects, thus reducing the cardiovascular risk.

By using biologics (anti-TNF-alpha, anti-CD28, anti-CD20, anti-IL 6, anti-IL1), cardiovascular risk was reduced comparatively with the RA patients without this

Anti-TNF-alpha therapy improves endothelial function by means of inflammation reduction. It is important to know that the reduction in cardiovascular risk was

Anti-CD20 therapy reduces RA activity and has favorable effects on lipid profile,

The use of abatacept in RA treatment has generated conflicting data regarding vascular dysfunction. Tofacitinib increases total cholesterol levels but without change of atherogenic index. This new drug was associated with low rates of cardio-

All these factors contribute to disruption of vascular environment at the macro-

Anti-IL-6 therapy improves endothelial function (measured by means of flow-mediated vasodilation) very early during the treatment. This effect is determined by reducing inflammation, although total cholesterol, LDL-cholesterol, and

Leflunomide and cyclosporine are associated with arterial hypertension.

recorded only in patients responsive to anti-TNF-alpha treatment.

**3. Macro- and microvascular endothelial dysfunction**

and microcirculation levels, occurring endothelial dysfunction [2, 7].

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

and cardiovascular events, too, is described [8].

**2.5 Smoking**

RA patients who smoked [15].

**2.6 Inflammation**

(secondary to high rheumatoid inflammation, generating rheumatoid cachexia)

Another cardiovascular risk factor, smoking, is involved in RA appearance [24]. Rojas-Serrano et al. showed that the RA patients who smoked had a more severe RA evolution and positivity for rheumatoid factor and anticitrullinated protein antibodies [25]. Baghdadi et al. demonstrated that the cardiovascular risk was higher in

Baghdadi et al. revealed in their meta-analysis that in RA patients the increased cardiovascular morbidity is related to the presence of high blood pressure [relative risk (RR): 2.24, 95% confidence intervals (CI): 1.42–3.06], smoking (RR: 1.5, 95% CI: 1.15–1.84), obesity (RR: 1.16, 95% CI: 1.03–1.29), insulin resistance (RR: 1.94, 95% CI: 1.58–2.30), and atherogenic dyslipidemia (RR: 1.73, 95% CI: 1.03–2.44) [15].

Chronic inflammation is considered to be an independent risk factor for the atherosclerosis development. Together with immune dysregulation, it contributes to endothelial dysfunction and atheroma plaque development. The cardiovascular risk begins to be evident from the early stages of RA, making the cardiovascular

Chronic inflammation is considered to be of utmost importance in endothelial dysfunction onset. The previous studies have shown that the inflammatory processes in the rheumatoid synovium and atherosclerotic plaques are remarkably similar. TNF-alpha, interleukin-1 (IL-1), and interleukin-6 (IL-6) play an important role in RA pathogenesis, but they are involved in the development of endothelial dysfunction, too. TNF-alpha increases IL-1, IL-6, IL-8, and chemokines synthesis. On the other hand, this cytokine increases cellular infiltration in the synovium, through enhancing chemokine expression, endothelial cells activation, and neoangiogenesis. IL-1 stimulates the expression of adhesion molecules on the endothelial cells and neoangiogenesis. IL-6 contributes to endothelial cell activation; upregulates the expression of the chemokines that attract T cells, leading to enhanced cellular infiltration; and increases the concentration of VEGF with high vascular permeability appearance. VEGF induces the endothelial cell activation and differentiation, generating neoangiogenesis, too. These cytokines have metabolic effects, acting on the adipose tissue, the skeletal muscle, and the liver and contributing to the traditional cardiovascular risk factor production (insulin resistance,

investigation necessary even from the first medical visit [26].

obesity). They contribute to the endothelial dysfunction development.

lial dysfunction in RA patients [8, 27, 28].

**2.7 Reactive oxygen species**

The inflammatory environment increases the effect of traditional cardiovascular risk factors on endothelial cells, generating endothelial dysfunction development. Other studies revealed that the anti-inflammatory treatment improves the endothe-

Reactive oxygen species (ROS), generated at higher concentrations at sites of inflammation, can induce cellular injury. Vascular endothelial cells represent the main target for the ROS, increasing the endothelial permeability and promoting leukocyte adhesion. On the other hand, high levels of ROS and low levels of antioxidants in RA with high inflammatory activity generate the impairment of the HDL

**70**

function. Through these effects, ROS contributes to the endothelial dysfunction appearance in RA patients [7, 10].

### **2.8 RA treatment and vascular dysfunction**

The drugs used in RA therapy may contribute to vascular dysfunction and cardiovascular risk.

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent a class of drugs frequently used by these patients. The data regarding the NSAID use and cardiovascular risk in RA patients remain controversial. Data from the Danish nationwide registry revealed that the increased cardiovascular risk related to the overall use of NSAIDs in RA patients was modest and even significantly lower than in non-RA subjects. Rofecoxib and diclofenac were the exception, being associated with increased cardiovascular risk [29]. It is recommended to use NSAIDs with caution in RA patients in the presence of cardiovascular risk factors or in the presence of ischemic cardiovascular disease [8, 9].

Corticosteroids contribute to insulin resistance, high blood pressure, and atherogenic dyslipidemia; all these factors are associated with endothelial dysfunction and subsequently appearance of cardiovascular events. But, on the other hand, by controlling inflammation, corticoids may reduce cardiovascular risk in RA patients. EULAR recommended the corticoid use at lowest dose possible (<7.5 mg Prednisone/day), for the shortest period of time [9].

Among disease-modifying drugs (DMARDs), methotrexate, sulfasalazine, and hydroxychloroquine are associated with the cardiovascular risk reduction. By controlling inflammation (decrease of pro-inflammatory cytokine level), methotrexate improves the endothelial function in RA patients. But this drug contributes to endothelial protection by means of induction of AMPK-regulated protective genes. Sulfasalazine interferes with platelet function. Hydroxychloroquine improves lipid profile and has antithrombotic effects, thus reducing the cardiovascular risk. Leflunomide and cyclosporine are associated with arterial hypertension.

By using biologics (anti-TNF-alpha, anti-CD28, anti-CD20, anti-IL 6, anti-IL1), cardiovascular risk was reduced comparatively with the RA patients without this therapy.

Anti-TNF-alpha therapy improves endothelial function by means of inflammation reduction. It is important to know that the reduction in cardiovascular risk was recorded only in patients responsive to anti-TNF-alpha treatment.

Anti-IL-6 therapy improves endothelial function (measured by means of flow-mediated vasodilation) very early during the treatment. This effect is determined by reducing inflammation, although total cholesterol, LDL-cholesterol, and triglyceride levels are increased.

Anti-CD20 therapy reduces RA activity and has favorable effects on lipid profile, reducing endothelial dysfunction.

The use of abatacept in RA treatment has generated conflicting data regarding vascular dysfunction. Tofacitinib increases total cholesterol levels but without change of atherogenic index. This new drug was associated with low rates of cardiovascular events in RA patients [1, 8].

### **3. Macro- and microvascular endothelial dysfunction**

All these factors contribute to disruption of vascular environment at the macroand microcirculation levels, occurring endothelial dysfunction [2, 7].


#### **Table 2.**

*Methods for morphologic and functional vascular assessment.*

Macrovascular and microvascular endothelial dysfunction is identified in RA patients, not associated with each other, increasing cardiovascular risk in these patients [30]. The studies revealed a weak correlation between microvascular and macrovascular endothelial dysfunction in RA patients. Microvascular endothelial dysfunction results from the interaction between inflammation, immune dysregulation, and traditional cardiovascular risk factors, representing a significant factor related to accelerated atherosclerosis and future cardiovascular events in RA patients [31].

Structural and functional assessment of vasculature in RA patients uses different methods (**Table 2**). It is known that the functional and morphological vascular changes may coexist, especially in the early atherosclerosis [27].

#### **4. Macrovascular involvement in RA**

Endothelial dysfunction is present in RA patients compared to healthy controls. Although not all studies have shown the connection between endothelial dysfunction and inflammation, the use of specific RA medication (especially anti-TNF-alpha) has improved endothelial function in RA patients [32].

Arterial stiffness is increased in RA patients compared with controls, but an association between arterial stiffness and disease activity was not highlighted [27, 32].

Most studies identified that the cIMT was increased in RA patients, even in cases with newly established diagnosis. cIMT increases with the disease duration but is well known that the increase of cIMT is associated with the age of patients. The most studies did not reveal a consistent link between inflammation and vascular parameters. Van Zanten et al. explained that the long-standing, not current inflammation has had vascular impact in RA patients [33]. Carotid plaque (**Figure 1**) is common findings among RA patients. Roman et al. reported that the carotid plaque was three times more prevalent in RA patients than in controls [34]. Dessein et al. identified that the 31% of RA patients had carotid plaque [35]. Another study, performed by Pope et al., reported a prevalence of carotid atherosclerotic plaque about 35% in RA patients [36]. Protogerou et al. highlighted the importance of carotid ultrasonography associated with the femoral one in RA cardiovascular risk assessment [37].

Plaque rupture leads to the occurrence of clinical events. The risk of plaque rupture is determined by its composition (calcification, lipid-rich necrotic core, neovascularization, inflammatory cell infiltration) and, on the other hand, by the

**73**

*Vascular Involvement in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91142*

presence of inflammation. Pro-inflammatory cytokines (IL-6, TNF-alpha) are related to plaque progression and the appearance of complications [32, 35]. Skeoch et al. demonstrated in their study the increased prevalence of atherosclerosis in RA, providing data to confirm that atheroma plaques are at high risk of complications [38]. Ruscitti et al. have shown increased incidence and prevalence of subclinical and clinical atherosclerosis in RA patients, but reaching and maintaining remission had

*Common carotid artery: Ultrasonography (increased cIMT and plaques in a long-standing RA evolution;* 

Further longitudinal studies are necessary in order to characterize the acceler-

Yki-Jarvinen et al. studied the microvascular endothelial function in RA patients, using intrabrachial artery infusions of acetylcholine (endothelium dependent vasodilation) and sodium nitroprusside (endothelium independent vasodilation). The authors concluded that the basal blood flow was increased, correlated with the degree of RA inflammatory activity and more inhibited by NG-monomethyl-L-arginine, suggesting that the responsiveness to nitric oxide was reduced [40]. In another study, Galarraga et al. identified that the systemic inflammation (evaluated by serum levels of C-reactive protein) was independently associated with microvascular dysfunction in RA patients [41]. Studying 65 RA patients and 40 healthy controls, Arosio et al. showed that the RA patients presented impaired microcirculatory reactivity, endothelial dysfunction, and increased arterial stiffness. The authors concluded that these vascular alterations would be the link between RA and cardiovascular morbidity and mortality [42]. Endothelial dysfunction in RA patients was associated with high

Microvascular morphological assessment may be performed by nailfold capillaroscopy, a noninvasive and repeatable method. By using this method, the following parameters are evaluated: tortuosity, loop size, density, angiogenesis, capillary loss, microbleeding, subpapillary venous plexus, and architectural structure [44].

values of C-reactive protein and inducible nitric oxide synthase [43].

positive effect on the atherogenesis development [39].

ated atherosclerosis in RA patients [32].

**Figure 1.**

*personal collection).*

**5. Microvascular involvement in RA**

*Vascular Involvement in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91142*

#### **Figure 1.**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

Capillaries Nailfold capillaroscopy

*Methods for morphologic and functional vascular assessment.*

Conduit artery Pulse wave velocity (PWV)

Conducting artery Carotid intima-media thickness (cIMT)

Arterioles Laser Doppler imaging with iontophoresis

**Morphological assessment**

**Functional assessment**

Macrovascular and microvascular endothelial dysfunction is identified in RA patients, not associated with each other, increasing cardiovascular risk in these patients [30]. The studies revealed a weak correlation between microvascular and macrovascular endothelial dysfunction in RA patients. Microvascular endothelial dysfunction results from the interaction between inflammation, immune dysregulation, and traditional cardiovascular risk factors, representing a significant factor related to accelerated atherosclerosis and future cardiovascular events in RA

Pulse wave analysis (PWA) Flow-mediated dilation (FMD) Nitroglycerin-mediated dilation (NMD)

Venous occlusion plethysmography

Structural and functional assessment of vasculature in RA patients uses different methods (**Table 2**). It is known that the functional and morphological vascular

Endothelial dysfunction is present in RA patients compared to healthy controls. Although not all studies have shown the connection between endothelial dysfunction and inflammation, the use of specific RA medication (especially anti-TNF-alpha) has improved endothelial function in RA patients [32].

Arterial stiffness is increased in RA patients compared with controls, but an association between arterial stiffness and disease activity was not highlighted

Most studies identified that the cIMT was increased in RA patients, even in cases with newly established diagnosis. cIMT increases with the disease duration but is well known that the increase of cIMT is associated with the age of patients. The most studies did not reveal a consistent link between inflammation and vascular parameters. Van Zanten et al. explained that the long-standing, not current inflammation has had vascular impact in RA patients [33]. Carotid plaque (**Figure 1**) is common findings among RA patients. Roman et al. reported that the carotid plaque was three times more prevalent in RA patients than in controls [34]. Dessein et al. identified that the 31% of RA patients had carotid plaque [35]. Another study, performed by Pope et al., reported a prevalence of carotid atherosclerotic plaque about 35% in RA patients [36]. Protogerou et al. highlighted the importance of carotid ultrasonography associated with the femoral one in RA cardiovascular risk

Plaque rupture leads to the occurrence of clinical events. The risk of plaque rupture is determined by its composition (calcification, lipid-rich necrotic core, neovascularization, inflammatory cell infiltration) and, on the other hand, by the

changes may coexist, especially in the early atherosclerosis [27].

**4. Macrovascular involvement in RA**

**72**

assessment [37].

patients [31].

**Table 2.**

[27, 32].

*Common carotid artery: Ultrasonography (increased cIMT and plaques in a long-standing RA evolution; personal collection).*

presence of inflammation. Pro-inflammatory cytokines (IL-6, TNF-alpha) are related to plaque progression and the appearance of complications [32, 35]. Skeoch et al. demonstrated in their study the increased prevalence of atherosclerosis in RA, providing data to confirm that atheroma plaques are at high risk of complications [38].

Ruscitti et al. have shown increased incidence and prevalence of subclinical and clinical atherosclerosis in RA patients, but reaching and maintaining remission had positive effect on the atherogenesis development [39].

Further longitudinal studies are necessary in order to characterize the accelerated atherosclerosis in RA patients [32].

#### **5. Microvascular involvement in RA**

Yki-Jarvinen et al. studied the microvascular endothelial function in RA patients, using intrabrachial artery infusions of acetylcholine (endothelium dependent vasodilation) and sodium nitroprusside (endothelium independent vasodilation). The authors concluded that the basal blood flow was increased, correlated with the degree of RA inflammatory activity and more inhibited by NG-monomethyl-L-arginine, suggesting that the responsiveness to nitric oxide was reduced [40]. In another study, Galarraga et al. identified that the systemic inflammation (evaluated by serum levels of C-reactive protein) was independently associated with microvascular dysfunction in RA patients [41]. Studying 65 RA patients and 40 healthy controls, Arosio et al. showed that the RA patients presented impaired microcirculatory reactivity, endothelial dysfunction, and increased arterial stiffness. The authors concluded that these vascular alterations would be the link between RA and cardiovascular morbidity and mortality [42]. Endothelial dysfunction in RA patients was associated with high values of C-reactive protein and inducible nitric oxide synthase [43].

Microvascular morphological assessment may be performed by nailfold capillaroscopy, a noninvasive and repeatable method. By using this method, the following parameters are evaluated: tortuosity, loop size, density, angiogenesis, capillary loss, microbleeding, subpapillary venous plexus, and architectural structure [44].

McGill and Gow studied by nailfold capillaroscopy the microvascular changes in patients with systemic sclerosis (10 pts.), systemic lupus erythematosus (9 pts.), and rheumatoid arthritis (11 pts.). They reported that the nailfold capillaroscopy had a specificity of 89% and a sensitivity of 80% in the differentiation of the capillaroscopic models of these three diseases [45]. In another study, performed by Altomonte et al., the authors identified that in RA patients the common capillaroscopic changes were represented by elongation and capillary tortuosity. Besides them, the visibility of the subpapillary venous plexus was correlated with the endothelial dysfunction [46]. In the study performed on 80 RA patients and 30 healthy controls, Kuryliszyn-Moskal identified a significant correlation between soluble CD4 levels and the capillaroscopy findings [47].

In present, it is considered that there is no specific capillaroscopic model for RA [48]. Elongated and tiny loops, microhemorrhages, capillary low density, and subpapillary venous plexus visibility are common among RA patients [5].

Microvascular involvement appears early in the RA evolution. In their study, Scardina and Messina revealed that in patients with early RA, labial mucosa capillaries presented alterations, as: elongation, decreased capillaries caliber compared to healthy subjects. The authors suggested that the microvascular alterations could be extremely important in the diagnosis of suspected RA patients [5].

In their article, Lin et al. presented that in RA, the most common findings were represented by elongated and tiny capillaries and capillary tortuosity. The subpapillary venous plexus was visualized in RA patients who had antinuclear antibodies [44]. Sag et al. analyzed nailfold findings in 201 RA patients and 50 healthy controls. The authors examined the relationship between nailfold capillaroscopic findings and disease activity, expressed as DAS28. In 45.77% of RA patients, the authors identified nonspecific capillaroscopy findings: tortuosity, dilated capillaries, and bushy capillaries. The association of Raynaud's phenomenon increased the incidence of nailfold capillaroscopy abnormalities. No relation was found between microvascular abnormalities and RA activity score [49] (**Figure 2**).

Bernardino et al. identified mainly a non-scleroderma capillaroscopic pattern in RA patients. The authors suggested that the microvascular abnormalities identified in RA patients represented the results of inflammation and endothelial dysfunction [50]. Cutolo et al. highlighted that in RA patients "scleroderma-like" capillaroscopic pattern may be found, especially in association with rheumatoid vasculitis [51].

#### **Figure 2.**

*Nailfold capillaroscopy (×200; subpapillary venous plexus visible, fragmentation of capillary blood circulation in patient with early RA; personal collection).*

**75**

*Vascular Involvement in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91142*

Rheumatoid vasculitis (RV) is the most serious extra-articular complication of RA with long-term evolution, generating high rates of morbidity and mortality (up

It can affect any organ or system, but the most frequent involved are the skin (nailfold lesions, palpable purpura, and leg ulcers) and peripheral nervous system (mononeuritis multiplex, distal symmetric sensory or sensorimotor neuropathy)

Due to earlier diagnosis and new therapeutic strategies for RA, the prevalence of RV had progressively reduced over time. RV appears in RA patients with severe immunological abnormalities, associating with other extra-articular manifestations [1]. RV is characterized by inflammation of small- and medium-sized arteries and capillaries. The risk factors associated with RV are represented by RA with prolonged evolution (> 10 years), rheumatoid nodules, males, smoking, seropositivity of rheumatoid factor, HLA-DRB1\*0401/\*0401, \*0401/\*0404, and \*0101/\*0401,

Clinical features of RV are cutaneous manifestations (digital infarcts, livedo reticularis, palpable purpura, ulcers, painful nodules, or even digital gangrene), peripheral nervous system manifestations (mononeuritis multiplex, distal symmetric sensory or sensorimotor neuropathy), and internal organ manifestations (due to coronary, cerebral, mesenteric, renal artery involvement, much less common, but with significant morbidity and mortality). The patients with Felty's syndrome

Laboratory features of RV are represented by high levels of sedimentation rate and C-reactive protein, thrombocytosis, anemia, high levels of anti-cyclic citrullinated peptide antibodies and rheumatoid factor, and decreased levels of complement in patients with RV than the patients without this complication [1, 56, 57]. The RV diagnosis is easily established in the presence of cutaneous or nervous manifestations. Internal organ manifestations represent a challenge in establishing the correct RV diagnosis. Diagnosis confirmation is established by histopathological examination of the involved skin, muscle, nerve, or another affected organ [56]. In present, there are no guidelines for the RV treatment. Corticosteroids and cyclophosphamide have been used in severe, life-threatening cases of RV. In milder forms of RV, corticosteroids and methotrexate or azathioprine have been used. Rituximab and corticosteroids are preferred, due to higher efficiency and lower

Vascular involvement in RA patients remains a chapter open to further research,

in order to develop preventive measures, early diagnosis, and efficient therapy.

RV can affect any organ or system of the body [1].

develop more frequent RV [1, 54, 56].

**6. Rheumatoid vasculitis**

to 40%, during 5 years) [52].

[53–55].

HLA-C3 [55, 56].

toxicity [55, 58, 59].

**Conflict of interest**

The authors declare no conflict of interest.

**7. Conclusion**

### **6. Rheumatoid vasculitis**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

soluble CD4 levels and the capillaroscopy findings [47].

McGill and Gow studied by nailfold capillaroscopy the microvascular changes in patients with systemic sclerosis (10 pts.), systemic lupus erythematosus (9 pts.), and rheumatoid arthritis (11 pts.). They reported that the nailfold capillaroscopy had a specificity of 89% and a sensitivity of 80% in the differentiation of the capillaroscopic models of these three diseases [45]. In another study, performed by Altomonte et al., the authors identified that in RA patients the common capillaroscopic changes were represented by elongation and capillary tortuosity. Besides them, the visibility of the subpapillary venous plexus was correlated with the endothelial dysfunction [46]. In the study performed on 80 RA patients and 30 healthy controls, Kuryliszyn-Moskal identified a significant correlation between

In present, it is considered that there is no specific capillaroscopic model for RA [48]. Elongated and tiny loops, microhemorrhages, capillary low density, and

Microvascular involvement appears early in the RA evolution. In their study, Scardina and Messina revealed that in patients with early RA, labial mucosa capillaries presented alterations, as: elongation, decreased capillaries caliber compared to healthy subjects. The authors suggested that the microvascular alterations could be extremely important in the diagnosis of suspected RA patients [5]. In their article, Lin et al. presented that in RA, the most common findings were represented by elongated and tiny capillaries and capillary tortuosity. The subpapillary venous plexus was visualized in RA patients who had antinuclear antibodies [44]. Sag et al. analyzed nailfold findings in 201 RA patients and 50 healthy controls. The authors examined the relationship between nailfold capillaroscopic findings and disease activity, expressed as DAS28. In 45.77% of RA patients, the authors identified nonspecific capillaroscopy findings: tortuosity, dilated capillaries, and bushy capillaries. The association of Raynaud's phenomenon increased the incidence of nailfold capillaroscopy abnormalities. No relation was found between

subpapillary venous plexus visibility are common among RA patients [5].

microvascular abnormalities and RA activity score [49] (**Figure 2**).

Bernardino et al. identified mainly a non-scleroderma capillaroscopic pattern in RA patients. The authors suggested that the microvascular abnormalities identified in RA patients represented the results of inflammation and endothelial dysfunction [50]. Cutolo et al. highlighted that in RA patients "scleroderma-like" capillaroscopic pattern may be found, especially in association with rheumatoid

*Nailfold capillaroscopy (×200; subpapillary venous plexus visible, fragmentation of capillary blood circulation* 

**74**

**Figure 2.**

*in patient with early RA; personal collection).*

vasculitis [51].

Rheumatoid vasculitis (RV) is the most serious extra-articular complication of RA with long-term evolution, generating high rates of morbidity and mortality (up to 40%, during 5 years) [52].

It can affect any organ or system, but the most frequent involved are the skin (nailfold lesions, palpable purpura, and leg ulcers) and peripheral nervous system (mononeuritis multiplex, distal symmetric sensory or sensorimotor neuropathy) [53–55].

Due to earlier diagnosis and new therapeutic strategies for RA, the prevalence of RV had progressively reduced over time. RV appears in RA patients with severe immunological abnormalities, associating with other extra-articular manifestations [1].

RV is characterized by inflammation of small- and medium-sized arteries and capillaries. The risk factors associated with RV are represented by RA with prolonged evolution (> 10 years), rheumatoid nodules, males, smoking, seropositivity of rheumatoid factor, HLA-DRB1\*0401/\*0401, \*0401/\*0404, and \*0101/\*0401, HLA-C3 [55, 56].

RV can affect any organ or system of the body [1].

Clinical features of RV are cutaneous manifestations (digital infarcts, livedo reticularis, palpable purpura, ulcers, painful nodules, or even digital gangrene), peripheral nervous system manifestations (mononeuritis multiplex, distal symmetric sensory or sensorimotor neuropathy), and internal organ manifestations (due to coronary, cerebral, mesenteric, renal artery involvement, much less common, but with significant morbidity and mortality). The patients with Felty's syndrome develop more frequent RV [1, 54, 56].

Laboratory features of RV are represented by high levels of sedimentation rate and C-reactive protein, thrombocytosis, anemia, high levels of anti-cyclic citrullinated peptide antibodies and rheumatoid factor, and decreased levels of complement in patients with RV than the patients without this complication [1, 56, 57].

The RV diagnosis is easily established in the presence of cutaneous or nervous manifestations. Internal organ manifestations represent a challenge in establishing the correct RV diagnosis. Diagnosis confirmation is established by histopathological examination of the involved skin, muscle, nerve, or another affected organ [56].

In present, there are no guidelines for the RV treatment. Corticosteroids and cyclophosphamide have been used in severe, life-threatening cases of RV. In milder forms of RV, corticosteroids and methotrexate or azathioprine have been used. Rituximab and corticosteroids are preferred, due to higher efficiency and lower toxicity [55, 58, 59].

### **7. Conclusion**

Vascular involvement in RA patients remains a chapter open to further research, in order to develop preventive measures, early diagnosis, and efficient therapy.

### **Conflict of interest**

The authors declare no conflict of interest.

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

### **Author details**

Alexandru Caraba1 \*, Stela Iurciuc2 and Mircea Iurciuc2

1 Division of Rheumatology, Department of Internal Medicine, University of Medicine and Pharmacy "Victor Babeș", Timișoara, Romania

2 Department of Cardiology, University of Medicine and Pharmacy "Victor Babeș", Timișoara, Romania

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

© 2020 The Author(s). Licensee IntechOpen. 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.

**77**

*Vascular Involvement in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91142*

> [9] Agca R, Heslinga SC, Rollefstad S, Heslinga M, McInnes IB, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Annals of the Rheumatic Diseases. 2017;**76**:17-28

[10] Hadi HAR, Carr CS, Suwaidi JA. Endothelial dysfunction: Cardiovascular risk factors, therapy, and outcome. Vascular Health and Risk Management.

[11] Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care.

[12] Hill CE, Phillips JK, Sandow SL. Heterogeneous control of blood flow amongst different vascular beds. Medicinal Research Reviews.

[13] Bocci EB, Delle Monache F,

views on the pathogenesis of cardiovascular damage associated

[14] Dougados M, Soubrier M, Antunez A, Balint P, Balsa A, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: Results of an international, crosssectional study (COMORA). Annals of the Rheumatic

with rheumatoid arthritis. Recenti Progressi in Medicina.

2005;**96**(2):65-120

Diseases. 2014;**73**:62-68

2015;**10**:e0117952

[15] Baghdadi L, Woodman R,

Shanahan E, Mangoni A. The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: A systematic review and meta-analysis. PLoS One.

Cesarotti M, Angrisani C, Gerli R. Recent

2009;**32**(Suppl 2):S314-S321

2005;**1**(3):183-198

2001;**21**(1):1-60

[1] Padjen I, Gabay C, Aletaha D. Pathogenesis and clinical aspects of rheumatoid arthritis. In: Bijlsma JWJ, Hachula E, editors. Textbook on Rheumatic Disease. 3rd ed. London: BMJ Publishing Group Ltd; 2018.

[2] Rajaei A, Dehghan P, Amiri A. Nail fold capillaroscopy in 430 patients with rheumatoid arthritis. Caspian Journal of Internal Medicine.

[3] Safiri S, Kolahi AA, Hoy D, Smith E, Bettampadi D, et al. Global, regional and national burden of rheumatoid arthritis 1990-2017: A systematic analysis of the global burden of disease study 2017. Annals of the Rheumatic

Diseases. 2019;**78**:1463-1471

abnormalities in patients with

[6] Das S, Padhan P. An overview of the extraarticular involvement in rheumatoid arthritis and its

[7] Rawla P. Cardiac and vascular complications in rheumatoid arthritis. Reumatologia. 2019;**57**(1):27-36. DOI:

[8] Zegkos T, Kitas G, Dimitroulas T. Cardiovascular risk in rheumatoid arthritis: Assessment, management and next steps. Therapeutic Advances in Musculoskeletal Disease.

10.5114/reum.2019.83236

2016;**8**(3):86-101

[4] Szekanecz Z, Koch AE. Vascular involvement in rheumatic diseases: 'vascular rheumatology'. Arthritis Research & Therapy. 2008;**10**:224. DOI:

[5] Scardina GA, Messina P. Microvascular

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*Vascular Involvement in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91142*

### **References**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

**76**

**Author details**

Alexandru Caraba1

Timișoara, Romania

\*, Stela Iurciuc2

Medicine and Pharmacy "Victor Babeș", Timișoara, Romania

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

provided the original work is properly cited.

and Mircea Iurciuc2

1 Division of Rheumatology, Department of Internal Medicine, University of

2 Department of Cardiology, University of Medicine and Pharmacy "Victor Babeș",

© 2020 The Author(s). Licensee IntechOpen. 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,

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A retrospective cohort study. ACR Open Rheumatology. 2019;**1**(3):173-181. DOI:

[24] Bergstrom U, Jacobsson L, Nilsson J, Berglund G, Turesson C. Pulmonary dysfunction, smoking, socioeconomic status and the risk of developing rheumatoid arthritis. Rheumatology.

[25] Rojas-Serrano J, Perez L, Garcia C, Moctezuma F, Álvarez-Hernández E, et al. Current smoking status is associated to a non-ACR 50 response in early rheumatoid arthritis. A cohort study. Clinical Rheumatology.

[26] Aziz M, Yadav KS. Atherosclerosis: An extraarticular manifestation of rheumatoid arthritis. Annals of Clinical and Laboratory Research. 2016;**4**:4

Metsios GS, Carroll D, Kitas GD. Vascular

2125-2139. DOI: 10.1093/rheumatology/

[27] Sandoo A, van Zanten JJCSV,

function and morphology in rheumatoid arthritis: A systematic review. Rheumatology. 2011;**50**:

[28] Yang XZ, Chang Y, Wei W. Endothelial dysfunction and inflammation: Immunity in rheumatoid arthritis. Mediators of Inflammation. 2016;**2016**:6813016. DOI:

[29] Lindhardsen J, Gislason G,

Jacobsen S, Ahlehoff O, Olsen A, et al. Non-steroidal antiinflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: A nationwide cohort study. Annals of the Rheumatic Diseases. 2013;**73**:1515-1521

10.1155/2016/6813016

[23] Toms T, Symmons D, Kitas G. Dyslipidaemia in rheumatoid arthritis: The role of inflammation, drugs, lifestyle and genetic factors. Current Vascular Pharmacology. 2010;

10.1002/acr2.1029

2011;**50**:2005-2013

2011;**30**:1589-1593

ker275

**8**:301-326

[16] Panoulas VF, Toms TE, Metsios GS,

Kosovitsas A, et al. Target organ damage in patients with rheumatoid arthritis: The role of blood pressure and heart rate. Atherosclerosis. 2010;**209**:255-260

[17] Rihacek I, Nemec P, Rihacek M, Kianicka B, Berukstis A, et al.

risk in patients with rheumatoid arthritis. International Journal of Clinical Rheumatology.

[18] Panoulas VF, Douglas KM,

Nightingale P, et al. Prevalence and associations of hypertension and its control in patients with rheumatoid arthritis. Rheumatology.

[19] Desai SS, Myles JD, Kaplan MJ. Suboptimal cardiovascular risk factor identification and management in patients with rheumatoid arthritis: A cohort analysis. Arthritis Research &

[20] Alemao E, Cawston H, Bourhis F, Al M, Rutten-van Mölken MP, et al. Cardiovascular risk factor management

[21] An J, Cheetham TC, Reynolds K, Alemao E, Kawabata H, et al.

Traditional cardiovascular disease risk factor management in rheumatoid arthritis compared to matched nonrheumatoid arthritis in a US managed care setting. Arthritis Care and Research. 2016;**68**:629-637

in patients with RA compared to matched non-RA patients. Rheumatology. 2016;**55**:809-816

[22] Boersma P, McElwee MK, Hashmi H, Schreiner P, Demmer RT, Shmagel A. Blood pressure trends in patients with seropositive rheumatoid arthritis compared with controls without rheumatoid arthritis:

2017;**12**(6):142-150

2007;**46**:1477-1482

Therapy. 2012;**14**:R270

Ambulatory blood pressure monitoring and hypertension related cardiovascular

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[31] Erre GL, Piga M, Fedele AL, Mura S, Piras A, et al. Prevalence and determinants of peripheral microvascular endothelial dysfunction in rheumatoid arthritis patients: A multicenter cross-sectional study. Mediators of Inflammation. 2018;**2018**:6548715. DOI: 10.1155/ 2018/6548715

[32] Dimitroulas T, Sandoo A, Skeoch S, O'Sullivan M, Yessirkepov M, et al. Rheumatoid arthritis. In: Nussinovitch U, editor. The Heart in Rheumatic, Autoimmune and Inflammatory Diseases. Elsevier; 2017. pp. 129-165

[33] van Zanten VJJ, Kitas GD. Inflammation, carotid intima-media thickness and atherosclerosis in rheumatoid arthritis. Arthritis Research & Therapy. 2008;**10**:102

[34] Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, et al. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Annals of Internal Medicine. 2006;**144**(4):249-256. DOI: 10.7326/0003-4819-144-4-200602210- 00006

[35] Dessein PH, Joffe BI, Veller MG, Stevens BA, Tobias M, et al. Traditional and nontraditional cardiovascular risk factors are associated with atherosclerosis in rheumatoid arthritis. The Journal of Rheumatology. 2005; **32**(3):435-442

[36] Pope JE, Nevskaya T, Barra L, Parraga G. Carotid artery atherosclerosis in patients with active rheumatoid arthritis: Predictors of plaque occurrence and progression over 24 weeks. The Open Rheumatology

Journal. 2016;**10**:49-59. DOI: 10.2174/1874312901610010049

[37] Protogerou AD, Fransen J, Zampeli E, Argyris AA, Aissopou E, et al. The additive value of femoral ultrasound for subclinical atherosclerosis assessment in a single center cohort of 962 adults, including high risk patients with rheumatoid arthritis, human immunodeficiency virus infection and type 2 diabetes mellitus. PLoS One. 2015;**10**(7):e0132307. DOI: 10.1371/ journal.pone.0132307

[38] Skeoch S, Cristinacce PLH, Williams H, Pemberton P, Xu D, et al. Imaging atherosclerosis in rheumatoid arthritis: Evidence for increased prevalence, altered phenotype and a link between systemic and localised plaque inflammation. Scientific Reports. 2017;**7**(1):827. DOI: 10.1038/ s41598-017-00989-w

[39] Ruscitti P, Cipriani P, Liakouli V, Iacono D, Pantano I, et al. Subclinical and clinical atherosclerosis in rheumatoid arthritis: Results from the 3-year, multicentre, prospective, observational GIRRCS (*Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale*) study. Arthritis Research & Therapy. 2019;**21**:204. DOI: 10.1186/ s13075-019-1975-y

[40] Yki-Jarvinen H, Bergholm R, Leirisalo-Repo M. Increased inflammatory activity parallels increased basal nitric oxide production and blunted response to nitric oxide in vivo in rheumatoid arthritis. Annals of the Rheumatic Diseases. 2003;**62**:630-634

[41] Galarraga B, Khan F, Kumar P, Pullar T, Belch JJ. C-reactive protein: The underlying cause of microvascular dysfunction in rheumatoid arthritis. Rheumatology. 2008;**47**:1780-1784

[42] Arosio E, De Marchi S, Rigoni A, Prior M, Delva P, Lechi A. Forearm

haemodynamics, arterial stiffness and microcirculatory reactivity in rheumatoid arthritis. Journal of Hypertension. 2007;**25**:1273-1278

[43] Maki-Petaja KM, Cheriyan J, Booth AD, Hall FC, Brown J, et al. Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction. International Journal of Cardiology. 2008;**129**:399-405

[44] Lin KM, Cheng TT, Chen CJ. Clinical applications of nailfold capillaroscopy in different rheumatic diseases. Journal of Internal Medicine of Taiwan. 2009;**20**:238-247

[45] McGill NW, Gow PJ. Nailfold capillaroscopy: A blinded study of its discriminatory value in scleroderma, systemic lupus erythematosus, and rheumatoid arthritis. Australian and New Zealand Journal of Medicine. 1986;**16**(4):457-460. DOI: 10.1111/ j.1445-5994.1986.tb02010.x

[46] Altomonte L, Zoli A, Galossi A, Mirone L, Tulli A, et al. Microvascular capillaroscopic abnormalities in rheumatoid arthritis patients. Clinical and Experimental Rheumatology. 1995;**13**:83-86

[47] Kuryliszyn-Moskal A. Cytokines and soluble CD4 and CD8 molecules in rheumatoid arthritis: Relationship to systematic vasculitis and microvascular capillaroscopic abnormalities. Clinical Rheumatology. 1998;**17**(6):489

[48] Ali AM, Hamza SM, Aboud FM, El-Shahat NM. Nailfold capillaroscopic changes in Egyptian patients with psoriatic arthritis in comparison to rheumatoid arthritis. The Egyptian Rheumatologist. 2019;**41**:303-307

[49] Sag S, Sag MS, Tekeoglu I, Kamanli A, Nas K, Aydın Y. Nailfold videocapillaroscopy results in patients with rheumatoid arthritis. Clinical

Rheumatology. 2017;**36**(9):1969-1974. DOI: 10.1007/s10067-017-3696-4

[50] Bernardino V, Rodrigues A, Lladó A, Panarra A. Nailfold capillaroscopy and autoimmune connective tissue diseases in patients from a Portuguese nailfold capillaroscopy clinic. Rheumatology International. 2019;**40**(2):295-301. DOI: 10.1007/s00296-019-04427-0

[51] Cutolo M, Paolino S, Smith V. Nailfold capillaroscopy in rheumatology: Ready for the daily use but with care in terminology. Clinical Rheumatology. 2019;**38**(9):2293-2297. DOI: 10.1007/s10067-019-04716-w

[52] Puechal X, Said G, Hilliquin P, Coste J, Job-Deslandre C, et al. Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis. A clinicopathologic and prognostic study of thirty-two patients. Arthritis & Rheumatism. 1995;**38**(11):1618-1629

[53] Makol A, Crowson CS, Wetter DA, Sokumbi O, Matteson EL, Warrington KJ. Vasculitis associated with rheumatoid arthritis: A casecontrol study. Rheumatology. 2014;**53**:890-899. DOI: 10.1093/ rheumatology/ket475

[54] Anwar MM, Tariq E, Khan U, Zaheer M, Ijaz SH. Rheumatoid vasculitis: Is it always a late manifestation of rheumatoid arthritis? Cureus. 2019;**11**(9):e5790. DOI: 10.7759/ cureus.5790

[55] Upreti S, Oudah M, Hauptman H, Minn H. Vasculitic neuropathy associated with rheumatoid arthritis, a case report. Journal of Community Hospital Internal Medicine Perspectives. 2019;**9**(5):430-432. DOI: 10.1080/20009666.2019.1676507

[56] Bartels CM, Bridges AJ. Rheumatoid vasculitis: Vanishing menace or target for new treatments? Current Rheumatology Reports.

**81**

*Vascular Involvement in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91142*

2010;**12**(6):414-419. DOI: 10.1007/

[57] Laskaria K, Ahmadi-Simab K, Lamken M, Csernok E, Gross WL, Hellmich B. Are anti-cyclic citrullinated peptide autoantibodies seromarkers for rheumatoid vasculitis in a cohort of patients with systemic vasculitis? Annals of the Rheumatic Diseases.

[58] Puéchal X, Gottenberg JE,

Berthelot JM, Gossec L, Meyer O, et al. Investigators of the autoimmunity rituximab registry. Rituximab therapy for systemic vasculitis associated with rheumatoid arthritis: Results from the auto immunity and rituximab registry. Arthritis Care and Research.

[59] Maher LV, Wilson JG. Successful treatment of rheumatoid vasculitisassociated foot drop with rituximab. Rheumatology. 2006;**45**:1450-1451

s11926-010-0130-1

2010;**69**:469-471

2012;**64**:331-339

*Vascular Involvement in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91142*

2010;**12**(6):414-419. DOI: 10.1007/ s11926-010-0130-1

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

Rheumatology. 2017;**36**(9):1969-1974. DOI: 10.1007/s10067-017-3696-4

[50] Bernardino V, Rodrigues A, Lladó A, Panarra A. Nailfold capillaroscopy and autoimmune connective tissue diseases in patients from a Portuguese nailfold capillaroscopy clinic. Rheumatology International. 2019;**40**(2):295-301. DOI:

10.1007/s00296-019-04427-0

Nailfold capillaroscopy in

[51] Cutolo M, Paolino S, Smith V.

[52] Puechal X, Said G, Hilliquin P, Coste J, Job-Deslandre C, et al.

[53] Makol A, Crowson CS,

rheumatology/ket475

cureus.5790

Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis. A clinicopathologic and prognostic study of thirty-two patients. Arthritis & Rheumatism. 1995;**38**(11):1618-1629

Wetter DA, Sokumbi O, Matteson EL, Warrington KJ. Vasculitis associated with rheumatoid arthritis: A casecontrol study. Rheumatology. 2014;**53**:890-899. DOI: 10.1093/

[54] Anwar MM, Tariq E, Khan U, Zaheer M, Ijaz SH. Rheumatoid vasculitis: Is it always a late

manifestation of rheumatoid arthritis? Cureus. 2019;**11**(9):e5790. DOI: 10.7759/

[55] Upreti S, Oudah M, Hauptman H, Minn H. Vasculitic neuropathy associated

Perspectives. 2019;**9**(5):430-432. DOI: 10.1080/20009666.2019.1676507

[56] Bartels CM, Bridges AJ. Rheumatoid

with rheumatoid arthritis, a case report. Journal of Community Hospital Internal Medicine

vasculitis: Vanishing menace or target for new treatments? Current Rheumatology Reports.

rheumatology: Ready for the daily use but with care in terminology. Clinical Rheumatology. 2019;**38**(9):2293-2297. DOI: 10.1007/s10067-019-04716-w

haemodynamics, arterial stiffness and microcirculatory reactivity in rheumatoid arthritis. Journal of Hypertension. 2007;**25**:1273-1278

[43] Maki-Petaja KM, Cheriyan J, Booth AD, Hall FC, Brown J, et al. Inducible nitric oxide synthase activity is increased in patients with rheumatoid arthritis and contributes to endothelial dysfunction. International Journal of Cardiology. 2008;**129**:399-405

[44] Lin KM, Cheng TT, Chen CJ. Clinical applications of nailfold capillaroscopy in different rheumatic diseases. Journal of Internal Medicine of

[45] McGill NW, Gow PJ. Nailfold capillaroscopy: A blinded study of its discriminatory value in scleroderma, systemic lupus erythematosus, and rheumatoid arthritis. Australian and New Zealand Journal of Medicine. 1986;**16**(4):457-460. DOI: 10.1111/ j.1445-5994.1986.tb02010.x

[46] Altomonte L, Zoli A, Galossi A, Mirone L, Tulli A, et al. Microvascular capillaroscopic abnormalities in rheumatoid arthritis patients. Clinical and Experimental Rheumatology.

[47] Kuryliszyn-Moskal A. Cytokines and soluble CD4 and CD8 molecules in rheumatoid arthritis: Relationship to systematic vasculitis and microvascular capillaroscopic abnormalities. Clinical

[48] Ali AM, Hamza SM, Aboud FM, El-Shahat NM. Nailfold capillaroscopic changes in Egyptian patients with psoriatic arthritis in comparison to rheumatoid arthritis. The Egyptian Rheumatologist. 2019;**41**:303-307

Rheumatology. 1998;**17**(6):489

[49] Sag S, Sag MS, Tekeoglu I, Kamanli A, Nas K, Aydın Y. Nailfold videocapillaroscopy results in patients with rheumatoid arthritis. Clinical

1995;**13**:83-86

Taiwan. 2009;**20**:238-247

**80**

[57] Laskaria K, Ahmadi-Simab K, Lamken M, Csernok E, Gross WL, Hellmich B. Are anti-cyclic citrullinated peptide autoantibodies seromarkers for rheumatoid vasculitis in a cohort of patients with systemic vasculitis? Annals of the Rheumatic Diseases. 2010;**69**:469-471

[58] Puéchal X, Gottenberg JE, Berthelot JM, Gossec L, Meyer O, et al. Investigators of the autoimmunity rituximab registry. Rituximab therapy for systemic vasculitis associated with rheumatoid arthritis: Results from the auto immunity and rituximab registry. Arthritis Care and Research. 2012;**64**:331-339

[59] Maher LV, Wilson JG. Successful treatment of rheumatoid vasculitisassociated foot drop with rituximab. Rheumatology. 2006;**45**:1450-1451

**83**

**Chapter 5**

**Abstract**

Myopenia and Musculoskeletal

Aging in Rheumatoid Arthritis

Rheumatoid arthritis (RA), the commonest inflammatory arthritis, is a debilitating disease leading to decreased functional capacity, social disability and reduced quality of life. RA affects multisystems with chronic inflammatory disease characterized by destructive synovitis and muscular dysfunction leading to premature musculoskeletal aging, which has been coined with many terms including myopenia, sarcopenia, cachexia, muscle failure and muscle wasting. Myopenia is described as the presence of clinically relevant muscle wasting due to any illness at any age, associated with impaired muscle function, increased morbidity and mortality. RA myopenia has significantly less muscle mass compared to the general population muscle loss showing preservation or slight increase in fat mass. RA myopenia is unique compared to chronic disease-related myopenia in cancer, chronic heart failure, kidney disease and chronic infection as it is rarely accompanied by a net weight loss. RA myopenia has younger-age onset compared to elderly primary sarcopenia, while higher-grade inflammation has been considered as the pathophysiology of muscle wasting. Research, however, indicates that inflammation itself cannot fully explain the high prevalence of muscle wasting in RA. This chapter aims to review the literature on the casual relationships among RA myopenia, premature musculoskeletal aging and management strategies to

**Keywords:** myopenia, rheumatoid arthritis, musculoskeletal aging, chronic

Muscle mass decreases on advancing age with men losing more absolute and relative muscle mass, especially most prevalent in the seventh decade and beyond [1]. After the age of 50, approximately 1–2% per year of muscle mass is lost, and this age-related reduction in muscle mass and strength is accompanied by intramuscular fat accumulation, muscle atrophy (especially the type IIa fibers), decreased satellite cell proliferation and differentiation capacity, and reduction in motor unit quantity. This muscle remodeling results in changes in muscle architecture that is believed to play a key role in the loss of muscle force and power characteristic of advanced age [2, 3]. Mitchell's group [1] reported only 0.5–1.0% loss of muscle mass per year after 70 and a 4.7% loss compared with peak muscle mass in men and 3.7% decrease for women per decade. Muscle strength simultaneously declines by 10–15% per decade up to 70 years of age, while the muscle strength loss accelerates to between 25 and 40% per decade [4, 5]. Frailty may be regarded as a condition

**1. Musculoskeletal aging in the healthy elderly**

*Dan Xu, Jiake Xu and Lei Dai*

delay musculoskeletal aging.

inflammation

### **Chapter 5**

## Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis

*Dan Xu, Jiake Xu and Lei Dai*

### **Abstract**

Rheumatoid arthritis (RA), the commonest inflammatory arthritis, is a debilitating disease leading to decreased functional capacity, social disability and reduced quality of life. RA affects multisystems with chronic inflammatory disease characterized by destructive synovitis and muscular dysfunction leading to premature musculoskeletal aging, which has been coined with many terms including myopenia, sarcopenia, cachexia, muscle failure and muscle wasting. Myopenia is described as the presence of clinically relevant muscle wasting due to any illness at any age, associated with impaired muscle function, increased morbidity and mortality. RA myopenia has significantly less muscle mass compared to the general population muscle loss showing preservation or slight increase in fat mass. RA myopenia is unique compared to chronic disease-related myopenia in cancer, chronic heart failure, kidney disease and chronic infection as it is rarely accompanied by a net weight loss. RA myopenia has younger-age onset compared to elderly primary sarcopenia, while higher-grade inflammation has been considered as the pathophysiology of muscle wasting. Research, however, indicates that inflammation itself cannot fully explain the high prevalence of muscle wasting in RA. This chapter aims to review the literature on the casual relationships among RA myopenia, premature musculoskeletal aging and management strategies to delay musculoskeletal aging.

**Keywords:** myopenia, rheumatoid arthritis, musculoskeletal aging, chronic inflammation

### **1. Musculoskeletal aging in the healthy elderly**

Muscle mass decreases on advancing age with men losing more absolute and relative muscle mass, especially most prevalent in the seventh decade and beyond [1]. After the age of 50, approximately 1–2% per year of muscle mass is lost, and this age-related reduction in muscle mass and strength is accompanied by intramuscular fat accumulation, muscle atrophy (especially the type IIa fibers), decreased satellite cell proliferation and differentiation capacity, and reduction in motor unit quantity. This muscle remodeling results in changes in muscle architecture that is believed to play a key role in the loss of muscle force and power characteristic of advanced age [2, 3]. Mitchell's group [1] reported only 0.5–1.0% loss of muscle mass per year after 70 and a 4.7% loss compared with peak muscle mass in men and 3.7% decrease for women per decade. Muscle strength simultaneously declines by 10–15% per decade up to 70 years of age, while the muscle strength loss accelerates to between 25 and 40% per decade [4, 5]. Frailty may be regarded as a condition

of transition from health to disability during aging. The concept of frailty is often defined as the presence of fatigue, slowness, weakness, low physical activity and exhaustion, which are all mainly related to muscle loss [6].

### **2. Prevalence of musculoskeletal aging in rheumatoid arthritis**

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by erosive arthritis and systemic organ involvement with the worldwide prevalence of roughly 5 per 1000 adults. The disease may affect all ages and both sexes; usually, it is seen in young women aged 25–45. The peak incidence is in the sixth decade with recent studies showing that RA is among the most common inflammatory disease in the elderly, accounting for 2% of the geriatric population [7]. The general consensus in the literature is defining rheumatoid arthritis onset after 65 years of age being known as elderly onset RA (EORA). EORA incidence and prevalence in different population-based studies in the world may vary widely, depending on sex and ethnicity [8]. One study showed the incidence rate of RA per 100,000 population over the age of 60 being 9.1 in men and 14.5 in women [9]. A USA study showed the prevalence of RA being 0.5–1%, with 2% in the population over 60 years [10]. The UK-based database Norwalk Arthritis Research (NOAR) showed the incidence of RA increasing with age [11]. The Chinese pooled prevalence showed the estimated population prevalence of RA being 0.37% with 10% elderly onset RA [12]. This fact will likely increase the number of patients with EORA in the coming years to encourage research into the impact of ethnic and geographic differences on the management of RA.

### **3. Myopenia, sarcopenia, cachexia, muscle failure and muscle wasting disease as one concept in muscle aging of rheumatoid arthritis**

#### **3.1 Myopenia and sarcopenia**

Myopenia is a relatively new term [13] describing the presence of clinically relevant muscle wasting due to any illness and at any age, associated with clinically relevant degree of muscle wasting, impaired muscle function and increased risks of morbidity or mortality. This term would translate more sufficiently and specifically in clinical settings than sarcopenia, which was introduced in 1988 with the original definition being a "muscle loss" of the appendicular muscle mass in the older people as measured by dual-energy X-ray absorptiometry [14]. In 2010, the European Working Group on Sarcopenia for Older Persons recommended a new operational definition of sarcopenia of aging (primary sarcopenia) including the presence of low muscle mass, low muscle strength and low muscle function and performance [15]. In 2018, two pieces of consensus evidences on sarcopenia of aging were published to combine the update by the European Working Group on Sarcopenia [16] with management of sarcopenia of aging by the International Clinical Practice Guidelines for Sarcopenia [17]. The consensus statement confirms the requirements of low muscle strength (low muscle quality), low muscle mass (low muscle quantity) and muscle functional impairment (low muscle performance) for the clinical diagnosis. Secondary sarcopenia, a similar term to myopenia, is associated with the international consensus definitions specific to malignant sarcopenia in the recent sarcopenia positional review [18]. There are several points of relevance regarding age-related (primary sarcopenia) and disease-related (secondary sarcopenia) loss

**85**

**Figure 1.**

*Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis*

of muscle mass. Loss of appendicular skeletal muscle mass with aging (primary sarcopenia) occurs continuously in the order of ~5% in men and somewhat lower in women after reaching peak muscle mass in young adulthood at about 30 years of age by a variety of longitudinal observational studies [19, 20]. Another interesting terminology related to secondary sarcopenia is sarcopenic obesity, and the copresence of sarcopenia and obesity has been considered a more deleterious body composition phenotype [21]. In addition to a myriad of cardio-metabolic outcomes related to the effects of fat tissue, higher proportions of fat mass might further affect muscle quality and increase the risk of disability and mortality [22]. A recent Brazil study [23] concluded sarcopenic obesity, but obesity alone was not associated with obstructive sleep apnea (OSA). Both obesity and sarcopenic obesity but not sarcopenia were associated with nocturnal hypoxemia, suggesting a complex pathophysiologic relationship between adverse body composition states and OSA. There are cultural difference in sarcopenic obesity with recent published data of Chinese RA patients, which indicated the lower prevalence of obesity (Chinese 4.2% vs. Westerners 21.4–34.7%) and higher prevalence of underweight (Chinese 17.7% vs. Westerners 1.1–2.2%). Taking together, secondary sarcopenia or myopenia has a non-linear muscle loss curve with a considerably greater magnitude than the linear curve seen in primary sarcopenia. RA patients have significantly less muscle mass compared to the general population, leading to the statement (**Figure 1**) that myopenia is a form of premature disease-related muscular aging in association with connective tissue diseases like rheumatoid arthritis and other chronic diseases

*Myopenia in association with connective tissue diseases like rheumatoid arthritis and other chronic diseases.*

*DOI: http://dx.doi.org/10.5772/intechopen.91270*

shown in **Figure 1**.

#### *Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91270*

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

exhaustion, which are all mainly related to muscle loss [6].

of transition from health to disability during aging. The concept of frailty is often defined as the presence of fatigue, slowness, weakness, low physical activity and

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by erosive arthritis and systemic organ involvement with the worldwide prevalence of roughly 5 per 1000 adults. The disease may affect all ages and both sexes; usually, it is seen in young women aged 25–45. The peak incidence is in the sixth decade with recent studies showing that RA is among the most common inflammatory disease in the elderly, accounting for 2% of the geriatric population [7]. The general consensus in the literature is defining rheumatoid arthritis onset after 65 years of age being known as elderly onset RA (EORA). EORA incidence and prevalence in different population-based studies in the world may vary widely, depending on sex and ethnicity [8]. One study showed the incidence rate of RA per 100,000 population over the age of 60 being 9.1 in men and 14.5 in women [9]. A USA study showed the prevalence of RA being 0.5–1%, with 2% in the population over 60 years [10]. The UK-based database Norwalk Arthritis Research (NOAR) showed the incidence of RA increasing with age [11]. The Chinese pooled prevalence showed the estimated population prevalence of RA being 0.37% with 10% elderly onset RA [12]. This fact will likely increase the number of patients with EORA in the coming years to encourage research into the impact of ethnic and geographic differences on the

**3. Myopenia, sarcopenia, cachexia, muscle failure and muscle wasting disease as one concept in muscle aging of rheumatoid arthritis**

Myopenia is a relatively new term [13] describing the presence of clinically relevant muscle wasting due to any illness and at any age, associated with clinically relevant degree of muscle wasting, impaired muscle function and increased risks of morbidity or mortality. This term would translate more sufficiently and specifically in clinical settings than sarcopenia, which was introduced in 1988 with the original definition being a "muscle loss" of the appendicular muscle mass in the older people as measured by dual-energy X-ray absorptiometry [14]. In 2010, the European Working Group on Sarcopenia for Older Persons recommended a new operational definition of sarcopenia of aging (primary sarcopenia) including the presence of low muscle mass, low muscle strength and low muscle function and performance [15]. In 2018, two pieces of consensus evidences on sarcopenia of aging were published to combine the update by the European Working Group on Sarcopenia [16] with management of sarcopenia of aging by the International Clinical Practice Guidelines for Sarcopenia [17]. The consensus statement confirms the requirements of low muscle strength (low muscle quality), low muscle mass (low muscle quantity) and muscle functional impairment (low muscle performance) for the clinical diagnosis. Secondary sarcopenia, a similar term to myopenia, is associated with the international consensus definitions specific to malignant sarcopenia in the recent sarcopenia positional review [18]. There are several points of relevance regarding age-related (primary sarcopenia) and disease-related (secondary sarcopenia) loss

**2. Prevalence of musculoskeletal aging in rheumatoid arthritis**

**84**

management of RA.

**3.1 Myopenia and sarcopenia**

of muscle mass. Loss of appendicular skeletal muscle mass with aging (primary sarcopenia) occurs continuously in the order of ~5% in men and somewhat lower in women after reaching peak muscle mass in young adulthood at about 30 years of age by a variety of longitudinal observational studies [19, 20]. Another interesting terminology related to secondary sarcopenia is sarcopenic obesity, and the copresence of sarcopenia and obesity has been considered a more deleterious body composition phenotype [21]. In addition to a myriad of cardio-metabolic outcomes related to the effects of fat tissue, higher proportions of fat mass might further affect muscle quality and increase the risk of disability and mortality [22]. A recent Brazil study [23] concluded sarcopenic obesity, but obesity alone was not associated with obstructive sleep apnea (OSA). Both obesity and sarcopenic obesity but not sarcopenia were associated with nocturnal hypoxemia, suggesting a complex pathophysiologic relationship between adverse body composition states and OSA. There are cultural difference in sarcopenic obesity with recent published data of Chinese RA patients, which indicated the lower prevalence of obesity (Chinese 4.2% vs. Westerners 21.4–34.7%) and higher prevalence of underweight (Chinese 17.7% vs. Westerners 1.1–2.2%). Taking together, secondary sarcopenia or myopenia has a non-linear muscle loss curve with a considerably greater magnitude than the linear curve seen in primary sarcopenia. RA patients have significantly less muscle mass compared to the general population, leading to the statement (**Figure 1**) that myopenia is a form of premature disease-related muscular aging in association with connective tissue diseases like rheumatoid arthritis and other chronic diseases shown in **Figure 1**.

#### **Figure 1.**

*Myopenia in association with connective tissue diseases like rheumatoid arthritis and other chronic diseases.*

#### **3.2 Cachexia, muscle failure and muscle wasting disease**

Rheumatoid arthritis cachexia (RAC) is characterized by high degrees of muscle mass loss and muscle strength loss, associated with preservation or slight increase in fat mass [24]. RAC is unique in comparison to other forms of cachexia observed in cancer, chronic heart failure, kidney disease and chronic infection as it is rarely accompanied by a net weight loss [25]. RAC also differs from primary sarcopenia in the elderly as it occurs at much younger age associated with significantly higher muscle mass loss [26]. Higher-grade inflammation has been considered as the central component of the pathophysiology and the key driver of muscle wasting. More recent findings, however, indicate that inflammation on its own cannot fully explain the high prevalence of muscle wasting in RA. Thus, two lifestyle factors including nutrition and physical activity have also been studied to indicate that they play a significant role in muscle wasting in RA, but again neither of these factors seems to be able to fully explain the condition. Oxidative stress is one of the major mechanisms thought to contribute to the development and progression of RA, but its potential contribution to muscle wasting in these patients has received limited attention. Oxidative stress has been shown to promote muscle wasting in healthy populations and people with several chronic conditions. Moreover, all of the aforementioned potential contributors to muscle wasting in RA (i.e., inflammation, nutrition and physical activity) may promote pro- or anti-oxidative mechanisms. Muscle failure is another new term describing the combination of primary and secondary sarcopenia, leading to a more relevant functional definition of premature muscle aging related to rheumatoid arthritis, RA-related muscle failure instead of myopenia. This review will put more emphasis to highlight the important clinical implication of myopenia and premature muscular aging and discuss the various management strategies of delaying musculoskeletal aging in RA, including muscle regeneration *via* reduction in oxidative stress and early control of inflammation via lifestyle and pharmacological interventions.

#### **4. Genetics of RA and muscle aging**

RA develops in individuals with a genetic association in RA, which is the presence of DRB1 locus in the HLA class 2 gene. The RA-associated DRB1 alleles share a linear sequence of amino acids between positions 70 and 74 in the HLA-DRB1 chain of the HLA-DRa/b heterodimer, which has led to the 'shared epitope' (SE) hypothesis [27], posing a risk factor for RA development. Jnhi DRB1 allele was associated with early onset of disease, radiological erosion and extra-articular findings [28]. The results of studies investigating genetic predisposition in EORA are inadequate and contradictory [29]. RA-associated DRB1 alleles show differences in early and late onset RA as well as ethnic variants. A Spanish study found that YORA was related to DRB1/04, while EORA was associated with DRB1/01 [30]. This study also found that increased DRB1–13/14 frequency was detected in patients with seronegative EORA and polymyalgia rheumatica (PMR). Another prospective study established the facts that a relationship was found between PMR and DRB1\*0101/0102/0401, while seronegative EORA was associated with DRB1- 0401. Kim and colleagues investigated the impact of HLA-DRB1 and HLA-DQB1 genes on susceptibility to disease and disease severity in EORA and YORA patients [31]. Alleles encoding the common epitope were detected less frequently in EORA compared with YORA with the effect of the common epitope and HLA-DQ\*04 alleles being shown to be less significant. In comparison with YORA, EORA has also been found to have less common epitope presence and less radiological progression.

**87**

*Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis*

Hellier and colleagues investigated the effect of the HLA-DRB1 gene on disease susceptibility and disease severity in EORA and YORA [32] and demonstrated HLA-DRB1/04-related alleles were not closely associated in EORA. Thus, it is suggested that the impact of these genes on the susceptibility to disease in EORA is not very important. Wu and colleagues showed that the DRB1/04 allele was detected in half of the EORA population, while the DRB1/04 frequency was 92% in patients with

In terms of genetic contribution and impact on the individual variability in muscle aging phenotypes literature on specific gene variants, it remained controversial and no solid evidence exists supporting the existence of an 'unfavorable' genotype associated with accelerated age-related sarcopenia or loss of independent function [34]. Although the ACTN3 R577X polymorphism is the only structural gene for which a clear genotype effect has been shown in human muscle phenotypes, especially for athletic women, there is controversy with regard to which allele (R or X) plays a potential 'favorable' role in aging. The MSTN K153R variation is possibly the strongest candidate to explain variance among muscle phenotypes in the elderly, yet more research is still needed with large cohorts owing to the very low population frequency of the 'unfavorable' 153R allele. Recent evidence [34] indicates that age-related declines in muscle phenotypes are likely polygenic traits and thus not reducible to specific polymorphisms, suggesting that future studies should consider the association between muscle phenotypes in older people including complex gene-gene interactions, interactions between genetic variants that might not influence muscle phenotypes individually and the interaction between genes and chronic disease like rheumatoid arthritis and lifestyle risk factors such as physical activity. It is important to determine those genetic factors that interact with aging and thus modulate functional capacity and genetic predisposition of myopenia in rheumatoid arthritis. It would be also clinically relevant to identify 'unfavorable' genotypes

*DOI: http://dx.doi.org/10.5772/intechopen.91270*

RA starting before 30 years of age [33].

associated with myopenia in rheumatoid arthritis.

**5. Pathogenesis of myopenia and musculoskeletal aging in RA**

Two major subtypes of RA are classified according to the presence or absence of anti-citrullinated protein antibodies (ACPAs). Citrullination is catalyzed by the calcium-dependent enzyme peptidylarginine deiminase (PAD), changing a positively charged arginine to a polar but neutral citrulline as the result of a post-translational modification. ACPAs can be detected in approximately 67% of RA patients and serve as a useful diagnostic reference for patients with early, undifferentiated arthritis and provide an indication of likely disease progression through to RA [35, 36]. The ACPA-positive subset of RA has a more aggressive clinical phenotype compared to ACPA-negative subset of RA [37]. It is reported that ACPA-negative RA has different genetic association patterns [37] and differential responses of immune cells to citrullinated antigens [38] from those of ACPA-positive subset. In terms of standard treatment [39–41], less effective treatment response of methotrexate (MTX) or rituximab was observed in ACPA-negative subset. Future studies are needed on the potential pathophysiology difference between the two subsets, while this chapter will focus on the ACPA-positive subset of RA and divide the onset and progression of RA process into the above-mentioned EORA and YORA. Since the clinical, genetic and laboratory differences between EORA and YORA are not understood yet, the immunological and hormonal changes in the elderly population may be responsible for the physiological process characterized by reduced T-cell proliferation, reduced antibody synthesis to vaccination and elevated proinflammatory cytokine levels. Immune system changes include T-cell phenotype alteration,

#### *Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91270*

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

**3.2 Cachexia, muscle failure and muscle wasting disease**

lifestyle and pharmacological interventions.

**4. Genetics of RA and muscle aging**

Rheumatoid arthritis cachexia (RAC) is characterized by high degrees of muscle mass loss and muscle strength loss, associated with preservation or slight increase in fat mass [24]. RAC is unique in comparison to other forms of cachexia observed in cancer, chronic heart failure, kidney disease and chronic infection as it is rarely accompanied by a net weight loss [25]. RAC also differs from primary sarcopenia in the elderly as it occurs at much younger age associated with significantly higher muscle mass loss [26]. Higher-grade inflammation has been considered as the central component of the pathophysiology and the key driver of muscle wasting. More recent findings, however, indicate that inflammation on its own cannot fully explain the high prevalence of muscle wasting in RA. Thus, two lifestyle factors including nutrition and physical activity have also been studied to indicate that they play a significant role in muscle wasting in RA, but again neither of these factors seems to be able to fully explain the condition. Oxidative stress is one of the major mechanisms thought to contribute to the development and progression of RA, but its potential contribution to muscle wasting in these patients has received limited attention. Oxidative stress has been shown to promote muscle wasting in healthy populations and people with several chronic conditions. Moreover, all of the aforementioned potential contributors to muscle wasting in RA (i.e., inflammation, nutrition and physical activity) may promote pro- or anti-oxidative mechanisms. Muscle failure is another new term describing the combination of primary and secondary sarcopenia, leading to a more relevant functional definition of premature muscle aging related to rheumatoid arthritis, RA-related muscle failure instead of myopenia. This review will put more emphasis to highlight the important clinical implication of myopenia and premature muscular aging and discuss the various management strategies of delaying musculoskeletal aging in RA, including muscle regeneration *via* reduction in oxidative stress and early control of inflammation via

RA develops in individuals with a genetic association in RA, which is the presence of DRB1 locus in the HLA class 2 gene. The RA-associated DRB1 alleles share a linear sequence of amino acids between positions 70 and 74 in the HLA-DRB1 chain of the HLA-DRa/b heterodimer, which has led to the 'shared epitope' (SE) hypothesis [27], posing a risk factor for RA development. Jnhi DRB1 allele was associated with early onset of disease, radiological erosion and extra-articular findings [28]. The results of studies investigating genetic predisposition in EORA are inadequate and contradictory [29]. RA-associated DRB1 alleles show differences in early and late onset RA as well as ethnic variants. A Spanish study found that YORA was related to DRB1/04, while EORA was associated with DRB1/01 [30]. This study also found that increased DRB1–13/14 frequency was detected in patients with seronegative EORA and polymyalgia rheumatica (PMR). Another prospective study established the facts that a relationship was found between PMR and DRB1\*0101/0102/0401, while seronegative EORA was associated with DRB1- 0401. Kim and colleagues investigated the impact of HLA-DRB1 and HLA-DQB1 genes on susceptibility to disease and disease severity in EORA and YORA patients [31]. Alleles encoding the common epitope were detected less frequently in EORA compared with YORA with the effect of the common epitope and HLA-DQ\*04 alleles being shown to be less significant. In comparison with YORA, EORA has also been found to have less common epitope presence and less radiological progression.

**86**

Hellier and colleagues investigated the effect of the HLA-DRB1 gene on disease susceptibility and disease severity in EORA and YORA [32] and demonstrated HLA-DRB1/04-related alleles were not closely associated in EORA. Thus, it is suggested that the impact of these genes on the susceptibility to disease in EORA is not very important. Wu and colleagues showed that the DRB1/04 allele was detected in half of the EORA population, while the DRB1/04 frequency was 92% in patients with RA starting before 30 years of age [33].

In terms of genetic contribution and impact on the individual variability in muscle aging phenotypes literature on specific gene variants, it remained controversial and no solid evidence exists supporting the existence of an 'unfavorable' genotype associated with accelerated age-related sarcopenia or loss of independent function [34]. Although the ACTN3 R577X polymorphism is the only structural gene for which a clear genotype effect has been shown in human muscle phenotypes, especially for athletic women, there is controversy with regard to which allele (R or X) plays a potential 'favorable' role in aging. The MSTN K153R variation is possibly the strongest candidate to explain variance among muscle phenotypes in the elderly, yet more research is still needed with large cohorts owing to the very low population frequency of the 'unfavorable' 153R allele. Recent evidence [34] indicates that age-related declines in muscle phenotypes are likely polygenic traits and thus not reducible to specific polymorphisms, suggesting that future studies should consider the association between muscle phenotypes in older people including complex gene-gene interactions, interactions between genetic variants that might not influence muscle phenotypes individually and the interaction between genes and chronic disease like rheumatoid arthritis and lifestyle risk factors such as physical activity. It is important to determine those genetic factors that interact with aging and thus modulate functional capacity and genetic predisposition of myopenia in rheumatoid arthritis. It would be also clinically relevant to identify 'unfavorable' genotypes associated with myopenia in rheumatoid arthritis.

### **5. Pathogenesis of myopenia and musculoskeletal aging in RA**

Two major subtypes of RA are classified according to the presence or absence of anti-citrullinated protein antibodies (ACPAs). Citrullination is catalyzed by the calcium-dependent enzyme peptidylarginine deiminase (PAD), changing a positively charged arginine to a polar but neutral citrulline as the result of a post-translational modification. ACPAs can be detected in approximately 67% of RA patients and serve as a useful diagnostic reference for patients with early, undifferentiated arthritis and provide an indication of likely disease progression through to RA [35, 36]. The ACPA-positive subset of RA has a more aggressive clinical phenotype compared to ACPA-negative subset of RA [37]. It is reported that ACPA-negative RA has different genetic association patterns [37] and differential responses of immune cells to citrullinated antigens [38] from those of ACPA-positive subset. In terms of standard treatment [39–41], less effective treatment response of methotrexate (MTX) or rituximab was observed in ACPA-negative subset. Future studies are needed on the potential pathophysiology difference between the two subsets, while this chapter will focus on the ACPA-positive subset of RA and divide the onset and progression of RA process into the above-mentioned EORA and YORA. Since the clinical, genetic and laboratory differences between EORA and YORA are not understood yet, the immunological and hormonal changes in the elderly population may be responsible for the physiological process characterized by reduced T-cell proliferation, reduced antibody synthesis to vaccination and elevated proinflammatory cytokine levels. Immune system changes include T-cell phenotype alteration,

reduction in specific immune response, apoptosis defects, cytokine imbalance and inadequate antigen presentation. With increasing age, there is a decrease in the protective immunological response, while the reaction to autoantigens is increasing [42]. In addition, self-tolerance mechanism disorders occur. As a result of thymus involution in senescence, changes in T-cell composition, decrease in T-cell proliferation and cytokine synthesis, as well as decreased antibody synthesis after vaccination, were seen. In one study, elevated interleukin (IL)-6 secretion was associated with dehydroepiandrosterone and androstenedione synthesis in patients with EORA [43]. The acute onset and increased acute phase response seen in EORA may be explained by increased IL-6 levels. Punzi and colleagues showed elevated IL-6 as acute onset and increased acute phase response in the EORA synovial fluid compared with YORA, suggesting the role of IL-6 while no differences were detected in IL-1 and IL-8 levels [44]. Different immunoregulatory mechanisms may be at work in the pathogenesis of RA seen in different age groups with one study by Gamerith and colleagues showing a significantly increased anti-IgG-Fab/free aFab ratio in patients with YORA, compared with EORA, leading to increased rheumatoid factor (RF) presence [45]. Myopenia in RA will be mediated by a similar mechanism of rising IL-6, leading to premature muscle aging in YORA, while acute-onset-induced long-term muscle damage is equivalent to premature muscle aging in EORA. Further research is required to unlock the mechanism of premature muscular aging in RA patients.

### **6. Clinical features of myopenia in rheumatoid arthritis**

Myopenia in rheumatoid arthritis is a similar term to terms described above including secondary sarcopenia, rheumatoid arthritis cachexia and muscle failure or muscle wasting in rheumatoid arthritis. The clinical features follow the two forms of rheumatoid arthritis including EORA and YORA with their distinctive features. EORA has three distinct clinical patterns [46] with the most common clinical form (70%) displaying RF positivity, joint erosions and worse prognosis than YORA, while the second form (25%) is a PMR-like form with proximal limb joint involvement characterized by RF negativity, being associated with acute onset, lack of joint erosions and good prognosis. Non-erosive polyarthritis may be present in 25% of patients with PMR as one of the main differential diagnoses [47]. The presence of metacarpophalangeal (MCP)/proximal interphalangeal (PIP) joint arthritis with proximal limb joint involvement is considered a predictive factor for seronegative EORA. The third EORA pattern is featured by clinical and prognostic similarity to RS3PE syndrome [48] with sudden onset, wrist tenosynovitis, common pitting edema in the hands, HLA-B27 positivity and spontaneous remission within 3–18 months. EORA is not limited to the differentiate diagnosis of PMR, but also associated with other diseases including crystal arthritis, septic arthritis, sarcoidosis and hepatitis C [49]. In many studies [50, 51], simultaneous small and large joint involvement is frequently seen at the onset of the disease, while RF and anti-CCP positivity are seen at similar and/or slightly lower rates in comparison with YORA. Acute onset, PMR-like symptoms, less rheumatoid nodule and RF positivity were detected in EORA compared with YORA. Patients with EORA had a lower joint score and a higher Health Assessment Questionnaire (HAQ ) score. A recent study [52] reported the clinical and demographic characteristics of Turkish patients with EORA displaying shoulder joint involvement being more frequent in EORA, while PIP, MCP, elbow and ankle joint involvement were more common in YORA. RA deformities, Sjögren syndrome (SjS) and lung involvement are less common in EORA. Weight loss, myalgia, lymphadenopathy and PMR-like symptoms

**89**

*Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis*

were also more frequent in EORA, while the antibody profile (RF, ANA, anti-Ro and anti-La) was detected less frequently in EORA. In contrast, anemia of chronic disease, ESR and CRP elevation were more common in a study reported by van der Heijde and colleagues [53]. Another aggressive, destructive EORA form of EORA having more frequent acute onset, initially small and large joint involvement, PMRlike patterns and radiological narrowing of the joint space was reported by Lance and colleagues with radiographic erosive changes [54]. In this report, the patients are characterized by polyarticular small joint involvement, rapid progression, hand/wrist erosions and early hand function loss as well as 63% of these patients reported secondary SjS compared with 25% in patients with YORA. More recently, myopenia has been reported to be very common in Chinese RA patients that is associated with functional limitation and joint damage in RA [55]. In another report at the 2019 American College of Rheumatology meeting, myopenia, equivalent to body composition disorder in elderly Chinese patients with RA, showed that elderly female patients with myopenia were associated with severe joint damage in rheumatoid arthritis [56]. These studies reflected both the cultural and gender diversity of

It has been well documented that lower hemoglobin and higher ESR and CRP were detected in EORA in comparison with YORA [57]. In some studies, RF and anti-CCP antibody positivity were reported less frequently in EORA, while in other studies, the frequency of these antibodies was found to be similar in both groups [51, 53, 58]. Chen and colleagues compared the pro-inflammatory cytokine levels of patients with EORA and YORA [59] demonstrating that higher levels of IL-6 and lower levels of tumor necrosis factor α (TNFα) were detected in EORA, associated with higher IL-6 levels being detected in patients with EORA and PMR-like symptoms. Multivariate analysis showed that high IL-1 levels were associated with anti-CCP antibodies, while high TNFα levels were associated with constitutional symptoms in patients with EORA. In comparison with YORA, acute onset, constitutional symptoms and comorbidities were more frequent in patients with EORA.

There is no direct evidence for discussion with respect to the impact of myopenia on the prognosis of RA. The prognosis of RA in terms of RA's age of onset remains unclear with some studies showing EORA with better prognosis compared with YORA, while others report that they are similar or worse. The above contradictory results may be due to different disease durations between groups examined, bias in patient selection, and different frequencies of seropositivity between younger and older patients. In one study, persistent arthritis was seen in 39% of seropositive patients, while in seronegative patients, this rate was only 6% [60]. In another study, more swollen joints, radiological damage and mortality were reported in seropositive patients in comparison with seronegative patients [61]. In other words, RF and anti-CCP antibodies are considered poor prognostic markers in patients with EORA. Krams and colleagues compared the characteristics of patients with EORA and YORA in the ESPOIR cohort containing 681 patients with RA [62], and the one-year remission rates were higher in the patients with YORA than those with EORA showing more erosion and high HAQ scores in patients with EORA. As a result, at the end of the third year, patients with YORA had higher remission rates,

*DOI: http://dx.doi.org/10.5772/intechopen.91270*

**7. Laboratory findings in myopenia in RA**

**8. Prognosis of myopenia in RA**

myopenia in RA.

*Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91270*

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

muscular aging in RA patients.

**6. Clinical features of myopenia in rheumatoid arthritis**

Myopenia in rheumatoid arthritis is a similar term to terms described above including secondary sarcopenia, rheumatoid arthritis cachexia and muscle failure or muscle wasting in rheumatoid arthritis. The clinical features follow the two forms of rheumatoid arthritis including EORA and YORA with their distinctive features. EORA has three distinct clinical patterns [46] with the most common clinical form (70%) displaying RF positivity, joint erosions and worse prognosis than YORA, while the second form (25%) is a PMR-like form with proximal limb joint involvement characterized by RF negativity, being associated with acute onset, lack of joint erosions and good prognosis. Non-erosive polyarthritis may be present in 25% of patients with PMR as one of the main differential diagnoses [47]. The presence of metacarpophalangeal (MCP)/proximal interphalangeal (PIP) joint arthritis with proximal limb joint involvement is considered a predictive factor for seronegative EORA. The third EORA pattern is featured by clinical and prognostic similarity to RS3PE syndrome [48] with sudden onset, wrist tenosynovitis, common pitting edema in the hands, HLA-B27 positivity and spontaneous remission within 3–18 months. EORA is not limited to the differentiate diagnosis of PMR, but also associated with other diseases including crystal arthritis, septic arthritis, sarcoidosis and hepatitis C [49]. In many studies [50, 51], simultaneous small and large joint involvement is frequently seen at the onset of the disease, while RF and anti-CCP positivity are seen at similar and/or slightly lower rates in comparison with YORA. Acute onset, PMR-like symptoms, less rheumatoid nodule and RF positivity were detected in EORA compared with YORA. Patients with EORA had a lower joint score and a higher Health Assessment Questionnaire (HAQ ) score. A recent study [52] reported the clinical and demographic characteristics of Turkish patients with EORA displaying shoulder joint involvement being more frequent in EORA, while PIP, MCP, elbow and ankle joint involvement were more common in YORA. RA deformities, Sjögren syndrome (SjS) and lung involvement are less common in EORA. Weight loss, myalgia, lymphadenopathy and PMR-like symptoms

reduction in specific immune response, apoptosis defects, cytokine imbalance and inadequate antigen presentation. With increasing age, there is a decrease in the protective immunological response, while the reaction to autoantigens is increasing [42]. In addition, self-tolerance mechanism disorders occur. As a result of thymus involution in senescence, changes in T-cell composition, decrease in T-cell proliferation and cytokine synthesis, as well as decreased antibody synthesis after vaccination, were seen. In one study, elevated interleukin (IL)-6 secretion was associated with dehydroepiandrosterone and androstenedione synthesis in patients with EORA [43]. The acute onset and increased acute phase response seen in EORA may be explained by increased IL-6 levels. Punzi and colleagues showed elevated IL-6 as acute onset and increased acute phase response in the EORA synovial fluid compared with YORA, suggesting the role of IL-6 while no differences were detected in IL-1 and IL-8 levels [44]. Different immunoregulatory mechanisms may be at work in the pathogenesis of RA seen in different age groups with one study by Gamerith and colleagues showing a significantly increased anti-IgG-Fab/free aFab ratio in patients with YORA, compared with EORA, leading to increased rheumatoid factor (RF) presence [45]. Myopenia in RA will be mediated by a similar mechanism of rising IL-6, leading to premature muscle aging in YORA, while acute-onset-induced long-term muscle damage is equivalent to premature muscle aging in EORA. Further research is required to unlock the mechanism of premature

**88**

were also more frequent in EORA, while the antibody profile (RF, ANA, anti-Ro and anti-La) was detected less frequently in EORA. In contrast, anemia of chronic disease, ESR and CRP elevation were more common in a study reported by van der Heijde and colleagues [53]. Another aggressive, destructive EORA form of EORA having more frequent acute onset, initially small and large joint involvement, PMRlike patterns and radiological narrowing of the joint space was reported by Lance and colleagues with radiographic erosive changes [54]. In this report, the patients are characterized by polyarticular small joint involvement, rapid progression, hand/wrist erosions and early hand function loss as well as 63% of these patients reported secondary SjS compared with 25% in patients with YORA. More recently, myopenia has been reported to be very common in Chinese RA patients that is associated with functional limitation and joint damage in RA [55]. In another report at the 2019 American College of Rheumatology meeting, myopenia, equivalent to body composition disorder in elderly Chinese patients with RA, showed that elderly female patients with myopenia were associated with severe joint damage in rheumatoid arthritis [56]. These studies reflected both the cultural and gender diversity of myopenia in RA.

### **7. Laboratory findings in myopenia in RA**

It has been well documented that lower hemoglobin and higher ESR and CRP were detected in EORA in comparison with YORA [57]. In some studies, RF and anti-CCP antibody positivity were reported less frequently in EORA, while in other studies, the frequency of these antibodies was found to be similar in both groups [51, 53, 58]. Chen and colleagues compared the pro-inflammatory cytokine levels of patients with EORA and YORA [59] demonstrating that higher levels of IL-6 and lower levels of tumor necrosis factor α (TNFα) were detected in EORA, associated with higher IL-6 levels being detected in patients with EORA and PMR-like symptoms. Multivariate analysis showed that high IL-1 levels were associated with anti-CCP antibodies, while high TNFα levels were associated with constitutional symptoms in patients with EORA. In comparison with YORA, acute onset, constitutional symptoms and comorbidities were more frequent in patients with EORA.

### **8. Prognosis of myopenia in RA**

There is no direct evidence for discussion with respect to the impact of myopenia on the prognosis of RA. The prognosis of RA in terms of RA's age of onset remains unclear with some studies showing EORA with better prognosis compared with YORA, while others report that they are similar or worse. The above contradictory results may be due to different disease durations between groups examined, bias in patient selection, and different frequencies of seropositivity between younger and older patients. In one study, persistent arthritis was seen in 39% of seropositive patients, while in seronegative patients, this rate was only 6% [60]. In another study, more swollen joints, radiological damage and mortality were reported in seropositive patients in comparison with seronegative patients [61]. In other words, RF and anti-CCP antibodies are considered poor prognostic markers in patients with EORA. Krams and colleagues compared the characteristics of patients with EORA and YORA in the ESPOIR cohort containing 681 patients with RA [62], and the one-year remission rates were higher in the patients with YORA than those with EORA showing more erosion and high HAQ scores in patients with EORA. As a result, at the end of the third year, patients with YORA had higher remission rates,

less radiographic progression and lower HAQ scores compared with patients with EORA. A Korean study evaluated 3169 Korean patients with RA [58] and showed that the 486 patients with RA that started when they were over 60 years old were considered to have EORA and it has been found to be an independent risk factor for functional disability. In one study, the presence of acute pitting swelling in the hands at the onset of the disease was shown to be a good prognostic factor [60] with EORA presenting with pitting edema having fewer erosions compared with patients with EORA without pitting edema. In terms of EORA mortality related to myopenia, there was a statistically significant increase in mortality rates in patients with seropositive EORA compared with the general population [57], while there was not significant difference in patients who were seronegative.

#### **9. Treatment and management of myopenia in RA**

Management of myopenia in RA will translate the latest research evidence of treatment strategies for rheumatoid arthritis. These strategies include the optimization of lifestyle and risk factor modifications including nutrition and exercise; pharmacological interventions include early administration of disease-modifying antirheumatic drugs (DMARDs); and targeted strategies have been able to prevent radiological progression, reduce morbidity and mortality, and increase functional capacity [63, 64].

### **10. Exercise and myopenia/cachexia in rheumatoid arthritis**

RA and exercise have been thoroughly reviewed [65] to indicate the reduced and compromised exercise capacity in comparison with normal people due to their RA manifestations of pain, stiffness, structural joint damage, bone density loss and muscle weakness [66, 67]. It is well established that physical exercise programs promote prolonged improvements [68] without inducing harmful effects on disease activity and joint damage [69]. Recent evidence [65] has examined different modalities of exercises including resistance training, aerobic training and combination of the two modalities. Aerobic training consists of cycling, aquatics, dancing, walking and running. The final messages show that exercise is effective in reversing joint damage in RA patients as long as RA-specific considerations are being taken into account when developing exercise programs aiming to reduce CVD risk and improve quality of life and maintaining activity of daily living functions of RA patients. In another study [70] describing myopenia/cachexia and exercise types for treatment, intensive progressive resistance training (PRT) can increase lean mass, reduce fat mass, increase strength and improve function. PRT is the most effective exercise to improve skeletal muscle size and strength, even safe when performed at high intensity with RA patients. Resistance training increases tendon stiffness and strengthens connective tissue, while cyclic loading (e.g., walking, cycling and strength endurance exercises) enhances cartilage integrity and joint lubrication as well as mobility exercises increase range of motion. In terms of symptom control in RA patients, exercise can reduce pain and morning stiffness and even reduce fatigue as well as improve functional ability and psychological well-being without exacerbating disease activity. The review also discusses the improvement of patient perceptions regarding the effects and benefits of exercise, clarifies specific exercise recommendations and considers methods of overcoming individual barriers to exercise. A recent study showed that hydrotherapy had a positive role in reducing pain and improving health status of RA patients [71]. All RA patients should be

**91**

*Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis*

encouraged to include some form of aerobic and resistance exercise training as part of their routine care. More research is still required on the optimal and individualized frequency, intensity, time and types (FITT model) of exercises, or when it requires a combination of types as well as how best to incorporate exercise into the lives of RA patients across the variable course of the disease. Large cohort studies will be required to examine the potential ethnic differences in terms of myopenia

and muscle aging in diverse cultures such as in China, India or Africa.

**11. Management of frailty and prefrailty in rheumatoid arthritis** 

**12. Myopenia, heart failure and premature myocardial aging in RA**

RA and other autoimmune chronic inflammatory disorders including psoriasis and inflammatory bowel diseases have been well documented to be associated with considerably increased cardiovascular morbidity and mortality in comparison with the background population [78–82]. In particular, the cardiovascular disease risk in RA patients appears to be comparable with that found in type 2 diabetes mellitus patients [83–85]. Conventional cardiovascular risk factors including hypertension, obesity, dyslipidemia and diabetes mellitus with RA-specific risk factor of increased systemic inflammation have been implicated to contribute

Heart failure (HF), an alternative term describing myopenia in the cardiac muscle, has been shown by numerous public health studies to be associated with increased inflammation and a high prevalence of cardiovascular risk factors [87, 88]. The proinflammatory cytokines of HF promote myocardial damage leading to myopenia of cardiac muscle and other pathogenic manifestations through an array of mechanisms including increased arterial stiffness and endothelial dysfunction [89–95]. A number of review and population studies have examined the risk of developing HF in RA patients and found that RA-specific HF can be independent of cardiovascular risk factors [89, 93, 96, 97]. One of the commonest risk factors and potential cause of HF is ischemic heart disease, which was not shown to be responsible for the increased risks of HF in rheumatoid arthritis. This paper [93] also demonstrated that the increased risks of non-ischemic HF in RA presented early in association with RA severity. A more recent Danish cohort study [98] aimed to investigate the risk of incident HF in RA patients indicated that rheumatoid arthritis was associated with a 30% increased hospitalization for heart failure in

Frailty, which was originally considered a geriatric syndrome [72], is associated with reduced muscle strength, exhaustion and high inflammatory markers [73, 74], leading to perpetuation of the frailty and prefrailty cycle associated with different frailty assessment tools [75, 76]. Frailty and myopenia share a common cardinal clinical feature of reduced muscle strength. A recent study [77] showed that frailty and prefrailty are common in RA patients of younger age and are more prevalent than expected. As the prevalence of frailty increases with age, this study indicates that it is important to counteract frailty for the treatment of myopenia in RA patients. A very interesting aspect for further research would be to assess the frailty status in a large sample size to investigate if the frailty score is lower in RA patients who have entered into permanent remission after early treatment, whereby they did not develop any joint damage, compared to age- and sex-matched patients who have

*DOI: http://dx.doi.org/10.5772/intechopen.91270*

**myopenia**

been treated less aggressively.

significantly [81, 86].

*Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91270*

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

significant difference in patients who were seronegative.

**9. Treatment and management of myopenia in RA**

**10. Exercise and myopenia/cachexia in rheumatoid arthritis**

capacity [63, 64].

less radiographic progression and lower HAQ scores compared with patients with EORA. A Korean study evaluated 3169 Korean patients with RA [58] and showed that the 486 patients with RA that started when they were over 60 years old were considered to have EORA and it has been found to be an independent risk factor for functional disability. In one study, the presence of acute pitting swelling in the hands at the onset of the disease was shown to be a good prognostic factor [60] with EORA presenting with pitting edema having fewer erosions compared with patients with EORA without pitting edema. In terms of EORA mortality related to myopenia, there was a statistically significant increase in mortality rates in patients with seropositive EORA compared with the general population [57], while there was not

Management of myopenia in RA will translate the latest research evidence of treatment strategies for rheumatoid arthritis. These strategies include the optimization of lifestyle and risk factor modifications including nutrition and exercise; pharmacological interventions include early administration of disease-modifying antirheumatic drugs (DMARDs); and targeted strategies have been able to prevent radiological progression, reduce morbidity and mortality, and increase functional

RA and exercise have been thoroughly reviewed [65] to indicate the reduced and compromised exercise capacity in comparison with normal people due to their RA manifestations of pain, stiffness, structural joint damage, bone density loss and muscle weakness [66, 67]. It is well established that physical exercise programs promote prolonged improvements [68] without inducing harmful effects on disease activity and joint damage [69]. Recent evidence [65] has examined different modalities of exercises including resistance training, aerobic training and combination of the two modalities. Aerobic training consists of cycling, aquatics, dancing, walking and running. The final messages show that exercise is effective in reversing joint damage in RA patients as long as RA-specific considerations are being taken into account when developing exercise programs aiming to reduce CVD risk and improve quality of life and maintaining activity of daily living functions of RA patients. In another study [70] describing myopenia/cachexia and exercise types for treatment, intensive progressive resistance training (PRT) can increase lean mass, reduce fat mass, increase strength and improve function. PRT is the most effective exercise to improve skeletal muscle size and strength, even safe when performed at high intensity with RA patients. Resistance training increases tendon stiffness and strengthens connective tissue, while cyclic loading (e.g., walking, cycling and strength endurance exercises) enhances cartilage integrity and joint lubrication as well as mobility exercises increase range of motion. In terms of symptom control in RA patients, exercise can reduce pain and morning stiffness and even reduce fatigue as well as improve functional ability and psychological well-being without exacerbating disease activity. The review also discusses the improvement of patient perceptions regarding the effects and benefits of exercise, clarifies specific exercise recommendations and considers methods of overcoming individual barriers to exercise. A recent study showed that hydrotherapy had a positive role in reducing pain and improving health status of RA patients [71]. All RA patients should be

**90**

encouraged to include some form of aerobic and resistance exercise training as part of their routine care. More research is still required on the optimal and individualized frequency, intensity, time and types (FITT model) of exercises, or when it requires a combination of types as well as how best to incorporate exercise into the lives of RA patients across the variable course of the disease. Large cohort studies will be required to examine the potential ethnic differences in terms of myopenia and muscle aging in diverse cultures such as in China, India or Africa.

### **11. Management of frailty and prefrailty in rheumatoid arthritis myopenia**

Frailty, which was originally considered a geriatric syndrome [72], is associated with reduced muscle strength, exhaustion and high inflammatory markers [73, 74], leading to perpetuation of the frailty and prefrailty cycle associated with different frailty assessment tools [75, 76]. Frailty and myopenia share a common cardinal clinical feature of reduced muscle strength. A recent study [77] showed that frailty and prefrailty are common in RA patients of younger age and are more prevalent than expected. As the prevalence of frailty increases with age, this study indicates that it is important to counteract frailty for the treatment of myopenia in RA patients. A very interesting aspect for further research would be to assess the frailty status in a large sample size to investigate if the frailty score is lower in RA patients who have entered into permanent remission after early treatment, whereby they did not develop any joint damage, compared to age- and sex-matched patients who have been treated less aggressively.

### **12. Myopenia, heart failure and premature myocardial aging in RA**

RA and other autoimmune chronic inflammatory disorders including psoriasis and inflammatory bowel diseases have been well documented to be associated with considerably increased cardiovascular morbidity and mortality in comparison with the background population [78–82]. In particular, the cardiovascular disease risk in RA patients appears to be comparable with that found in type 2 diabetes mellitus patients [83–85]. Conventional cardiovascular risk factors including hypertension, obesity, dyslipidemia and diabetes mellitus with RA-specific risk factor of increased systemic inflammation have been implicated to contribute significantly [81, 86].

Heart failure (HF), an alternative term describing myopenia in the cardiac muscle, has been shown by numerous public health studies to be associated with increased inflammation and a high prevalence of cardiovascular risk factors [87, 88]. The proinflammatory cytokines of HF promote myocardial damage leading to myopenia of cardiac muscle and other pathogenic manifestations through an array of mechanisms including increased arterial stiffness and endothelial dysfunction [89–95]. A number of review and population studies have examined the risk of developing HF in RA patients and found that RA-specific HF can be independent of cardiovascular risk factors [89, 93, 96, 97]. One of the commonest risk factors and potential cause of HF is ischemic heart disease, which was not shown to be responsible for the increased risks of HF in rheumatoid arthritis. This paper [93] also demonstrated that the increased risks of non-ischemic HF in RA presented early in association with RA severity. A more recent Danish cohort study [98] aimed to investigate the risk of incident HF in RA patients indicated that rheumatoid arthritis was associated with a 30% increased hospitalization for heart failure in

comparison with the general population. The clinical Implications of these findings add to the existing evidence that rheumatoid arthritis may be a clinically relevant risk factor for heart failure and premature cardiac muscle aging in RA patients. Future studies examining the value of more extensive screening of RA patients for heart failure are warranted.

In terms of the potential mechanism for increased risks of HF in early course of RA, RA has been associated with left ventricular concentric remodeling and systolic and diastolic left ventricular dysfunction [89, 90, 93, 97]. RA patients are more likely to display significantly elevated levels of circulating cardiac biomarkers including troponins, pro-B-type natriuretic peptides, which are recognized as important prognostic markers of cardiac diseases, especially HF [99]. Thus, it is highly conceivable that chronic systemic inflammation in RA may confer an increased risk of HF and premature myocardial aging that is independent of traditional cardiovascular risk factors.

#### **13. Myopenia and pharmacological intervention in RA**

Delaying myopenia and premature muscle aging in RA patients is closely related to the age of onset and preclinical staging of RA. While there are no direct evidences specifically evaluating the impact of pharmacological interventions including synthetic DMARDS and biologics on the management of myopenia in RA, the European League Against Rheumatism guideline advocates early aggressive treatment with these synthetic DMARDS and biologics via their direct effect on reducing inflammation for the purpose of reducing myopenia, delaying premature muscle aging in RA and decreasing cardiovascular morbidity and mortality in RA [100, 101]. These agents are also expected to exert their benefits via their direct effect on reducing inflammation, subsequently improving joint inflammation and function and potentially leading to increased levels of physical activity with consequent reduction of other risk factors including diabetes mellitus and hypertension [100, 101]. A recent study also demonstrates the potential mechanism of how synthetic DMARDS and biologics reduce the risks of sudden cardiac death in RA patients [100].

Identifying a preclinical stage and a growing understanding of the natural history and mechanisms of RA development, alongside new potential pharmacological interventions, shape the prospect that myopenia with premature muscle aging in RA might be preventable in future [102]. The current treatment principles for established RA involve symptomatic management and disease modification. A meta-analysis of 12 published studies confirmed that patients receiving delayed DMARDs therapy were at higher risk of developing radiographic joint space narrowing and bony erosions [103] associated with myopenia in RA with a recent cross-sectional study [55]. In poorly controlled RA patients, bony erosions become more pronounced on radiographs within 2 years of onset and these erosive changes are predictive of poorer functional outcome [104]. In a patient with otherwise unexplained new onset polyarthritis, an urgent referral to a rheumatologist is thus mandatory to confirm an RA diagnosis and early initiation of a DMARDs-based treatment plan aiming for disease remission with delaying myopenia in RA and preventing deformity. Oral corticosteroids are potent and effective anti-inflammatory drugs that may contribute to disease modification [105] to delay myopenia and promote healthy aging. However, this needs to be weighed up against its well-known adverse effects of osteoporosis. Symptomatic management remains the cornerstone interventions throughout the course of the disease with everyday practical measures to deal with the primary symptoms of joint stiffness including pain and fatigue via

**93**

**Table 1.**

*Table from Ref. [106]. Permission from Bone Research is pending.*

*Modern pharmacologic therapies for rheumatoid arthritis.*

*Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis*

pharmacological therapies for RA (**Table 1**) [106].

the mechanism of reducing systemic inflammation. This chapter is not for detailed review and discussion of the pharmacological intervention of RA but endeavors to provide a table from the main author's previous review to summarize the modern

*DOI: http://dx.doi.org/10.5772/intechopen.91270*

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

**13. Myopenia and pharmacological intervention in RA**

heart failure are warranted.

traditional cardiovascular risk factors.

comparison with the general population. The clinical Implications of these findings add to the existing evidence that rheumatoid arthritis may be a clinically relevant risk factor for heart failure and premature cardiac muscle aging in RA patients. Future studies examining the value of more extensive screening of RA patients for

In terms of the potential mechanism for increased risks of HF in early course of RA, RA has been associated with left ventricular concentric remodeling and systolic and diastolic left ventricular dysfunction [89, 90, 93, 97]. RA patients are more likely to display significantly elevated levels of circulating cardiac biomarkers including troponins, pro-B-type natriuretic peptides, which are recognized as important prognostic markers of cardiac diseases, especially HF [99]. Thus, it is highly conceivable that chronic systemic inflammation in RA may confer an increased risk of HF and premature myocardial aging that is independent of

Delaying myopenia and premature muscle aging in RA patients is closely related to the age of onset and preclinical staging of RA. While there are no direct evidences specifically evaluating the impact of pharmacological interventions including synthetic DMARDS and biologics on the management of myopenia in RA, the European League Against Rheumatism guideline advocates early aggressive treatment with these synthetic DMARDS and biologics via their direct effect on reducing inflammation for the purpose of reducing myopenia, delaying premature muscle aging in RA and decreasing cardiovascular morbidity and mortality in RA [100, 101]. These agents are also expected to exert their benefits via their direct effect on reducing inflammation, subsequently improving joint inflammation and function and potentially leading to increased levels of physical activity with consequent reduction of other risk factors including diabetes mellitus and hypertension [100, 101]. A recent study also demonstrates the potential mechanism of how synthetic DMARDS and biologics reduce the risks of sudden cardiac death in RA

Identifying a preclinical stage and a growing understanding of the natural history and mechanisms of RA development, alongside new potential pharmacological interventions, shape the prospect that myopenia with premature muscle aging in RA might be preventable in future [102]. The current treatment principles for established RA involve symptomatic management and disease modification. A meta-analysis of 12 published studies confirmed that patients receiving delayed DMARDs therapy were at higher risk of developing radiographic joint space narrowing and bony erosions [103] associated with myopenia in RA with a recent cross-sectional study [55]. In poorly controlled RA patients, bony erosions become more pronounced on radiographs within 2 years of onset and these erosive changes are predictive of poorer functional outcome [104]. In a patient with otherwise unexplained new onset polyarthritis, an urgent referral to a rheumatologist is thus mandatory to confirm an RA diagnosis and early initiation of a DMARDs-based treatment plan aiming for disease remission with delaying myopenia in RA and preventing deformity. Oral corticosteroids are potent and effective anti-inflammatory drugs that may contribute to disease modification [105] to delay myopenia and promote healthy aging. However, this needs to be weighed up against its well-known adverse effects of osteoporosis. Symptomatic management remains the cornerstone interventions throughout the course of the disease with everyday practical measures to deal with the primary symptoms of joint stiffness including pain and fatigue via

**92**

patients [100].

the mechanism of reducing systemic inflammation. This chapter is not for detailed review and discussion of the pharmacological intervention of RA but endeavors to provide a table from the main author's previous review to summarize the modern pharmacological therapies for RA (**Table 1**) [106].


*Table from Ref. [106]. Permission from Bone Research is pending.*

#### **Table 1.**

*Modern pharmacologic therapies for rheumatoid arthritis.*

In terms of the age of onset of rheumatoid arthritis, the ultimate goal of RA treatment including EORA and YORA is to control the disease, delay myopenia and maintain functional capacity. As discussed above on genetics, clinical features, pathogenesis and prognosis of EORA and YORA, treatment of EORA should not be so different from treatment of YORA. The goal of treatment should be complete remission or low disease activity based on the principles of treat-to-target strategies. DMARDs used in YORA may also be safely used in the treatment of EORA as long as drug pharmacokinetics and pharmacodynamics in the elderly can be clinically considered with closely monitoring the drug side effect profile [107]. EORA has more comorbid diseases and high number of medications used and consequently increasing drug-drug interactions exacerbating the potential side effect profile [108]. DMARDs used in patients with EORA are limited and contradictory and are receiving less aggressive treatment based on data from patients with EORA in the CORONA database in comparison with those of age- and sex-matched patients with YORA [109]. The study [109] also showed that disease activity and disease severity were similar in both groups. Methotrexate (MTX) use was found to be higher in patients with EORA compared with those with YORA (63.9% vs. 59.6%), while mean MTX dose was found to be higher in patients with YORA. The number of patients using multiple conventional DMARDs or biological DMARDs was found to be lower in those with EORA compared with YORA. Treatment-related toxicity was similar in both groups, whereas toxicity due to MTX was found to be more frequent in the case of YORA. Despite similar disease duration, disease activity and severity, patients with EORA used combined conventional DMARDs and biological DMARDs less frequently compared with patients with YORA. It has been well documented that the age of onset determines the severity of the disease and the choice of treatment [110]. According to Swiss registries, the use of fırstline corticosteroids was significantly higher in patients with EORA compared with those with YORA, in contrast to the much lower follow-up on the use of biological drugs [111]. Genevay and colleagues evaluated 1571 patients with RA receiving anti-TNFα drugs [112] and demonstrated similar changes with drug withdrawal rates and mean Disease Activity Score (DAS28) score changes in both groups at the end of the second year. Despite clinical responses, improvement in Health Assessment Questionnaire (HAQ ) scores was significantly less in patients with EORA. TNF inhibitors were slightly less or equally effective in reducing disease activity in elderly compared with younger patients with HAQ scores showing less improvement in patients with EORA, especially in patients aged over 75 years [113]. There is limited evidence for the effectiveness of tocilizumab, abatacept, rituximab and tofacitinib in EORA. Tocilizumab was less effective in EORA compared with YORA, while the drug retention rate and discontinuation rates because of adverse events were similar between the two age groups [114]. There is no data on abatacept in EORA, while RCTs showed tofacitinib to be similarly effective in both EORA and YORA [115]. In terms of myopenia in both EORA and YORA, a recent study [116] indicates that EORA is characterized by more equal distribution of sex, higher frequency of acute onset with constitutional symptoms, more frequent involvement of large joints, and lower frequency of RF positivity. Earlier diagnosis, less erosive disease and less DMARD usage were reported as distinguishing patients with EORA from those with YORA. Further studies require the exploration of myopenia and its severity and impact on the prognosis of RA including both EORA and YORA, reflecting the above-mentioned concepts of secondary sarcopenia, cachexia and frailty with old age, potentially impacting RA prognosis in the presence of DMARD side effects.

**95**

**Author details**

Australia

Dan Xu1,2\*, Jiake Xu3

and Lei Dai4

The University of Western Australia, Perth, Australia

\*Address all correspondence to: daniel.xu@curtin.edu.au

University, Guangzhou, Guangdong, China

University, Guangzhou, Guangdong, China

provided the original work is properly cited.

1 Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth,

2 Department of Medical Education, The First Affiliated Hospital, Sun Yat-Sen

4 Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen

© 2020 The Author(s). Licensee IntechOpen. 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,

3 School of Biomedical Sciences, Faculty of Health and Medical Sciences,

*Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis*

Myopenia and premature muscular aging in RA are similar concepts, raising a lot of research questions in terms of mechanism, lifestyle intervention, comorbidity management and new pharmacological approach. The chapter provides the plat-

form for a discussion about the new term of myopenia and its impact.

*DOI: http://dx.doi.org/10.5772/intechopen.91270*

**14. Conclusion and future perspectives**

### **14. Conclusion and future perspectives**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

In terms of the age of onset of rheumatoid arthritis, the ultimate goal of RA treatment including EORA and YORA is to control the disease, delay myopenia and maintain functional capacity. As discussed above on genetics, clinical features, pathogenesis and prognosis of EORA and YORA, treatment of EORA should not be so different from treatment of YORA. The goal of treatment should be complete remission or low disease activity based on the principles of treat-to-target strategies. DMARDs used in YORA may also be safely used in the treatment of EORA as long as drug pharmacokinetics and pharmacodynamics in the elderly can be clinically considered with closely monitoring the drug side effect profile [107]. EORA has more comorbid diseases and high number of medications used and consequently increasing drug-drug interactions exacerbating the potential side effect profile [108]. DMARDs used in patients with EORA are limited and contradictory and are receiving less aggressive treatment based on data from patients with EORA in the CORONA database in comparison with those of age- and sex-matched patients with YORA [109]. The study [109] also showed that disease activity and disease severity were similar in both groups. Methotrexate (MTX) use was found to be higher in patients with EORA compared with those with YORA (63.9% vs. 59.6%), while mean MTX dose was found to be higher in patients with YORA. The number of patients using multiple conventional DMARDs or biological DMARDs was found to be lower in those with EORA compared with YORA. Treatment-related toxicity was similar in both groups, whereas toxicity due to MTX was found to be more frequent in the case of YORA. Despite similar disease duration, disease activity and severity, patients with EORA used combined conventional DMARDs and biological DMARDs less frequently compared with patients with YORA. It has been well documented that the age of onset determines the severity of the disease and the choice of treatment [110]. According to Swiss registries, the use of fırstline corticosteroids was significantly higher in patients with EORA compared with those with YORA, in contrast to the much lower follow-up on the use of biological drugs [111]. Genevay and colleagues evaluated 1571 patients with RA receiving anti-TNFα drugs [112] and demonstrated similar changes with drug withdrawal rates and mean Disease Activity Score (DAS28) score changes in both groups at the end of the second year. Despite clinical responses, improvement in Health Assessment Questionnaire (HAQ ) scores was significantly less in patients with EORA. TNF inhibitors were slightly less or equally effective in reducing disease activity in elderly compared with younger patients with HAQ scores showing less improvement in patients with EORA, especially in patients aged over 75 years [113]. There is limited evidence for the effectiveness of tocilizumab, abatacept, rituximab and tofacitinib in EORA. Tocilizumab was less effective in EORA compared with YORA, while the drug retention rate and discontinuation rates because of adverse events were similar between the two age groups [114]. There is no data on abatacept in EORA, while RCTs showed tofacitinib to be similarly effective in both EORA and YORA [115]. In terms of myopenia in both EORA and YORA, a recent study [116] indicates that EORA is characterized by more equal distribution of sex, higher frequency of acute onset with constitutional symptoms, more frequent involvement of large joints, and lower frequency of RF positivity. Earlier diagnosis, less erosive disease and less DMARD usage were reported as distinguishing patients with EORA from those with YORA. Further studies require the exploration of myopenia and its severity and impact on the prognosis of RA including both EORA and YORA, reflecting the above-mentioned concepts of secondary sarcopenia, cachexia and frailty with old age, potentially impacting RA prognosis in the presence of DMARD

**94**

side effects.

Myopenia and premature muscular aging in RA are similar concepts, raising a lot of research questions in terms of mechanism, lifestyle intervention, comorbidity management and new pharmacological approach. The chapter provides the platform for a discussion about the new term of myopenia and its impact.

## **Author details**

Dan Xu1,2\*, Jiake Xu3 and Lei Dai4

1 Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, Australia

2 Department of Medical Education, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

3 School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Australia

4 Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

\*Address all correspondence to: daniel.xu@curtin.edu.au

© 2020 The Author(s). Licensee IntechOpen. 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.

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[2] Narici MV, Maffulli N. Sarcopenia: Characteristics, mechanisms and functional significance. British Medical Bulletin. 2010;**95**:139-159

[3] Thomas DR. Loss of skeletal muscle mass in aging: Examining the relationship of starvation, sarcopenia and cachexia. Clinical Nutrition. 2007;**26**(4):389-399

[4] Goodpaster BH, Park SW, Harris TB, et al. The loss of skeletal muscle strength, mass, and quality in older adults: The health, aging and body composition study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2006;**61**:1059-1064

[5] Hughes VA, Frontera WR, Wood M, et al. Longitudinal muscle strength changes in older adults: Influence of muscle mass, physical activity, and health. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2001;**56**:B209-B217

[6] Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: Evidence for a phenotype. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2001;**56**(3):M146-M156

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[9] Carbonell J, Cobo T, Descalzo MA, et al. The incidence of rheumatoid arthritis in Spain: Results from a nationwide primary care registry. Rheumatology. 2008;**47**:1088-1092

[10] Rasch EK, Hirsch R, Paulose-Ram R, et al. Prevalence of rheumatoid arthritis in persons 60 years of age and older in the United States. Arthritis & Rheumatology. 2003;**48**:917-926

[11] Symmonds DPM, Barrett EM, Bankhead CR, et al. The incidence of rheumatoid arthritis in the United Kingdom: Results from the Norfolk arthritis register. British Journal of Rheumatology. 1994;**33**:735-739

[12] Xiang YJ, Dai SM. Prevalence of rheumatic diseases and disability in China. Rheumatology International. 2009;**29**:481-490. DOI: 10.1007/ s00296-008-0809-z

[13] Fearon K, Evans WJ, Anker SD. Myopenia—A new universal term for muscle wasting. Journal of Cachexia, Sarcopenia and Muscle. 2011;**2**:1-3. DOI: 10.1007/ s13539-011-0025-7

[14] Rosenberg IH. Sarcopenia: Origins and clinical relevance. Journal of Nutrition. 1997;**127**(Suppl):990S-991S

[15] Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age and Ageing. 2010;**39**:412-423

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[31] Kim EJ, Lee J, Ryu YS, et al. Shared epitope and radiologic progression are less prominent in elderly onset RA than young onset RA. Rheumatology International. 2013;**33**:2135-2140

et al. Independent association of rheumatoid factor and the HLA–DRB1 shared epitope with radiographic outcome in rheumatoid arthritis. Arthritis and Rheumatism.

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[19] Siparsky PN, Kirkendall DT, Garrett WE. Muscle changes in aging: Understanding sarcopenia. Sports

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D'Almeida V, Tufik S, et al. Associations between sleep conditions and body composition states: Results of the EPISONO study. Journal of Cachexia, Sarcopenia and Muscle. 2019;**10**:962- 973. DOI: 10.1002/jcsm.12445

[24] Roubenoff R, Roubenoff RA, Cannon JG, Kehayias JJ, Zhuang H,

[21] Molino S, Dossena M,

process. Age and strength loss. Muscles,

Age and Ageing. 2019;**48**:16-31

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*Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91270*

consensus on definition and diagnosis. Age and Ageing. 2019;**48**:16-31

[17] Dent E, Morley JE, Cruz-Jentoft AJ, et al. International clinical practice guidelines for sarcopenia (ICFSR): Screening, diagnosis and management. The Journal of Nutrition, Health & Aging. 2018;**22**:1148-1161

[18] Bauer J, Morley JE, Schols AMWJ, Ferrucci L, Cruz-Jentoft AJ, Dent E, et al. Sarcopenia: A time for action. An SCWD position paper journal of cachexia. Sarcopenia and Muscle. 2019;**10**:956-961

[19] Siparsky PN, Kirkendall DT, Garrett WE. Muscle changes in aging: Understanding sarcopenia. Sports Health. 2014;**6**:36-40

[20] Keller K, Engelhardt M. Strength and muscle mass loss with aging process. Age and strength loss. Muscles, Ligaments and Tendons Journal. 2013;**3**(4):346-350

[21] Molino S, Dossena M, Buonocore D, Verri M. Sarcopenic obesity: An appraisal of the current status of knowledge and management in elderly people. The Journal of Nutrition, Health & Aging. 2016;**20**:780-788

[22] Zamboni M, Mazzali G, Fantin F, Rossi A, Di Francesco V. Sarcopenic obesity: A new category of obesity in the elderly. Nutrition, Metabolism, and Cardiovascular Diseases. 2008;**18**:388-395

[23] Piovezan RD, Hirotsu C, Moizinho R, de Sá Souza H, D'Almeida V, Tufik S, et al. Associations between sleep conditions and body composition states: Results of the EPISONO study. Journal of Cachexia, Sarcopenia and Muscle. 2019;**10**:962- 973. DOI: 10.1002/jcsm.12445

[24] Roubenoff R, Roubenoff RA, Cannon JG, Kehayias JJ, Zhuang H, Dawson-Hughes B, et al. Rheumatoid cachexia: Cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. The Journal of Clinical Investigation. 1994;**93**:2379-2386. DOI: 10.1172/JCI117244

[25] Rajbhadary R, Khezri A, Panush RS. Rheumatoid cachexia: What is it and why is it important? The Journal of Rheumatology. 2011;**38**(3):406-408. DOI: 10.3899/jrheum.101036

[26] Roubenoff R. Rheumatoid cachexia: A complication of rheumatoid arthritis moves into the 21st century. Arthritis Research & Therapy. 2009;**11**:108

[27] Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis: An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis & Rheumatology. 1987;**30**:1205-1213

[28] Mattey DL, Hassell AB, Dawes PT, et al. Independent association of rheumatoid factor and the HLA–DRB1 shared epitope with radiographic outcome in rheumatoid arthritis. Arthritis and Rheumatism. 2001;**44**:1529-1533

[29] Weyand CM, Hicok KC, Conn DL, et al. The influence of HLA–DRB1 genes on disease severity in rheumatoid arthritis. Annals of Internal Medicine. 1992;**117**:801-806

[30] Gonzalez-Gay MA, Hajeer AH, Dababneh A, et al. Sero-negative rheumatoid arthritis in elderly and polymyalgia rheumatica have similar patterns of HLA association. Journal of Rheumatology. 2001;**28**:122-125

[31] Kim EJ, Lee J, Ryu YS, et al. Shared epitope and radiologic progression are less prominent in elderly onset RA than young onset RA. Rheumatology International. 2013;**33**:2135-2140

**96**

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

arthritis, based on the 1987 ACR criteria: A systematic review. Seminars

[9] Carbonell J, Cobo T, Descalzo MA, et al. The incidence of rheumatoid arthritis in Spain: Results from a nationwide primary care registry. Rheumatology. 2008;**47**:1088-1092

[10] Rasch EK, Hirsch R, Paulose-Ram R, et al. Prevalence of

rheumatoid arthritis in persons 60 years of age and older in the United States. Arthritis & Rheumatology.

[11] Symmonds DPM, Barrett EM, Bankhead CR, et al. The incidence of rheumatoid arthritis in the United Kingdom: Results from the Norfolk arthritis register. British Journal of Rheumatology. 1994;**33**:735-739

[12] Xiang YJ, Dai SM. Prevalence of rheumatic diseases and disability in China. Rheumatology International. 2009;**29**:481-490. DOI: 10.1007/

[13] Fearon K, Evans WJ, Anker SD. Myopenia—A new universal term for muscle wasting. Journal

of Cachexia, Sarcopenia and Muscle.

[14] Rosenberg IH. Sarcopenia: Origins and clinical relevance. Journal of Nutrition. 1997;**127**(Suppl):990S-991S

[16] Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: Revised European

[15] Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age and

Ageing. 2010;**39**:412-423

in Arthritis and Rheumatism.

2006;**36**:182-188

2003;**48**:917-926

s00296-008-0809-z

2011;**2**:1-3. DOI: 10.1007/ s13539-011-0025-7

[1] Mitchell WK, Williams J, Atherton P, Larvin M, Lund J, Narici M. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Frontiers in Physiology. 2012;**3**:260

[2] Narici MV, Maffulli N. Sarcopenia: Characteristics, mechanisms and functional significance. British Medical

Bulletin. 2010;**95**:139-159

**References**

2007;**26**(4):389-399

2006;**61**:1059-1064

[3] Thomas DR. Loss of skeletal muscle mass in aging: Examining the relationship of starvation, sarcopenia and cachexia. Clinical Nutrition.

[4] Goodpaster BH, Park SW, Harris TB, et al. The loss of skeletal muscle strength, mass, and quality in older adults: The health, aging and body composition study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences.

[5] Hughes VA, Frontera WR, Wood M, et al. Longitudinal muscle strength changes in older adults: Influence of muscle mass, physical activity, and health. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2001;**56**:B209-B217

[6] Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: Evidence for a phenotype. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences.

[7] Laiho K, Tuomilehto J, Tilvis R. Prevalence of rheumatoid arthritis and musculoskeletal diseases in the elderly population. Rheumatology International. 2001;**20**:85-87

[8] Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid

2001;**56**(3):M146-M156

[32] Hellier JP, Eliaou JF, Daur JP, et al. HLA-DRB1 genes and patients with late onset rheumatoid arthritis. Annals of the Rheumatic Diseases. 2001;**60**:531-533

[33] Wu H, Khanna D, Park G, et al. Interaction between RANKL and HLA-DRB1 genotypes may contribute to younger age at onset of seropositive rheumatoid arthritis in an inception cohort. Arthritis & Rheumatology. 2004;**50**:3093-3103

[34] Garatachea N, Lucía A. Genes and the ageing muscle: A review on genetic association studies. Age. 2013;**35**:207- 233. DOI: 10.1007/s11357-011-9327-0

[35] Nishimura K et al. Meta-analysis: Diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Annals of Internal Medicine. 2007;**146**:797-808

[36] Bizzaro N et al. Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis onset in patients with undifferentiated arthritis: Results from a 2-year prospective study. Arthritis Research & Therapy. 2013;**15**:R16

[37] Malmstrom V, Catrina AI, Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: From triggering to targeting. Nature Reviews. Immunology. 2017;**17**:60-75

[38] Padyukov L et al. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Annals of the Rheumatic Diseases. 2011;**70**:259-265

[39] Schuerwegh AJ et al. Evidence for a functional role of IgE anticitrullinated protein antibodies in rheumatoid arthritis. Proceedings of the National Academy of Sciences of the United States of America. 2010;**107**:2586-2591

[40] van Dongen H et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double-blind, randomized, placebo-controlled trial. Arthritis and Rheumatism. 2007;**56**:1424-1432

[41] Sellam J et al. B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six-month, national, multicenter, open-label study. Arthritis and Rheumatism. 2011;**63**:933-938

[42] Seegobin SD et al. ACPA-positive and ACPA-negative rheumatoid arthritis differ in their requirements for combination DMARDs and corticosteroids: Secondary analysis of a randomized controlled trial. Arthritis Research & Therapy. 2014;**16**:R13

[43] Raychaudhuri S et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nature Genetics. 2012;**44**:291-296

[44] Okada Y et al. Risk for ACPApositive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Human Molecular Genetics. 2014;**23**:6916-6926

[45] Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K. Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. Journal of Human Genetics. 2005;**50**:264-266

[46] Healey LA. Subsets of rheumatoid arthritis in the aged. Arthritis & Rheumatology. 1986;**29**:149

[47] Healey LA, Sheets PK. The relation of polymyalgia rheumatica to rheumatoid arthritis. Journal of Rheumatology. 1988;**15**:750-752

[48] McCartey DJ, O'Duffy JD, Pearson L, et al. Remitting seronegative

**99**

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elderly female patients with rheumatoid arthritis is associated with severe joint damage: A cross-sectional study. In: 2019 ACR/ARP Annual Meeting

[57] van Schaardenburg D, Hazes JM, de Boer A, et al. Outcome of rheumatoid

rheumatoid factor at diagnosis. Journal of Rheumatology. 1993;**20**:45-52

Seminars in Arthritis and Rheumatism.

[59] Chen DY, Hsieh TY, Chen YM, et al. Proinflammatory cytokine profiles of patients with elderly-onset rheumatoid

younger-onset disease. Gerontology.

[60] Pease CT, Bhakta BB, Devlin J, et al. Does the age of onset of rheumatoid arthritis influence phenotype? A prospective study of outcome and prognostic factors. Rheumatology

arthritis in relation to age and

[58] Cho SK, Sung YK, Choi CB, et al. Do patients with elderly-onset

rheumatoid arthritis have severe functional disability?

arthritis: A comparison with

(Oxford). 1999;**38**:228-234

of late-onset rheumatoid

2005;**24**:485-489

2016;**83**:511-515

2017;**23**:486-493

[61] Calvo-Alen J, Corrales A, Sanchez-Andrada S, et al. Outcome

arthritis. Clinical Rheumatology.

[62] Krams T, Ruyssen-Witrand A, Nigon D, et al. Effect of age at

[63] Wabe N, Wiese MD. Treating rheumatoid arthritis to target: Physician and patient adherence issues in contemporary rheumatoid

of Evaluation in Clinical Practice.

arthritis therapy. Journal

rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: The ESPOIR cohort. Joint, Bone, Spine.

2012;**42**:23-31

2009;**55**:250-258

Abstract 475

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symmetrical synovitis with pitting edema. JAMA. 1985;**254**:2763-2767

[49] Inoue K, Shichikawa K, Nishioka J, et al. Older age onset rheumatoid arthritis with or without osteoarthritis. Annals of the Rheumatic

Diseases. 1987;**46**:908-911

1990;**17**:1620-1622

2006;**42**:225-231

[50] Goemaere S, Ackerman C, Goethals K, et al. Onset of symptoms of rheumatoid arthritis in relation to age, sex and menopausal

[51] Ferraccioli GF, Cavalieri F, Mercandati M, et al. Clinical features, scintiscan characteristics and X-ray progression of late onset rheumatoid arthritis. Clinical and Experimental Rheumatology. 1984;**2**:157-161

[52] Türkçapar N, Demir O, Atli T, et al. Late onset rheumatoid arthritis: Clinical and laboratory comparisons with younger onset patients. Archives of Gerontology and Geriatrics.

[53] van der Heijde DM, van Riel PL, van Leeuwen MA, et al. Older versus younger onset rheumatoid arthritis: Results at onset and after 2 years of a prospective follow-up study of early rheumatoid arthritis. Journal of Rheumatology. 1991;**18**:1285-1289

[54] Lance NJ, Curran JJ. Late-onset, seropositive, erosive rheumatoid arthritis. Seminars in Arthritis and Rheumatism. 1993;**23**:177-182

[55] Lin JZ, Liang JJ, Ma JD, Li QH, Mo YQ, Cheng WM, et al. Myopenia is associated with joint damage in rheumatoid arthritis: A cross-sectional study. Journal of Cachexia, Sarcopenia and Muscle. 2019;**10**:355-367. DOI:

[56] Chen CT, Lin JZ, Ma JD, Li QH, Mo YQ, Chen LF, et al. Myopenia in

10.1002/jcsm.12381

transition. Journal of Rheumatology.

*Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis DOI: http://dx.doi.org/10.5772/intechopen.91270*

symmetrical synovitis with pitting edema. JAMA. 1985;**254**:2763-2767

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

[40] van Dongen H et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double-blind, randomized,

placebo-controlled trial. Arthritis and Rheumatism. 2007;**56**:1424-1432

[41] Sellam J et al. B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six-month, national, multicenter, open-label study. Arthritis and Rheumatism. 2011;**63**:933-938

[42] Seegobin SD et al. ACPA-positive and ACPA-negative rheumatoid arthritis differ in their requirements for combination DMARDs and corticosteroids: Secondary analysis of a randomized controlled trial. Arthritis Research & Therapy. 2014;**16**:R13

[43] Raychaudhuri S et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nature Genetics. 2012;**44**:291-296

[44] Okada Y et al. Risk for ACPApositive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European

populations. Human Molecular Genetics. 2014;**23**:6916-6926

Kobayashi K, Kawaida R, Yamamoto K. Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. Journal of Human Genetics.

[45] Mori M, Yamada R,

[46] Healey LA. Subsets of rheumatoid arthritis in the aged. Arthritis & Rheumatology. 1986;**29**:149

[47] Healey LA, Sheets PK. The relation of polymyalgia rheumatica to rheumatoid arthritis. Journal of Rheumatology. 1988;**15**:750-752

[48] McCartey DJ, O'Duffy JD,

Pearson L, et al. Remitting seronegative

2005;**50**:264-266

[32] Hellier JP, Eliaou JF, Daur JP, et al. HLA-DRB1 genes and patients with late onset rheumatoid arthritis. Annals of the Rheumatic Diseases.

[33] Wu H, Khanna D, Park G, et al. Interaction between RANKL and HLA-DRB1 genotypes may contribute to younger age at onset of seropositive rheumatoid arthritis in an inception cohort. Arthritis & Rheumatology.

[34] Garatachea N, Lucía A. Genes and the ageing muscle: A review on genetic association studies. Age. 2013;**35**:207- 233. DOI: 10.1007/s11357-011-9327-0

[35] Nishimura K et al. Meta-analysis: Diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Annals of Internal Medicine.

[36] Bizzaro N et al. Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis onset in patients with undifferentiated

arthritis: Results from a 2-year

[37] Malmstrom V, Catrina AI,

Therapy. 2013;**15**:R16

2011;**70**:259-265

prospective study. Arthritis Research &

Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: From triggering to targeting. Nature Reviews. Immunology. 2017;**17**:60-75

[38] Padyukov L et al. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Annals of the Rheumatic Diseases.

[39] Schuerwegh AJ et al. Evidence for a functional role of IgE anticitrullinated protein antibodies in rheumatoid arthritis. Proceedings of the National Academy of Sciences of the United States of America. 2010;**107**:2586-2591

2001;**60**:531-533

2004;**50**:3093-3103

2007;**146**:797-808

**98**

[49] Inoue K, Shichikawa K, Nishioka J, et al. Older age onset rheumatoid arthritis with or without osteoarthritis. Annals of the Rheumatic Diseases. 1987;**46**:908-911

[50] Goemaere S, Ackerman C, Goethals K, et al. Onset of symptoms of rheumatoid arthritis in relation to age, sex and menopausal transition. Journal of Rheumatology. 1990;**17**:1620-1622

[51] Ferraccioli GF, Cavalieri F, Mercandati M, et al. Clinical features, scintiscan characteristics and X-ray progression of late onset rheumatoid arthritis. Clinical and Experimental Rheumatology. 1984;**2**:157-161

[52] Türkçapar N, Demir O, Atli T, et al. Late onset rheumatoid arthritis: Clinical and laboratory comparisons with younger onset patients. Archives of Gerontology and Geriatrics. 2006;**42**:225-231

[53] van der Heijde DM, van Riel PL, van Leeuwen MA, et al. Older versus younger onset rheumatoid arthritis: Results at onset and after 2 years of a prospective follow-up study of early rheumatoid arthritis. Journal of Rheumatology. 1991;**18**:1285-1289

[54] Lance NJ, Curran JJ. Late-onset, seropositive, erosive rheumatoid arthritis. Seminars in Arthritis and Rheumatism. 1993;**23**:177-182

[55] Lin JZ, Liang JJ, Ma JD, Li QH, Mo YQ, Cheng WM, et al. Myopenia is associated with joint damage in rheumatoid arthritis: A cross-sectional study. Journal of Cachexia, Sarcopenia and Muscle. 2019;**10**:355-367. DOI: 10.1002/jcsm.12381

[56] Chen CT, Lin JZ, Ma JD, Li QH, Mo YQ, Chen LF, et al. Myopenia in elderly female patients with rheumatoid arthritis is associated with severe joint damage: A cross-sectional study. In: 2019 ACR/ARP Annual Meeting Abstract 475

[57] van Schaardenburg D, Hazes JM, de Boer A, et al. Outcome of rheumatoid arthritis in relation to age and rheumatoid factor at diagnosis. Journal of Rheumatology. 1993;**20**:45-52

[58] Cho SK, Sung YK, Choi CB, et al. Do patients with elderly-onset rheumatoid arthritis have severe functional disability? Seminars in Arthritis and Rheumatism. 2012;**42**:23-31

[59] Chen DY, Hsieh TY, Chen YM, et al. Proinflammatory cytokine profiles of patients with elderly-onset rheumatoid arthritis: A comparison with younger-onset disease. Gerontology. 2009;**55**:250-258

[60] Pease CT, Bhakta BB, Devlin J, et al. Does the age of onset of rheumatoid arthritis influence phenotype? A prospective study of outcome and prognostic factors. Rheumatology (Oxford). 1999;**38**:228-234

[61] Calvo-Alen J, Corrales A, Sanchez-Andrada S, et al. Outcome of late-onset rheumatoid arthritis. Clinical Rheumatology. 2005;**24**:485-489

[62] Krams T, Ruyssen-Witrand A, Nigon D, et al. Effect of age at rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: The ESPOIR cohort. Joint, Bone, Spine. 2016;**83**:511-515

[63] Wabe N, Wiese MD. Treating rheumatoid arthritis to target: Physician and patient adherence issues in contemporary rheumatoid arthritis therapy. Journal of Evaluation in Clinical Practice. 2017;**23**:486-493

[64] Aletah D, Smolen JS. Diagnosis and management of rheumatoid arthritis: A review. JAMA. 2018;**320**(13)

[65] Metsios GS, Stavropoulos-Kalinoglou A, Veldhuijzen van Zanten JJCS, Treharne GJ, Panoulas VF, Douglas KMJ, et al. Rheumatoid arthritis, cardiovascular disease and physical exercise: A systematic review. Rheumatology. 2008;**47**:239-248. DOI: 10.1093/rheumatology/kem260

[66] Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001;**358**:903-911

[67] Ekdahl C, Broman G. Muscle strength, endurance, and aerobic capacity in rheumatoid arthritis: A comparative study with healthy subjects. Annals of the Rheumatic Diseases. 1992;**51**:35-40

[68] de Jong Z, Munneke M, Zwinderman AH, et al. Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial. Arthritis and Rheumatism. 2003;**48**:2415-2424

[69] Hakkinen A. Effectiveness and safety of strength training in rheumatoid arthritis. Current Opinion in Rheumatology. 2004;**16**:132-137

[70] Cooney JK, Law R-J, Matschke V, Lemmey AB, Moore JP, Ahmad Y, et al. Benefits of exercise in rheumatoid arthritis. Journal of Aging Research. 2011; Article ID 681640, 14 p. DOI: 10.4061/2011/681640

[71] Al-Qubaeissy KY, Fatoye FA, Goodwin PC, et al. The effectiveness of hydrotherapy in the Management of Rheumatoid Arthritis: A systematic review Musculoskelet. Care. 2013;**11**:3-18

[72] Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: Implications for improved targeting and care. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2004;**59**:25563

[73] Espinoza SE, Fried LP. Risk factors for frailty in the older adult. Clinical Geriatrics. 2007;**15**:37-44

[74] Yao X, Li H, Leng SX. Inflammation and immune system alterations in frailty. Clinics in Geriatric Medicine. 2011;**27**:79-87

[75] Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research and clinical practice: A review. European Journal of Internal Medicine. 2016;**31**:3-10

[76] De Vries NM, Staal JB, van Ravensberg CD, Hobbelen JS, Olde Rikkert MG, Nijhuis-van Der Sanden MW. Outcome instruments to measure frailty: A systematic review. Ageing Research Reviews. 2011;**10**:104-114

[77] Haider S, Grabovac I, Berner C, Lamprecht T, Fenzl K-H, Erlacher L, et al. Frailty in seropositive rheumatoid arthritis patients of working age: A cross-sectional. Clinical and Experimental Rheumatology. 2019;**37**:585-592

[78] Armstrong EJ, Harskamp CT, Armstrong AW. Psoriasis and major adverse cardiovascular events: A systematic review and meta-analysis of observational studies. Journal of the American Heart Association. 2013;**2**:e000062. DOI: 10.1161/ JAHA.113.000062

[79] Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: A meta-analysis of observational studies.

**101**

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Erikson JM, Restrepo JF, et al. Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Annals of the Rheumatic Diseases.

2015;**74**:1118-1123

[87] Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB. Heart disease and stroke statistics—2013 update: A report from the American Heart Association.

Circulation. 2013;**127**:e6-e245

[88] Kalogeropoulos A, Georgiopoulou V, Psaty BM, Rodondi N, Smith AL, Harrison DG, et al. Inflammatory markers and incident heart failure risk in older adults: The health ABC (health, aging, and body composition) study. Journal of the American College of Cardiology. 2010;**55**:2129-2137

[89] Aslam F, Bandeali SJ, Khan NA, Alam M. Diastolic dysfunction in rheumatoid arthritis: A meta-analysis and systematic review. Arthritis Care and Research. 2013;**65**:534-543

[90] Cioffi G, Viapiana O, Ognibeni F, Dalbeni A, Giollo A, Gatti D, et al. Prognostic role of subclinical left ventricular systolic dysfunction evaluated by speckle-tracking echocardiography in rheumatoid arthritis. Journal of the American Society of Echocardiography.

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2010;**37**:711-716

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arthritis: Effect of treatment. The Journal of Rheumatology.

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Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial dysfunction, arterial stiffness, and heart failure. Journal of the American College of Cardiology. 2012;**60**:1455-1469

Lip GY, Blann AD. Inflammation and microvascular and macrovascular endothelial dysfunction in rheumatoid

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Annals of the Rheumatic Diseases.

[81] Soubrier M, Barber Chamoux N, Tatar Z, Couderc M, Dubost JJ, Mathieu S. Cardiovascular risk in rheumatoid arthritis. Joint, Bone, Spine.

Lindhardsen J, Olesen JB, et al. Psoriasis is associated with clinically significant

[82] Ahlehoff O, Gislason GH, Charlot M, Jorgensen CH,

cardiovascular risk: A Danish nationwide cohort study. Journal of Internal Medicine. 2011;**270**:147-157

[83] Brady SR, de Courten B, Reid CM, Cicuttini FM, de Courten MP, Liew D. The role of traditional cardiovascular risk factors among patients with rheumatoid arthritis. The Journal of Rheumatology.

[84] Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Torp-Pedersen C, et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: A Danish nationwide cohort study. Annals of the Rheumatic Diseases. 2011;**70**(6):929- 934. DOI: 10.1136/ard.2010.143396

[85] Peters MJ, van Halm VP,

2009;**61**:1571-1579

[86] del Rincon I, Polak JF, O'Leary DH, Battafarano DF,

Voskuyl AE, Smulders YM, Boers M, Lems WF, et al. Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis and Rheumatism.

[80] Filimon AM, Negreanu L, Doca M, Ciobanu A, Preda CM, Vinereanu D. Cardiovascular involvement in inflammatory bowel disease: Dangerous liaisons. World Journal of Gastroenterology.

2012;**71**:1524-1529

2015;**21**:9688-9692

2014;**81**:298-302

2009;**36**:34-40

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Annals of the Rheumatic Diseases. 2012;**71**:1524-1529

*Rheumatoid Arthritis - Other Perspectives towards a Better Practice*

the concepts of disability, frailty, and comorbidity: Implications for improved targeting and care. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences.

[73] Espinoza SE, Fried LP. Risk factors for frailty in the older adult. Clinical

[74] Yao X, Li H, Leng SX. Inflammation and immune system alterations in frailty. Clinics in Geriatric Medicine.

[75] Dent E, Kowal P, Hoogendijk EO. Frailty measurement in research and clinical practice: A review. European

Journal of Internal Medicine.

[76] De Vries NM, Staal JB, van Ravensberg CD, Hobbelen JS, Olde Rikkert MG, Nijhuis-van Der Sanden MW. Outcome instruments to measure frailty: A systematic review. Ageing Research Reviews.

[77] Haider S, Grabovac I, Berner C, Lamprecht T, Fenzl K-H, Erlacher L, et al. Frailty in seropositive rheumatoid arthritis patients of working age: A cross-sectional. Clinical and Experimental Rheumatology.

[78] Armstrong EJ, Harskamp CT, Armstrong AW. Psoriasis and major adverse cardiovascular events: A systematic review and meta-analysis of observational studies. Journal of the American Heart Association. 2013;**2**:e000062. DOI: 10.1161/

[79] Avina-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: A meta-analysis of observational studies.

2004;**59**:25563

2011;**27**:79-87

2016;**31**:3-10

2011;**10**:104-114

2019;**37**:585-592

JAHA.113.000062

Geriatrics. 2007;**15**:37-44

[64] Aletah D, Smolen JS. Diagnosis and management of rheumatoid arthritis: A

Zanten JJCS, Treharne GJ, Panoulas VF, Douglas KMJ, et al. Rheumatoid arthritis, cardiovascular disease and physical exercise: A systematic review.

Rheumatology. 2008;**47**:239-248. DOI:

10.1093/rheumatology/kem260

[67] Ekdahl C, Broman G. Muscle strength, endurance, and aerobic capacity in rheumatoid arthritis: A comparative study with healthy subjects. Annals of the Rheumatic

[66] Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet.

2001;**358**:903-911

Diseases. 1992;**51**:35-40

[68] de Jong Z, Munneke M,

[69] Hakkinen A. Effectiveness and safety of strength training in rheumatoid arthritis. Current Opinion in Rheumatology. 2004;**16**:132-137

10.4061/2011/681640

[70] Cooney JK, Law R-J, Matschke V, Lemmey AB, Moore JP, Ahmad Y, et al. Benefits of exercise in rheumatoid arthritis. Journal of Aging Research. 2011; Article ID 681640, 14 p. DOI:

[71] Al-Qubaeissy KY, Fatoye FA, Goodwin PC, et al. The effectiveness of hydrotherapy in the Management of Rheumatoid Arthritis: A systematic

review Musculoskelet. Care.

[72] Fried LP, Ferrucci L, Darer J,

Williamson JD, Anderson G. Untangling

Zwinderman AH, et al. Is a long-term high-intensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial. Arthritis and Rheumatism. 2003;**48**:2415-2424

review. JAMA. 2018;**320**(13)

[65] Metsios GS, Stavropoulos-Kalinoglou A, Veldhuijzen van

**100**

2013;**11**:3-18

[80] Filimon AM, Negreanu L, Doca M, Ciobanu A, Preda CM, Vinereanu D. Cardiovascular involvement in inflammatory bowel disease: Dangerous liaisons. World Journal of Gastroenterology. 2015;**21**:9688-9692

[81] Soubrier M, Barber Chamoux N, Tatar Z, Couderc M, Dubost JJ, Mathieu S. Cardiovascular risk in rheumatoid arthritis. Joint, Bone, Spine. 2014;**81**:298-302

[82] Ahlehoff O, Gislason GH, Charlot M, Jorgensen CH, Lindhardsen J, Olesen JB, et al. Psoriasis is associated with clinically significant cardiovascular risk: A Danish nationwide cohort study. Journal of Internal Medicine. 2011;**270**:147-157

[83] Brady SR, de Courten B, Reid CM, Cicuttini FM, de Courten MP, Liew D. The role of traditional cardiovascular risk factors among patients with rheumatoid arthritis. The Journal of Rheumatology. 2009;**36**:34-40

[84] Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Torp-Pedersen C, et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: A Danish nationwide cohort study. Annals of the Rheumatic Diseases. 2011;**70**(6):929- 934. DOI: 10.1136/ard.2010.143396

[85] Peters MJ, van Halm VP, Voskuyl AE, Smulders YM, Boers M, Lems WF, et al. Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis and Rheumatism. 2009;**61**:1571-1579

[86] del Rincon I, Polak JF, O'Leary DH, Battafarano DF, Erikson JM, Restrepo JF, et al. Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Annals of the Rheumatic Diseases. 2015;**74**:1118-1123

[87] Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB. Heart disease and stroke statistics—2013 update: A report from the American Heart Association. Circulation. 2013;**127**:e6-e245

[88] Kalogeropoulos A, Georgiopoulou V, Psaty BM, Rodondi N, Smith AL, Harrison DG, et al. Inflammatory markers and incident heart failure risk in older adults: The health ABC (health, aging, and body composition) study. Journal of the American College of Cardiology. 2010;**55**:2129-2137

[89] Aslam F, Bandeali SJ, Khan NA, Alam M. Diastolic dysfunction in rheumatoid arthritis: A meta-analysis and systematic review. Arthritis Care and Research. 2013;**65**:534-543

[90] Cioffi G, Viapiana O, Ognibeni F, Dalbeni A, Giollo A, Gatti D, et al. Prognostic role of subclinical left ventricular systolic dysfunction evaluated by speckle-tracking echocardiography in rheumatoid arthritis. Journal of the American Society of Echocardiography. 2017;**30**:602-611

[91] Foster W, Carruthers D, Lip GY, Blann AD. Inflammation and microvascular and macrovascular endothelial dysfunction in rheumatoid arthritis: Effect of treatment. The Journal of Rheumatology. 2010;**37**:711-716

[92] Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial dysfunction, arterial stiffness, and heart failure. Journal of the American College of Cardiology. 2012;**60**:1455-1469

[93] Midtbo H, Semb AG, Matre K, Kvien TK, Gerdts E. Disease activity is associated with reduced left ventricular systolic myocardial function in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 2017;**76**:371-376

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[97] Nicola PJ, Maradit-Kremers H, Roger VL, Jacobsen SJ, Crowson CS, Ballman KV, et al. The risk of congestive heart failure in rheumatoid arthritis: A population-based study over 46 years. Arthritis and Rheumatism. 2005;**52**:412-420

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[100] Masoud S, Lim PB, Kitas GD, Panoulas V. Sudden cardiac death in patients with rheumatoid arthritis. World Journal of Cardiology. 2017;**9**(7):562-573

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[109] Tutuncu Z, Reed G, Kremer J, et al. Do patients with older-onset rheumatoid arthritis receive less aggressive treatment? Annals of the Rheumatic Diseases. 2006;**65**:1226-1229

[110] Innala L, Berglin E, Moler B, et al. Age at onset determines severity and choice of treatment in early rheumatoid arthritis: A prospective study. Arthritis Research & Therapy. 2014;**16**:R94

[111] Mueller RB, Reshiti N, Kaegi T, et al. Does addition of glucocorticoids to the initial therapy influence the later course of the disease in patients with early RA? Results from the Swiss prospective observational registry (SCQM). Clinical Rheumatology. 2017;**36**:59-66

[112] Genevay S, Finckh A, Ciurea A, et al. Tolerance and effectiveness of anti-tumor necrosis-alpha therapies in elderly patients with rheumatoid arthritis: A population based cohort study. Arthritis and Rheumatism. 2007;**57**:679-685

[113] Bathon JM, Fleischmann RM, Van der Heijde D, et al. Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. The Journal of Rheumatology. 2006;**33**:234-243

[114] Pers YM, Schaub R, Constant E, et al. Efficacy and safety of tocilizumab in elderly patients with rheumatoid arthritis. Joint, Bone, Spine. 2015;**82**:25-30

[115] Curtis JR, Schulze-Koops H, Takiya L, et al. Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 2013;**65** (Suppl 10):2331

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Section 4

Medical and Patient Self

Management Programs in

Rheumatoid Arthritis

## Section 4
