**4. Rheumatoid arthritis (RA)**

RA is a chronic inflammatory systemic disorder which primarily involves the joint synovial membrane. The purpose of this chapter section is to describe the occurrence and pathophysi‐ ology of vasculitis and vasculopathy in RA.

#### **4.1. Rheumatoid vasculitis**

Rheumatoid vasculitis typically affects small and medium-size blood vessels. It is associated with high rates of premature mortality with up to 40% of patients dying by 5 years as well as significant morbidity due to both organ damage from vasculitis and consequences of the treatment [89, 90]. Diagnostic criteria for systemic rheumatoid vasculitis were proposed in 1984 by Scott et al. [91], although the classification of RA-associated vasculitis remains poorly codified. It shares many characteristics with a classic polyarteritis nodosa and may affect peripheral nerves, causing mononeuritis multiplex, skin, gastrointestinal tract, and other organs, but it is not usually associated with the development of microaneurysms [92]. High levels of circulating immune complexes have been observed in patients with rheumatoid vasculitis [93], and in particular high serum levels of rheumatoid factor are often detected at the time of onset of vasculitis [94]. Deposition of immune complexes most likely contributes to small vessel inflammation and organ damage. Anti CCP levels also tend to be higher in patients with RA who have systemic vasculitis than in those who do not. Rheumatoid vasculitis has been reported in a substantial number of patients with RA [95]. It is more common in men and patients with longstanding disease [91]. The annual incidence of rheumatoid vasculitis in men to be 15.8 per million and in women, 9.4 per million [95]. Nevertheless, the 30-year incidence of vasculitis in patients with RA was estimated to be 3.6% [96].

Predictors of vasculitis in RA patients include clinical and generic factors (Table 2) [97-103]. Smoking, which is also a risk factor for development of RA in the general population [104], is associated with an increased risk of vasculitis among patients with RA [99, 100]. Rheumatoid nodules early during the disease predict the occurrence of systemic rheumatoid vasculitis [97, 98]. However, genetic predisposition toward developed RA, as HLA-DRB1-shared epitope genotypes is strongly associated with extraarticular disease manifestations such as rheumatoid vasculitis [101, 102]. In particular, double dose of RA-associated HLADRB1\*04 alleles is associated with an increased risk of vasculitis [105]. Rheumatoid vasculitis is associated with an increased mortality as compared with that in patients with RA in general [89]. In particular, a poor survival has been observed after diagnosis of vasculitis-related neuropathy [106]. In such patients, a low serum level of complement factor C4 is a negative prognostic marker [90]. The increased mortality may be due to a high risk of cardiovascular comorbidity [107, 108] and severe infections [109].


#### **Table 2.** Predictors for vasculitis in RA patients

[2] some of them, as cytomegalovirus, may permeate and activate endothelial cells leading to vasculitis and [3] bacterial *Staphylococcus* antigens, as for example neutral phosphatase, may bind with basement membranes and adhere specifically to IgG, which in turn induces an

RA is a chronic inflammatory systemic disorder which primarily involves the joint synovial membrane. The purpose of this chapter section is to describe the occurrence and pathophysi‐

Rheumatoid vasculitis typically affects small and medium-size blood vessels. It is associated with high rates of premature mortality with up to 40% of patients dying by 5 years as well as significant morbidity due to both organ damage from vasculitis and consequences of the treatment [89, 90]. Diagnostic criteria for systemic rheumatoid vasculitis were proposed in 1984 by Scott et al. [91], although the classification of RA-associated vasculitis remains poorly codified. It shares many characteristics with a classic polyarteritis nodosa and may affect peripheral nerves, causing mononeuritis multiplex, skin, gastrointestinal tract, and other organs, but it is not usually associated with the development of microaneurysms [92]. High levels of circulating immune complexes have been observed in patients with rheumatoid vasculitis [93], and in particular high serum levels of rheumatoid factor are often detected at the time of onset of vasculitis [94]. Deposition of immune complexes most likely contributes to small vessel inflammation and organ damage. Anti CCP levels also tend to be higher in patients with RA who have systemic vasculitis than in those who do not. Rheumatoid vasculitis has been reported in a substantial number of patients with RA [95]. It is more common in men and patients with longstanding disease [91]. The annual incidence of rheumatoid vasculitis in men to be 15.8 per million and in women, 9.4 per million [95]. Nevertheless, the 30-year

Predictors of vasculitis in RA patients include clinical and generic factors (Table 2) [97-103]. Smoking, which is also a risk factor for development of RA in the general population [104], is associated with an increased risk of vasculitis among patients with RA [99, 100]. Rheumatoid nodules early during the disease predict the occurrence of systemic rheumatoid vasculitis [97, 98]. However, genetic predisposition toward developed RA, as HLA-DRB1-shared epitope genotypes is strongly associated with extraarticular disease manifestations such as rheumatoid vasculitis [101, 102]. In particular, double dose of RA-associated HLADRB1\*04 alleles is associated with an increased risk of vasculitis [105]. Rheumatoid vasculitis is associated with an increased mortality as compared with that in patients with RA in general [89]. In particular, a poor survival has been observed after diagnosis of vasculitis-related neuropathy [106]. In such patients, a low serum level of complement factor C4 is a negative prognostic marker [90].

incidence of vasculitis in patients with RA was estimated to be 3.6% [96].

immune response and an inflammatory process.

**4. Rheumatoid arthritis (RA)**

172 Updates in the Diagnosis and Treatment of Vasculitis

**4.1. Rheumatoid vasculitis**

ology of vasculitis and vasculopathy in RA.

According to the data from the literature very little is known of what events trigger the development of vasculits in RA patients at a particular time point. This probably includes a number of different infectious agents and other immune exposures. For example, rare cases of rheumatoid vasculitis following influenza vaccination have been described [110].

#### **4.2. Clinical manifestations of rheumatoid vasculits**

Rheumatoid vasculitis often affects more than single organ. Patients may develop nailfold infarcts and leg ulcers. These patients may go on to have more widespread vascular disease but usually do not [111]. Cutaneous manifestations of rheumatoid vasculitis may present as digital digital infarcts, livedo, palpable purpura, bulla, ulcerations, painful nodules, or gangrene. Histologically, rheumatoid vasculitis involves blood vessels of the small arteries, and all layers of the vessel wall are infiltrated by neutrophils, lymphocytes, and plasma cells. Cutaneous manifestation of rheumatoid vasculitis is classified into three grades: severe, moderate, and mild. The severe type presents with digital gangrene, nail fold infarcts, large cutaneous ulcers; the moderate type presents with palpable purpura; and the mild type presents with nailfold telangiectasias with thromboses, minute digital ulcerations, petechiae, and livedo reticularis. Minor bleeding from the nail folds, finger pulp, and the edge of the nails results from digital infarcts (isolated nailfold vasculitis) [112]. RA patients who develop leg ulcers and digital ulcers should be more closely monitored, especially patients who have high titers of rheumatoid factor, positive anti CCPs, cryoglobulins, and low complements, as more ominous manifestations of RA are more likely to occur in these patients [113]. The diagnosis of leg ulcers in patients with RA is often associated with trivial trauma. There is often an underlying vasculitis, which promotes the lesion.

Systemic vasculitis in RA usually occurs in patients who have longstanding disease, generally of more than 10-year duration. Even so, it may occur at any time during the disease course, and, irrespective of when it occurs, it is associated with a poor prognosis. From a clinical standpoint, patients have more severe RA with destructive joint disease and other features of extraarticular disease [98]. Patients with Felty's syndrome are particularly prone to develop rheumatoid vasculitis. The appearance of rheumatoid vasculitis may be associated with a rise in acute-phase markers, including the sedimentation rate and C-reactive protein, together with longstanding thrombocytosis and anemia of chronic disease [98]. RA-associated vasculitis may involve any blood vessel bed in the body, including cerebral, mesenteric, and coronary arteries [114]. More severe features of rheumatoid vasculitis are frank infarctions of the digits and mononeuritis multiplex [113, 115]. Unfortunately, patients with systemic rheumatoid vascu‐ litis may develop mononeuritis multiplex [116]. Mononeuritis in RA often begins with numbness and then progresses to tingling and muscle weakness. Initially, the mononeuritis is asymmetric but may become symmetrical. Other early manifestations of rheumatoid vasculitis include pericarditis and scleritis. Rheumatoid vasculitis is also strongly associated with the presence of rheumatoid nodules, and most RA patients with vasculitis have nodulosis [98]. Rheumatoid vasculitis may also affect the coronary arteries. In the kidney, renal artery involvement, as occurs in polyarteritis nodosa with vasculitis, may cause renal failure, although the disorder should be distinct from polyarteritis nodosa [117, 118].

**4.4. Vasculopathy in RA**

**5. Conclusion**

Atherogenesis is a precocious feature in RA, as extraarticular manifestation of the syn‐ drome, and might be defined as rheumatoid vasculopathy. RA has been associated with precocious and accelerated atherosclerosis [128-134] and with increased CV morbidity and mortality [135]. Notably, atherosclerosis has been proposed as extraarticular manifesta‐ tion of the disease [130]. Several disease-related mechanisms may be involved in the development of premature vascular damage in RA, including increased synthesis of proinflammatory mediators (such as cytokines, chemokines, adhesion molecules), autoanti‐ bodies against endothelial cell components, perturbations in T-cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, and abnormal vascular repair, as well as iatrogenic factors [136, 137]. Hyperhomocysteinemia, which is a common finding in patients with RA, is a further contributor to the impaired endothelial function, potenti‐ ates the oxidation of lipoproteins, and has prothrombotic effects [138]. Inflammation severity was found to be associated with functional and structural arterial wall changes in patients with recent RA onset, and early control of inflammation is associated with

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improved arterial function that may reduce atherosclerosis progression [139].

not cause the fever, pain, and local tenderness associated with vasculitis.

Vascular damage in humans develops on various grounds. It may be inflammatory or noninflammatory. The damages may be induced by environmental factors (toxic agents, medications, microorganisms), through cancer as a paraneoplastic syndrome, or may be directly associated with an active immune process. Distinguishing between noninflammatory vasculopathy and vasculitis can pose a significant diagnostic challenge in the absence of histological examination. Vasculitis should not be confused with *vasculopathy*, which simply means something is wrong with the blood vessels, although it's usually not vasculitis. When a blood vessel becomes inflamed and narrowed, blood supply to that area can become partially or completely blocked. Complete blockage is called *occlusion*; it causes the vessel wall to swell and makes things stick to the wall -- so a clot forms. When vasculitis interferes with circulation in any part of the body, it causes local tenderness and pain. If the blood vessels are close to the skin, characteristic *rashes* occur. Depending on where the blockage occurs, almost any organ in the body can be affected. However, vasculopathy can also block blood vessels, but it does

As this chapter illustrates, vascular involvement is an important part in the RA, SLE and SSc pathogenesis. Vasculitis in RA is generally associated with longstanding disease, has an important impact on s patient's well being and markedly influences patient life expectancy. Predictors of vasculitis in RA patients include clinical and genetic factors. Vaculitis in RA generally affects small and medium-seized vessels. It shares many characteristics with a classic polyarteritis nodosa and may affect peripheral nerves, causing mononeuritis multiplex, skin, gastrointestinal tract and other organs. It is not usually associated with the development of microaneurysms. Atherogenesis is a precocious feature in RA, as extraarticular manifestation

Rheumatoid vasculitis is an unusual complication of RA, which has profound impact on disease severity and life expectancy of patients who develop this extraarticular disease manifestation.

#### **4.3. Angiogenesis in RA**

RA is the rheumatic disease in which the role of angiogenesis has been studied most exten‐ sively; it is characterized by excessive angiogenesis [119]. Proangiogenic mediators associated with RA include the following: growth factors such as VEGF; cytokines such as TNF-α (which has many effects in addition to angiogenesis); chemokines such as IL-8; and other mediators, including ET-1. VEGF, an endothelial selective mitogen that is secreted predominantly by macrophages, is an important cytokine in both angiogenesis and vasculogenesis [120]. In RA, VEGF expression is induced by hypoxia. Hypoxic environment of the inflamed RA joint activates the VEGF gene via binding of hypoxia inducible factor. This in turn augments IL-1 or transforming growth factor (TGF)-β induced synovial fibroblast VEGF [121], which contributes significantly to angiogenesis in the synovium and progression of RA. Evidence of the importance of TNF-α as a proangiogenic mediator in RA is illustrated by the effect of giving anti-TNF-a to patients with RA. Administration of anti-TNF-α drugs to patients with RA leads to vascular deactivation, including decreased angiogenesis and endothelial cell markers [122]. Chemokines are also very important in angiogenesis in RA. Recent studies have shown that the chemokine IL-8/CXC chemokine ligand (CXCL)8 plays a role in the pathogenesis of RA synovitis. This molecule is angiogenic and appears to be responsible for much of the macro‐ phage-derived angiogenic activity seen in RA [123]. In addition to its well recognized effects as a potent endogenous vasoconstrictor and smooth muscle mitogen, ET-1 also appears to have proangiogenic effects in some rheumatic diseases. In patients with RA, levels of ET-1 in synovial fluid, serum and plasma are elevated in comparison with those in normal individuals [124-127]. Although this clearly does not demonstrate a causal role for ET-1 in the pathophysi‐ ology of RA, it may suggest some degree of involvement.

#### **4.4. Vasculopathy in RA**

extraarticular disease [98]. Patients with Felty's syndrome are particularly prone to develop rheumatoid vasculitis. The appearance of rheumatoid vasculitis may be associated with a rise in acute-phase markers, including the sedimentation rate and C-reactive protein, together with longstanding thrombocytosis and anemia of chronic disease [98]. RA-associated vasculitis may involve any blood vessel bed in the body, including cerebral, mesenteric, and coronary arteries [114]. More severe features of rheumatoid vasculitis are frank infarctions of the digits and mononeuritis multiplex [113, 115]. Unfortunately, patients with systemic rheumatoid vascu‐ litis may develop mononeuritis multiplex [116]. Mononeuritis in RA often begins with numbness and then progresses to tingling and muscle weakness. Initially, the mononeuritis is asymmetric but may become symmetrical. Other early manifestations of rheumatoid vasculitis include pericarditis and scleritis. Rheumatoid vasculitis is also strongly associated with the presence of rheumatoid nodules, and most RA patients with vasculitis have nodulosis [98]. Rheumatoid vasculitis may also affect the coronary arteries. In the kidney, renal artery involvement, as occurs in polyarteritis nodosa with vasculitis, may cause renal failure,

although the disorder should be distinct from polyarteritis nodosa [117, 118].

ology of RA, it may suggest some degree of involvement.

manifestation.

**4.3. Angiogenesis in RA**

174 Updates in the Diagnosis and Treatment of Vasculitis

Rheumatoid vasculitis is an unusual complication of RA, which has profound impact on disease severity and life expectancy of patients who develop this extraarticular disease

RA is the rheumatic disease in which the role of angiogenesis has been studied most exten‐ sively; it is characterized by excessive angiogenesis [119]. Proangiogenic mediators associated with RA include the following: growth factors such as VEGF; cytokines such as TNF-α (which has many effects in addition to angiogenesis); chemokines such as IL-8; and other mediators, including ET-1. VEGF, an endothelial selective mitogen that is secreted predominantly by macrophages, is an important cytokine in both angiogenesis and vasculogenesis [120]. In RA, VEGF expression is induced by hypoxia. Hypoxic environment of the inflamed RA joint activates the VEGF gene via binding of hypoxia inducible factor. This in turn augments IL-1 or transforming growth factor (TGF)-β induced synovial fibroblast VEGF [121], which contributes significantly to angiogenesis in the synovium and progression of RA. Evidence of the importance of TNF-α as a proangiogenic mediator in RA is illustrated by the effect of giving anti-TNF-a to patients with RA. Administration of anti-TNF-α drugs to patients with RA leads to vascular deactivation, including decreased angiogenesis and endothelial cell markers [122]. Chemokines are also very important in angiogenesis in RA. Recent studies have shown that the chemokine IL-8/CXC chemokine ligand (CXCL)8 plays a role in the pathogenesis of RA synovitis. This molecule is angiogenic and appears to be responsible for much of the macro‐ phage-derived angiogenic activity seen in RA [123]. In addition to its well recognized effects as a potent endogenous vasoconstrictor and smooth muscle mitogen, ET-1 also appears to have proangiogenic effects in some rheumatic diseases. In patients with RA, levels of ET-1 in synovial fluid, serum and plasma are elevated in comparison with those in normal individuals [124-127]. Although this clearly does not demonstrate a causal role for ET-1 in the pathophysi‐

Atherogenesis is a precocious feature in RA, as extraarticular manifestation of the syn‐ drome, and might be defined as rheumatoid vasculopathy. RA has been associated with precocious and accelerated atherosclerosis [128-134] and with increased CV morbidity and mortality [135]. Notably, atherosclerosis has been proposed as extraarticular manifesta‐ tion of the disease [130]. Several disease-related mechanisms may be involved in the development of premature vascular damage in RA, including increased synthesis of proinflammatory mediators (such as cytokines, chemokines, adhesion molecules), autoanti‐ bodies against endothelial cell components, perturbations in T-cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress, and abnormal vascular repair, as well as iatrogenic factors [136, 137]. Hyperhomocysteinemia, which is a common finding in patients with RA, is a further contributor to the impaired endothelial function, potenti‐ ates the oxidation of lipoproteins, and has prothrombotic effects [138]. Inflammation severity was found to be associated with functional and structural arterial wall changes in patients with recent RA onset, and early control of inflammation is associated with improved arterial function that may reduce atherosclerosis progression [139].

#### **5. Conclusion**

Vascular damage in humans develops on various grounds. It may be inflammatory or noninflammatory. The damages may be induced by environmental factors (toxic agents, medications, microorganisms), through cancer as a paraneoplastic syndrome, or may be directly associated with an active immune process. Distinguishing between noninflammatory vasculopathy and vasculitis can pose a significant diagnostic challenge in the absence of histological examination. Vasculitis should not be confused with *vasculopathy*, which simply means something is wrong with the blood vessels, although it's usually not vasculitis. When a blood vessel becomes inflamed and narrowed, blood supply to that area can become partially or completely blocked. Complete blockage is called *occlusion*; it causes the vessel wall to swell and makes things stick to the wall -- so a clot forms. When vasculitis interferes with circulation in any part of the body, it causes local tenderness and pain. If the blood vessels are close to the skin, characteristic *rashes* occur. Depending on where the blockage occurs, almost any organ in the body can be affected. However, vasculopathy can also block blood vessels, but it does not cause the fever, pain, and local tenderness associated with vasculitis.

As this chapter illustrates, vascular involvement is an important part in the RA, SLE and SSc pathogenesis. Vasculitis in RA is generally associated with longstanding disease, has an important impact on s patient's well being and markedly influences patient life expectancy. Predictors of vasculitis in RA patients include clinical and genetic factors. Vaculitis in RA generally affects small and medium-seized vessels. It shares many characteristics with a classic polyarteritis nodosa and may affect peripheral nerves, causing mononeuritis multiplex, skin, gastrointestinal tract and other organs. It is not usually associated with the development of microaneurysms. Atherogenesis is a precocious feature in RA, as extraarticular manifestation of the syndrome, and might be defined as rheumatoid vasculopathy. Several disease-related mechanisms may be involved in the development of premature vascular damage in RA. Increased synthesis of proinflammatory mediators, autoantibodies against endothelial cell components, perturbations in T-cell subsets, genetic polymorphisms, hyperhomocysteinemia, oxidative stress and abnormal vascular repair are associated with atherosclerosis in RA.

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Vascular involvement in SLE may be of inflammatory or thrombotic origin. Both mechanisms involve the immune system. The activation and consequent endothelial lesions play a very important role in the disease pathogenesis. The common hypothesis for vasculopathy in SLE concerns the endothelial deposition of circulating immune complexes. There are many various autoantibodies in SLE as circulating immune complexes which directly or indirectly affect endothelial cells, causing chronic vessel wall damage. Furthermore, vasculitis in SLE is proatherogenic condition and is characterized by leucocytes activation and production of cytokine and other inflammatory mediators.

Although SSc is considered a fibrosing disease, vascular involvement plays a major role in pathogenesis and organ dysfunction. SSc vascular disease involves vasculopathy with luminal occlusion, thrombosis and vasospasm. The vascular pathology in SSc is not necessarily an inflammatory process and would be better be characterised as a vasculopathy in the absence of vasculitis. In the current pathogenic model of SSc, a vascular injury of unknown cause leads to endothelial apoptosis and initiates the process of SSc vasculopathy. Histopathology of SSc vasculopathy reflects the underlying pathogenesis, with myofibroblast proliferation and matrix deposit in the subendothelial layer leading to obliterative thickening of vessel walls. Inflammatory infiltrates are absent, and the internal elastic lamina remains intact. In contrast to vasculopathy, concurrent vasculitis in SSc shows histopathological evidence of inflamma‐ tion with presence of mononuclear infiltrates and destruction of the vascular wall.
