**2. History**

Purpura was the first manifestation of vasculitis in vessels smaller than arteries. In 1808, Willan clearly distinguished purpura caused by infections from non-infectious purpura [8]. Over the next century, Henoch and his teacher, Schönlein, described a broad spectrum of signs and symptoms that were associated with purpura, and with small vessel vasculitis, including arthritis, peripheral neuropathy, abdominal pain, pulmonary hemorrhage, epistaxis, iritis, and nephritis [9].

In 1866, Kussmaul and Maier described a patient with general weakness caused by vasculitic neuropathy accompanied by tachycardia, abdominal pain, and the appearance of cutaneous nodules over the trunk. The patient's muscle paralysis progressed quickly causing death. At autopsy, visible nodules were present along the medium-sized arteries of the patient [10]. Kussmaul and Maier named this disease "periarteritis nodosa" because they observed inflammation in the perivascular sheaths and outer layers of the arterial walls and nodular thickening of the vessels. However, the name was later changed to "polyarteritis nodosa" because of the widespread involvement of vessels and the fact that it affects the entire thickness of the vessel wall [1].

A disorder of necrotizing vasculitis, granulomatous lesions of the entire respiratory tract, and glomerulonephritis was first described in 1897 by Peter McBride [11]. In 1931, Heinz Klinger described the pathological anatomical picture of this disease in two patients who died of systemic vasculitis [12]. In 1936, Friedrich Wegener, a German pathologist, described three patients with necrotizing granuloma and later interpreted the pathological and clinical findings to represent a distinctive disease entity in 1939 [13]. Goodman and Churg in 1954 wrote a detailed description of the disease known as "Wegener´s granulomatosis" (WG) presenting definite criteria: necrotizing granulomata of the respiratory tract, generalized vasculitis and necrotizing glomerulonephritis [14]. DeRemee and colleages in 1976 proposed the ELK classification (E= upper respiratory tract including paranasal sinuses; L= lung; K= kidney), allowing them to understand and manage cases that did not fit the strict criteria of Goodman and Churg [15]. In the early 1970s, Fauci and Wolff introduced treatment with cyclophosphamide and corticosteroids for WG, which resulted in a nearly complete and longlasting remission of the disease [16]. In addition, DeRemee published in 1985 a report on the benefits of using cotrimoxazole (trimethoprim/ sulfamethoxazole) in WG with local disease [17]. In the same year, a major breakthrough was made by Van der Woude et al who reported autoantibodies sensitive and specific for the disease. These autoantibodies reacted with the cytoplasm of ethanol-fixed neutrophils, and monocytes and were called Anti-neutrophil Cytoplasmic Autoantibodies (ANCA) [18].

#### **3. Classification**

antibodies that were first described in the 1980s by Davies et al. in patients with necrotizing glomerulonephritis [4]. These antibodies are directed against antigenic components of neutrophilic granules or lysosomes. Indirect immunofluorescence (IIF) of ethanol-fixed neutrophils reveals cytoplasmic (cANCA) or perinuclear (pANCA) staining. cANCA staining correlates with proteinase-3 (PR3) reactivity, while pANCA staining correlates with reactivity

PR3-ANCAs are mainly detected in patients with WG, whereas MPO-ANCAs are predomi‐ nantly detected in patients with MPA and CSS. These diseases exhibit similar pathological

Henoch-Schönlein purpura (HSP) is the most common systemic small-vessel vasculitis in children [6]. HSP is a systemic vasculitis affecting small vessels and capillaries. HSP is characterized by palpable purpura, edema, abdominal pain, joint pain and renal symptoms [7]. The prognosis is good as long as the patients have no renal symptoms. Renal symptoms vary from intermittent hematuria and proteinuria to rapidly progressive glomerulonephritis.

In this chapter, we shall discuss the pathophysiology of the most common primary small vessel vasculitis in adults, AASV, as well as the most common small vessel vasculitis in children,

Purpura was the first manifestation of vasculitis in vessels smaller than arteries. In 1808, Willan clearly distinguished purpura caused by infections from non-infectious purpura [8]. Over the next century, Henoch and his teacher, Schönlein, described a broad spectrum of signs and symptoms that were associated with purpura, and with small vessel vasculitis, including arthritis, peripheral neuropathy, abdominal pain, pulmonary hemorrhage, epistaxis, iritis, and

In 1866, Kussmaul and Maier described a patient with general weakness caused by vasculitic neuropathy accompanied by tachycardia, abdominal pain, and the appearance of cutaneous nodules over the trunk. The patient's muscle paralysis progressed quickly causing death. At autopsy, visible nodules were present along the medium-sized arteries of the patient [10]. Kussmaul and Maier named this disease "periarteritis nodosa" because they observed inflammation in the perivascular sheaths and outer layers of the arterial walls and nodular thickening of the vessels. However, the name was later changed to "polyarteritis nodosa" because of the widespread involvement of vessels and the fact that it affects the entire thickness

A disorder of necrotizing vasculitis, granulomatous lesions of the entire respiratory tract, and glomerulonephritis was first described in 1897 by Peter McBride [11]. In 1931, Heinz Klinger described the pathological anatomical picture of this disease in two patients who died of

focal necrotizing lesions, though WG and CSS also have granulomatous lesions [5].

towards myeloperoxidase (MPO) or other antigens.

2 Updates in the Diagnosis and Treatment of Vasculitis

HSP.

**2. History**

nephritis [9].

of the vessel wall [1].

There are 20 recognized primary forms of vasculitis, which are classified according to the size of the affected blood vessels. The large vessel vasculitides, giant cell (temporal) arteritis and Takayasu arteritis, are caused by a granulomatous inflammation of the aorta and its major branches. In the case of giant cell arteritis, there is a particular predeliction for the extracranial branches of the carotid artery, often with involvement of the temporal artery and frequent association with polymyalgia rheumatica. The age of the patient is helpful in distinguishing between the two conditions, because giant cell arteritis is rare in patients under the age of 50 and Takayasu's disease is more common in younger patients [19].

Classical polyarteritis nodosa affects medium-sized vessels and therefore should not involve glomerulonephritis or vasculitis in arterioles, capillaries or venules. Kawasaki's disease is a medium-sized vessel vasculitis that frequently involves the coronary arteries, is associated with the mucocutaneous lymph node syndrome and is most common in children [2].

Small vessel vasculitides include the immune-complex associated vasculitis of Henoch-Shoenlein pupura and essential cryoglobulinemic vasculitis. Henoch-Schönlein pupura has predominantly IgA immune complex deposition and involves the skin, gut and glomeruli with arthritis and arthralgia, while essential cryoglobulinemic vasculitis is caused by the deposition of cryoglobulins predominantly in the small vessels of the skin and glomeruli and is frequently associated with Hepatitis C infection. Another small vessel vasculitis category is cutaneous leucocytoclastic vasculitis, which is confined only to the skin, has no systemic involvement and has a better prognosis than vasculitides with systemic involvement [2].

Examples of different types of vasculitis are depicted in Table 1.


Without treatment, patients with AASV have a very poor prognosis with a median survival time of 5 months [28]. Current treatment regimens based on cyclophosphamide and cortico‐ steroids have dramatically improved the prognosis for these patients and increased the median survival time to 21.7 years [29]. Although this regimen achieves long-lasting remission and prolonged survival of patients with AASV, it has its drawbacks; the worst being life-threat‐ ening infections early in the course of the disease and risk of malignancy in late stages of the disease [30,31]. Furthermore, the disease has a high relapse rate in spite of heavy immuno‐ suppression. Improved understanding of the mechanisms underlying AASV may help in the

History, Classification and Pathophysiology of Small Vessel Vasculitis

http://dx.doi.org/10.5772/55238

5

search for better treatment modalities for this serious and devastating illness.

**4.1. Pathogenic B-cell response and production of ANCA**

PR3 or an antigenic microbial epitope [33].

physiology of AASV.

**4. Pathophysiology of ANCA-Associated Systemic Vasculitis (AASV)**

The pathophysiology of AASV remains largely unknown. Clinical and laboratory evidence suggest a multifactorial origin. Although the association between ANCA and pauci-immune small vessel vasculitides has been established, the exact role of ANCA in the pathogenesis of AASV is yet not fully elucidated. It is not known whether ANCA play a direct role in disease manifestations, or whether the antibodies are secondary markers of the disease process. Available data suggest that neutrophils, B- and T- lymphocytes play a key role in the patho‐

B-cells are the direct precursors of antibody producing plasma cells. B-cells also produce autoantibodies and cytokines (Interleukin IL-6, Tumor Necrosis Factor alpha-TNFα, IL-10), act as antigen presenting cells, and differentiate into long lasting memory B-cells. Csernak et al. have shown that in WG patients, ANCA are produced following B-cell activation [32]. A polyclonal B-cell lymphoid infiltrate in the endonasal granulomatous lesion included PR3-ANCAproducing cells with copy number increase in three VH genes. The granulomatous lesions in WG consist of clusters of PR3 surrounded by an infiltrate consisting of maturing B-cells, antigen-presenting cells (APCs) and Th1-type CD4+CD28− T cells. This suggests that endo‐ nasal B-cell maturation is antigen-driven, and that B-cells generate ANCA via contact with

B-cells recognize soluble antigens via specific B-cell receptors (BCR) and co-receptor CD19 that augments BCR downstream signaling. CD19 dysregulation has been reported in patients with AASV. Culton et al. showed that CD19 expression is 20% lower in naive B-cells from patients with AASV than from normal controls [34]. In contrast, the memory B-cells from some patients with AASV express more CD19 than normal controls. This subset of B-cells shows evidence of antigenic selection, suggesting that in AASV, mechanisms of self-tolerance may be lost leading to production of auto-reactive B-cells [34]. Experiments in transgenic mice indicate that defective B-cell regulation, specifically in pathways responsible for deletion (central and peripheral) of auto-reactive B-cells, may also play a role in generating autoantibodies in AASV [35]. Interestingly, expression of B-cell activating factor of the TNF family (BAFF) is increased

(\*) Diseases most commonly associated with ANCA, pausi-immune crescentic glomerulonepghritis and which are most responsive to immunosuppression with cyclophosphamide. (\*\*) e.g. sulphonamides, penicillins, thiazide diuretics, and many others. PAN= Polyarteritis Nodosa. RA= Rheumatoid Arthritis. SLE= Systemic Lupus Erythematosus.

**Table 1.** Classification of systemic vasculitis.

ANCA-associated systemic vasculitis (AASV) are a group of diseases classified as small vessel vasculitides that are associated with anti-neutrophil cytoplasmic antibodies. AASV include microscopic polyangiitis, Wegener´s granulomatosis, Churg-Struass syndrome and renal limited vasculitis. Together they are responsible for 5-6% of cases presenting with renal failure. They are characterized histologically by necrotizing vasculitis preferentially affecting small blood vessels and often associated with pauci-immune necrotizing crescentic glomeruloneph‐ ritis. Serologically, these diseases present autoantibodies directed against constituents of neutrophil granules [20].

In1990, three independent groups showed that azurophilic granule enzyme proteinase 3 was the target autoantigen recognized by ANCA (PR3-ANCA) [21,22,23]. Together with proteinase 3, another granule protein, myeloperoxidase (MPO) was also identified as a target autoantigen of ANCA (MPO-ANCA) [24]. The discovery of ANCA has been critical to understanding the pathogenesis of the disease, as well as providing a valuable diagnostic tool. The American College of Rheumatology published criteria for classifying vasculitides in 1990, leading to improved categorization of patients for clinical trials [25]. However, these criteria were not adequate for diagnosing patients with ANCA-associated vasculitides. An individual patient could simultaneously meet the criteria for WG, Churg Strauss Syndrome (CSS), Polyarteritis Nodosa (PAN), hypersensitivity vasculitis and Henoch-Schönlein pupura. In 1994 the Chapel Hill Consensus conference (CHCC) adopted standardized names and definitions of vasculi‐ tides, based on the size of the affected blood vessels [26].

Recently a group of physicians from multiple medical disciplines met at the European Medicines Agency (EMEA) in London in September 2004 and January 2006 and developed a stepwise algorithm for classifying AASV and PAN for epidemiological studies. Their aim was to develop a consensus approach for applying CHCC definitions and ACR criteria to AASV and PAN, in order to facilitate comparison between epidemiological data for different vasculitides [27].

Without treatment, patients with AASV have a very poor prognosis with a median survival time of 5 months [28]. Current treatment regimens based on cyclophosphamide and cortico‐ steroids have dramatically improved the prognosis for these patients and increased the median survival time to 21.7 years [29]. Although this regimen achieves long-lasting remission and prolonged survival of patients with AASV, it has its drawbacks; the worst being life-threat‐ ening infections early in the course of the disease and risk of malignancy in late stages of the disease [30,31]. Furthermore, the disease has a high relapse rate in spite of heavy immuno‐ suppression. Improved understanding of the mechanisms underlying AASV may help in the search for better treatment modalities for this serious and devastating illness.
