1 Learning Objectives

By the end of this chapter, you should be able to:

  • Discuss pathologic mechanisms underlying vasculitis.

  • Review classification and nomenclature of vasculitis.

  • Compose a diagnostic approach to a patient with vasculitis.

  • Describe major forms of vasculitis.

Vasculitis is a clinicopathologic process characterized by inflammation and damage of blood vessels by leucocytes which leads to bleeding. Compromise of vascular lumen results in ischemia and necrosis of the tissues supplied by the involved vessels. Vasculitis can be a primary disease process, or it may be secondary to another underlying disease [1].

1.1 Pathologic Mechanisms Underlying Vasculitis

The exact mechanisms are unclear. However, three different models have been advanced [2]:

  1. 1.

    Pathogenic immune-complex formation and/or deposition

    (IgA vasculitis, hepatitis C-associated vasculitis, hepatitis B-associated vasculitis)

  2. 2.

    Production of antineutrophil cytoplasmic antibodies (ANCA)

    (Microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis)

  3. 3.

    Pathogenic T lymphocytic responses and granuloma formation

    (Giant cell arteritis, Takayasu’s arteritis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis)

The end result of these immunopathologic pathways is endothelial cell activation, with subsequent vessel obstruction and ischemia of dependent tissue. This may cause hemorrhage in the surrounding tissues and, in some cases, weakening of the vessel wall, which leads to the formation of aneurysms. For almost all forms of vasculitis, the triggering event initiating and driving this inflammatory response is unknown.

1.2 Classification of Vasculitis

Vasculitis is classified based on the predominant size of vessels affected. Types of vessels are defined in the (CHCC) 2012 [3, 4]. This is illustrated in Fig. 20.1.

Fig. 20.1
figure 1

Types of vessels that are defined by the 2012 Chapel Hill Consensus Conference nomenclature system. (a) Large vessels represents the aorta, its major branches and their corresponding veins. (b) Medium vessels are the visceral arteries, veins and their main branches. (c) Small vessels consist of interparenchymal arteries, arterioles, capillaries, venules and veins

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1.3 The 2012 Chapel Hill Consensus Conference (CHCC) on Nomenclature of Vasculitis

The CHCC is a nomenclature system. It is neither a classification system nor a diagnostic system. It specifies the name that should be used for a specifically defined disease process. The following names are adopted by the CHCC 2012 on the nomenclature of vasculitides [4], and their definitions are presented in Table 20.1.

Large Vessel Vasculitis (LVV):

  1. 1.

    Takayasu’s arthritis (TA).

  2. 2.

    Giant cell arthritis (GCA).

Medium Vessel Vasculitis (MVV):

  1. 1.

    Polyarteritis nodosa (PAN).

  2. 2.

    Kawasaki disease (KD).

Table 20.1 Definitions adopted by the 2012 CHCC on the nomenclature of vasculitides [4]
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Small Vessel Vasculitis (SVV):

  1. 1.

    Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis:

    1. (a)

      Granulomatosis with polyangiitis (GPA).

    2. (b)

      Microscopic polyangiitis (MPA).

    3. (c)

      Eosinophilic granulomatosis with polyangiitis (EGPA).

  2. 2.

    Immune-complex-associated vasculitis:

    1. (a)

      Anti-glomerular basement membrane (Anti-GBM) disease.

    2. (b)

      Cryoglobulinemic vasculitis (CV).

    3. (c)

      IgA vasculitis (IgAV).

    4. (d)

      Hypocomplementemic urticarial vasculitis (HUV) (Anti-C1q).

Variable Vessel Vasculitis (VVV):

  1. 1.

    Behcet’s disease (BD).

  2. 2.

    Cogan’s syndrome (CS).

Single Organ Vasculitis (SOV):

  1. 1.

    Cutaneous leukocytoclastic angiitis.

  2. 2.

    Cutaneous arteritis.

  3. 3.

    Primary central nervous system vasculitis.

  4. 4.

    Isolated aortitis.

Vasculitis Associated with Systemic Disease:

  1. 1.

    Lupus vasculitis.

  2. 2.

    Rheumatoid vasculitis.

  3. 3.

    Sarcoid vasculitis.

Vasculitis Associated with Probable Etiology:

  1. 1.

    Hepatitis C-associated cryoglobulinemic vasculitis.

  2. 2.

    Hepatitis B-associated vasculitis.

  3. 3.

    Syphilis-associated vasculitis.

  4. 4.

    Drug-associated immune-complex vasculitis.

  5. 5.

    Drug-associated ANCA-associated vasculitis.

  6. 6.

    Cancer-associated vasculitis.

1.4 How to Approach a Patient with Vasculitis?

1.4.1 A Case Scenario

A lady comes to the clinic with a rash over her legs. She is aged 32 years and for the last 6 months has been unwell, with intermittent fevers, loss of appetite, and fatigue. Recent blood tests show elevated erythrocyte sedimentation rate (ESR; 83 mm/h) and C-reactive protein (CRP; 46 mg/dL). Today she has palpable purpura on her lower legs. Urinalysis is positive for blood and protein.

  • What are the clinical clues to vasculitis?

  • What investigations will assist with a precise diagnosis?

  • How should the condition be treated and monitored?

Tables 20.2, 20.3 and 20.4 summarize history, physical examination findings (Fig. 20.3), and work-up of a patient presenting with suspected vasculitis. Figure 20.2 summarizes history taking from a patient presenting with suspected vasculitis. This includes review of systems, past medical history, and medication history. Figures 20.4, 20.5 and 20.6 show different mucocutaneous finding that can be present in a patient with vasculitis.

Table 20.2 What to ask a patient presenting with suspected vasculitis?
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Table 20.3 What to look for when physically examining a patient with suspected vasculitis?
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Table 20.4 What are the laboratory tests that help ascertain the type of vasculitis?
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Fig. 20.2
figure 2

History taking from a patient presenting with suspected vasculitis. This includes review of systems, past medical history and medication history

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Fig. 20.3
figure 3

Physical signs that should be checked for in a patient presenting with suspected vasculitis

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Fig. 20.4
figure 4

Erythema nodosum in polyarteritis nodosa. Courtesy of Prof. Hani Almoallim

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Fig. 20.5
figure 5

Leukocytoclastic vasculitis with palpable purpura in a patient with immune-complex-associated small vessel vasculitis. Courtesy of Prof. Hani Almoallim

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Fig. 20.6
figure 6

Oral ulcer in a patient with Behcet’s disease. Courtesy of Dr. Lujain Homeida

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1.5 Major Forms of Vasculitis

1.5.1 Takayasu’s Arteritis (TA)

TA primarily affects the aorta and its primary branches [5]. It is an uncommon form of vasculitis. Up to 90% of the cases are women of reproductive age, and it is more prevalent in Asia [6]. The inflammation is characterized by thickening of the arterial wall. This can lead to narrowing, occlusion, or dilatation of the arteries [7].

The pathogenesis of TA is not clear. Presence of mononuclear cells is thought to cause active inflammation that leads to granuloma formation [8]. Aneurysms are formed due to laminal destruction. Arterial plaques were also found in patients with TA [9].

Systemic symptoms are manifested early in TA [10]. As the disease progresses, vascular involvement becomes evident. Subclavian artery stenosis proximal to the origin of the vertebral artery can lead to the so-called subclavian steal syndrome [11]. Ischemic ulcerations and gangrene may develop as results of vascular occlusion.

The differential diagnosis of TA includes fibromuscular dysplasia, excess ergotamine intake, Ehlers-Danlos syndrome, and GCA.

Glucocorticoids are the mainstay treatment. They reduce both systemic symptoms and disease progression [12]. Azathioprine, mycophenolate, methotrexate, tocilizumab, or leflunomide can be used in glucocorticoid-resistant cases, while cyclophosphamide is for those who have continued disease activity despite those medications [13, 14]. Percutaneous transluminal angioplasty or bypass grafts may be considered in late cases when irreversible arterial stenosis has occurred and when significant ischemic symptoms develop [15].

Table 20.5 summarizes CHCC12 definition, epidemiology, clinical manifestation, diagnostic studies, American College of Rheumatology (ACR) 1990 classification criteria, and treatment of TA.

Table 20.5 Takayasu’s arteritis (pulseless disease)
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1.5.2 Giant Cell Arteritis (GCA)

GCA is a vasculitis of large-sized vessels. Up to 90% of cases are above the age of 60 [16]. It affects the aorta and its major branches, mainly the carotid and vertebral arteries [17].

The pathogenesis of GCA is poorly understood. It is thought that an initial trigger (e.g., viral infection or other factor) activates monocytes in a susceptible host. These monocytes cause systemic symptoms. Release of inflammatory mediators and tissue injury may lead to fibrosis, scarring, and narrowing or occlusion of the arteries [18].

Symptoms of GCA start gradually but may manifest acutely in some patients. An efficient history should include questions about systemic symptoms, such as fever, fatigue, and weight loss; headache; jaw claudication, which is the most specific symptom of GCA; visual symptoms; and symptoms of polymyalgia rheumatica [19,20,21].

Temporal artery biopsy is the gold standard modality for the diagnosis of GCA. However, if the clinical suspicion is high or vision is threatened, high-dose glucocorticoid therapy should be started immediately. Appropriate measures to prevent glucocorticoid-induced osteoporosis should be taken [22]. Methotrexate is moderately effective as a glucocorticoid-sparing agent. Tocilizumab was recently granted a breakthrough designation status by the US Food and Drug Association for GCA based on positive results from a phase 3 clinical trial [23].

Table 20.6 summarizes CHCC12 definition, epidemiology, clinical manifestation, diagnostic studies, ACR 1990 classification criteria, and treatment of GCA.

Table 20.6 Giant cell arteritis
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1.5.3 Polyarteritis Nodosa (PAN)

PAN is a systemic necrotizing arteritis of the medium-sized muscular arteries, with occasional involvement of small muscular arteries. It is not associated with the presence of ANCA. It is more common in men in the sixth decade of life [24].

PAN is mostly idiopathic, although hepatitis B virus infection, hepatitis C virus infection, and hairy cell leukemia are important in the pathogenesis of some cases. The pathogenesis is poorly understood. It is characterized by segmental transmural inflammation of muscular arteries which leads to fibrinoid necrosis and disruption of the elastic lamina. Unlike other forms of systemic vasculitis, it does not involve veins [25].

Like most types of vasculitis, patients with PAN present with systemic symptoms (fatigue, weight loss, weakness, fever, arthralgias) and signs of multisystem involvement (skin lesions, hypertension, renal insufficiency, neurologic dysfunction, and abdominal pain). PAN has a striking tendency to spare the lungs.

The differential diagnosis of PAN is broad, including infectious diseases that affect the vasculature or that are complicated by systemic vasculitis; noninfectious disorders, particularly those that can cause widespread arterial embolism, thrombosis, or vasospasm; and other systemic vasculitides.

Treatment of PAN depends on the severity of the disease. Mild disease can be treated with prednisolone at a dose of 1 mg/kg per day (maximum 60 to 80 mg/day) for approximately 4 weeks and then to be tapered based on clinical improvement [26]. Moderate to severe disease is treated with methotrexate, azathioprine, mycophenolate, or cyclophosphamide [26].

Table 20.7 summarizes CHCC12 definition, epidemiology, clinical manifestation, diagnostic studies, ACR 1990 classification criteria, and treatment of PAN.

Table 20.7 Polyarteritis nodosa
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1.5.4 Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA)

These are types of vasculitis that affect small vessels. They occur mostly in older adults, and both genders are equally affected. Both types are associated with ANCA and have similar features on renal histology (crescentic, pauci-immune glomerulonephritis) [27].

An initiating event (e.g., infection or drug) causes tissue injury and immune response [28]. This leads to production of ANCA. Up to 80% of the antigens observed in granulomatosis with polyangiitis are proteinase 3 (PR3) (c-ANCA), while myeloperoxidase (MPO) (p-ANCA) is observed in 10% of patients. About 70% of microscopic polyangiitis patients have positive ANCA which is mostly p-ANCA.

Patients typically present with constitutional symptoms that may last for weeks to months without evidence of specific organ involvement. Both types affect multiple systems including pulmonary, renal, ocular, neurologic, and hematologic [29].

The distinction of these types of small vessel vasculitis from other systemic rheumatic diseases is challenging. Differential diagnosis includes diseases with similar general clinical features like EGPA, similar lung and/or renal signs like anti-GBM disease, and/or positive ANCA serologies like renal-limited vasculitis.

Therapy has two components: induction of remission with initial immunosuppressive therapy and maintenance immunosuppressive therapy for a variable period to prevent relapse. Choice of drug regimen in induction of remission depends on the severity of the disease. Mild disease can be treated by a combination therapy with glucocorticoids and methotrexate, while cyclophosphamide or rituximab [30] is required to treat severe disease. Plasma exchange is added in case of glomerulonephritis or pulmonary hemorrhage [31, 32].

Tables 20.8 and 20.9 summarize CHCC12 definition, epidemiology, clinical manifestation, diagnostic studies, ACR 1990 classification criteria, and treatment of GPA and MPA.

Table 20.8 Granulomatosis with polyangiitis
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Table 20.9 Microscopic polyangiitis
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1.5.5 Eosinophilic Granulomatosis with Polyangiitis (EGPA)

EGPA is a multisystem disease characterized by allergic rhinitis, asthma, and prominent peripheral blood eosinophilia [33].

In this disease, ANCA is detected in about 50% of patients. The etiology of EGPA is unknown. However, genetic factors such as HLA-DRB4 are thought to play a role. Presence of ANCA produces an immune response, which then leads to eosinophilic infiltration and necrotizing granuloma [34].

Clinical features of EGPA develop in several phases: the prodromal phase which is characterized by presence of asthma and allergic rhinitis; the eosinophilic phase with eosinophilic infiltration of multiple organs; and the vasculitis phase that may be heralded by nonspecific constitutional symptoms [35].

Differential diagnosis includes aspirin-exacerbated respiratory disease, the eosinophilic pneumonias, allergic bronchopulmonary aspergillosis, the hyper-eosinophilic syndrome, and other ANCA-associated vasculitides.

Treatment of EGPA consists of induction of remission and maintenance of remission. For mild disease, induction can be achieved with high-dose glucocorticoids. Cyclophosphamide is added to glucocorticoids in severe disease. For maintenance of remission, azathioprine or methotrexate can be used [36].

Table 20.10 summarizes CHCC12 definition, epidemiology, clinical manifestation, diagnostic studies, ACR 1990 classification criteria, and treatment of EGPA.

Table 20.10 Eosinophilic granulomatosis with polyangiitis
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1.5.6 IgA Vasculitis (IgAV)

IgA vasculitis, also previously called Henoch-Schönlein Purpura, is the most common systemic.

vasculitis of childhood. Up to 10% of IgA vasculitis occur in adults.

It is a self-limited disease and is characterized by the presence of the following: palpable purpura without thrombocytopenia and coagulopathy, arthralgias and/or arthritis, abdominal pain, and renal disease [37].

The underlying cause of IgA vasculitis is unknown. It is thought that IgA vasculitis represents an immune-mediated vasculitis that may be triggered by a variety of antigens, including various infections or immunizations [38].

Treatment of IgA vasculitis is supportive and should be directed toward adequate oral hydration, bed rest, and symptomatic relief of joint and abdominal pain. Nonsteroidal anti-inflammatory drugs can be used to alleviate joint or abdominal pain. Glucocorticoids are used for more severe cases [39].

Table 20.11 summarizes CHCC12 definition, epidemiology, clinical manifestation, diagnostic studies, ACR 1990 classification criteria, and treatment of IgA vasculitis.

Table 20.11 IgA vasculitis
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1.5.7 Cutaneous Leukocytoclastic Angiitis

Cutaneous leukocytoclastic angiitis, also previously called hypersensitivity vasculitis, is a form of single-organ vasculitis that involves cutaneous vessels of any size with no evidence of systemic vasculitis [4].

It is the most common type of vasculitis. It may be idiopathic, but it may be directly caused by drugs, infections, tumor antigens, and serum sickness.

It is difficult to distinguish cutaneous leukocytoclastic angiitis from other forms of vasculitis, particularly when confined to the skin. Many types of systemic vasculitis may present initially with cutaneous involvement, so careful evaluation is required.

Treatment of the underlying cause or withdrawal of the offending agent lead to resolution within a period of days to a few weeks. Glucocorticoids are preserved for progressive disease [40].

Table 20.12 summarizes CHCC12 definition, epidemiology, clinical manifestation, diagnostic studies, ACR 1990 classification criteria, and treatment of cutaneous leukocytoclastic angiitis.

Table 20.12 Cutaneous leukocytoclastic angiitis
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1.5.8 Behcet’s Disease (BD)

It is a type of vasculitis that can affect blood vessels of all sizes. It is characterized by recurrent oral aphthae and any of several systemic manifestations including genital aphthae, ocular disease, skin lesions, gastrointestinal involvement, neurologic disease, vascular disease, or arthritis. It is more common along the ancient silk road, which extends from Eastern Asia to the Mediterranean. It typically affects adults between the age of 20 and 40 with a similar prevalence between both genders [41].

The underlying cause of BD is unknown. It is thought that the immune response is triggered by exposure to an agent (e.g., infection, chemicals). It is also found to be associated with HLA-B51 [42]. Both cellular and humoral immunity responses are activated [43]. Endothelial dysfunction leads to inflammation and thrombus formation in BD [43].

Ocular, vascular, and neurological manifestations account for the greatest morbidity and mortality in BD. Cutaneous and articular involvement are also common [44].

Treatment of BD depends on the severity of the disease. Mild disease can be treated with colchicine and oral glucocorticoids. Severe disease requires addition of immunosuppressive therapy such as cyclophosphamide, TNF-alpha blockers, and azathioprine [45].

Table 20.13 summarizes CHCC12 definition, epidemiology, clinical manifestation, diagnostic studies, ACR 1990 classification criteria, and treatment of BD.

Table 20.13 Behcet’s disease
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The author of this chapter is grateful to Prof. Hani Almoallim and Dr. Lujain Homeida for providing some clinical images from their own collection.