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The Systemic Vasculitides
Definition
The vasculitides are a heterogeneous group of disorders linked by the common finding of destructive inflammation within blood vessel walls. The most current nomenclature scheme identifies at least 27 different forms of primary vasculitis ( Table 249-1 ).
TABLE 249-1
NAMES FOR VASCULITIDES ADOPTED BY THE 2012 INTERNATIONAL CHAPEL HILL CONSENSUS CONFERENCE ON THE NOMENCLATURE OF VASCULITIDES
From Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum . 2013;65:1-11.
| LARGE-VESSEL VASCULITIS |
| Takayasu arteritis Giant cell arteritis |
| MEDIUM-VESSEL VASCULITIS |
| Polyarteritis nodosa Kawasaki disease Buerger disease ∗ |
| SMALL-VESSEL VASCULITIS |
| Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis Microscopic polyangiitis Granulomatosis with polyangiitis (formerly Wegener granulomatosis) Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) Immune complex small-vessel vasculitis Antiglomerular basement membrane disease Cryoglobulinemic vasculitis Immunoglobulin (Ig)A vasculitis (Henoch-Schönlein purpura) Hypocomplementemic urticarial vasculitis |
| VARIABLE-VESSEL VASCULITIS |
| Behçet syndrome Cogan syndrome |
| SINGLE-ORGAN VASCULITIS |
| Cutaneous leukocytoclastic angiitis Cutaneous arteritis Primary central nervous system vasculitis Isolated aortitis |
| VASCULITIS ASSOCIATED WITH SYSTEMIC DISEASE |
| Lupus vasculitis Rheumatoid vasculitis Sarcoid vasculitis IgG4-related disease Others |
| VASCULITIS ASSOCIATED WITH PROBABLE ETIOLOGY |
| Hepatitis C virus–associated cryoglobulinemic vasculitis Hepatitis B virus–associated vasculitis Syphilis-associated aortitis Drug-associated immune complex vasculitis Drug-associated ANCA-associated vasculitis Cancer-associated vasculitis Others |
∗ Buerger disease (thromboangiitis obliterans) is not always considered to be a primary form of vasculitis and was not included in this consensus statement on nomenclature.
Classification
Classification by Vessel Size
The etiology of most forms of vasculitis remains unknown, and major gaps exist in our understanding of the pathophysiologic processes. The most valid basis for classification of the vasculitides is the size of the predominant blood vessels involved. The vasculitides are categorized initially by whether the vessels affected are primarily large, medium, or small (see Table 249-1 ). Large vessels are considered the aorta, its primary branches, and any vessel that is not located within an organ such as a muscle, kidney, nerve, or the skin. Medium-sized vessels, in contrast, consist of the main visceral arteries and their branches. Thus, the renal artery is considered a large vessel, but its intrarenal branches—the interlobar and arcuate arteries—are medium-sized vessels. Finally, small vessels include smaller intraparenchymal arteries as well as arterioles, capillaries, and venules.
Medium-vessel vasculitis and even large-vessel vasculitis can also affect small arteries. However, large-vessel vasculitis affects large arteries more often than medium- or small-vessel vasculitis, medium-vessel vasculitis affects predominantly medium arteries, and small-vessel vasculitis affects predominantly arterioles, capillaries, and venules.
Additional Considerations in Classification
Considerations other than the size of blood vessels that are relevant to the classification of vasculitis (see Table 249-2 ) include age, sex, and ethnic background of the patient; organ tropism; presence or absence of granulomatous inflammation; participation of immune complexes in the pathophysiologic process; and detection of characteristic autoantibodies, such as antineutrophil cytoplasmic antibodies (ANCAs), in the patient’s serum.
TABLE 249-2
CONSIDERATIONS IN THE CLASSIFICATION OF SYSTEMIC VASCULITIS
| Size of predominant blood vessels affected Epidemiologic features:
Pattern of organ involvement
Presence of ANCA in serum |
ANCA = antineutrophil cytoplasmic antibody.
The organ tropisms of these disorders are illustrated by the following examples. Whereas immunoglobulin (Ig)A vasculitis (also known as Henoch-Schönlein purpura) typically affects the skin, joints, kidneys, and the gastrointestinal tract, granulomatosis with polyangiitis classically involves the upper airways, lungs, and kidneys. In contrast to both IgA vasculitis and granulomatosis with polyangiitis, Cogan syndrome involves the eyes, the audiovestibular apparatus of the inner ear, and (in 10 to 15% of cases) the large arteries.
The presence or absence of granulomatous inflammation is a crucial element in the diagnosis and classification of vasculitis. The small number of vasculitides that demonstrate granulomatous inflammation includes granulomatosis with polyangiitis, giant cell arteritis, Takayasu arteritis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).
Immune complexes are essential to the pathophysiologic mechanism of some forms of small- and medium-vessel vasculitis. Complexes of IgA1, for example, are found in IgA vasculitis. Immune complexes consisting of IgG, IgM, complement components, and the hepatitis C virion characterize most cases of mixed cryoglobulinemia. In contrast, “pauci-immune” types of small- and medium-vessel vasculitis, such as granulomatosis with polyangiitis and microscopic polyangiitis, have comparatively little evidence of immune complex deposition within diseased tissues. Many, but not all, patients with pauci-immune forms of vasculitis are positive for antineutrophil cytoplasmic antibodies (ANCA).
Epidemiology
The epidemiologic features of individual forms of systemic vasculitis vary tremendously by geography ( Table 249-3 ) as a reflection of genetic influences, variations in environmental exposures, and other unknown risk factors. For example, whereas Behçet syndrome is rare in North Americans, affecting only 1 person in approximately 300,000, this condition is several hundred times more common among inhabitants of countries bordering the ancient Silk Route. Similarly, although Takayasu arteritis ( Chapter 63 ) is rare in the United States—on the order of 3 new cases per million people per year—this disease is reportedly the most common cause of renal artery stenosis in India, where the incidence may be as high as 200 to 300 per million per year.
TABLE 249-3
EPIDEMIOLOGY OF SELECTED VASCULITIDES
From Watts RA, Hatemi G, Burns JC, et al. Global epidemiology of vasculitis. Nat Rev Rheumatol 2022;18:22-34.
| DISEASE | UNITED STATES | ELSEWHERE | AGE, SEX, AND ETHNIC PREDISPOSITIONS |
|---|---|---|---|
| Giant cell arteritis | Incidence: 240/million (Olmsted County, MN) | 220-270/million (Scandinavian countries) | Age >50 yr, mean age 72 yr; females 3 : 1; Northern European ancestry |
| Takayasu arteritis | Incidence: 3/million | 200-300/million (India) | Age <40 yr; females 9 : 1; Asian |
| Behçet syndrome | Prevalence: 3/million | 3000/million (Turkey) | Silk Route countries |
| Polyarteritis nodosa | Incidence: 7/million | 7/million (Spain) | Slight male predominance |
| Kawasaki disease | Incidence: 100/million ∗ | 900/million (Japan) | Children of Asian ancestry |
| Granulomatosis with polyangiitis | Incidence: 4/million | 8.5/million (United Kingdom) | Whites >> Blacks |
Age is an important consideration in the epidemiology of vasculitis. Eighty percent of patients with Kawasaki disease are younger than age 5 years. In contrast, giant cell arteritis virtually never occurs in patients younger than age 50 years, and the mean age of patients with this disease is 72 years. Age may also have an impact on disease severity and outcome. In IgA vasculitis, the overwhelming majority of cases in children (who represent 90% of all cases) have self-limited courses, resolving within several weeks. In adults, however, IgA vasculitis has a higher likelihood of chronicity and a poor renal outcome.
The distribution of sex varies across many forms of vasculitis. The vasculitis associated with IgG4-related disease (e.g., aortitis, coronary arteritis, and even small-vessel vasculitis) is more likely to occur in males. Buerger disease ( Chapter 66 ), which is often considered a form of vasculitis albeit not included in the Chapel Hill consensus nomenclature, has a striking male predominance that is probably explained by the higher prevalence of smoking among males in most societies. In contrast, Takayasu arteritis has an overwhelming tendency to occur in females (a 9 : 1 female-to-male ratio). The pauci-immune forms of vasculitis, such as granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis, occur in males and females with approximately equal frequencies, but the phenotypic expression of these conditions may be affected by both age and sex. As an example, granulomatosis with polyangiitis limited to the subglottic region is more likely to occur in female patients.
The strongest link between any single gene and vasculitis is the association of HLA-B51 with Behçet syndrome. In Behçet syndrome, 80% of Asian patients have the HLA-B51 gene. The prevalence of HLA-B51 is significantly higher among patients with Behçet syndrome in Japan than among nondisease control subjects (55% versus <15%). Among the sporadic cases of Behçet syndrome involving Whites in the United States, however, HLA-B51 occurs in less than 15% of cases.
With the exception of Buerger disease and smoking, no definitive associations have been confirmed between disease and environmental or occupational exposures. Associations have been reported but not confirmed between exposures to silica and some types of pauci-immune vasculitis. Studies of potential associations between exposures of any type and vasculitis, however, are frequently complicated by difficulties in obtaining reliable measurements of the levels of the relevant exposure, the likelihood of recall bias among patients who are diagnosed with vasculitis, and the choice of appropriate control groups.
Pathobiology
Different forms of vasculitis have different pathologic characteristics ( Table 249-4 ). The type of inflammatory cell infiltrate in vasculitis is independent of the size of blood vessels involved. Mixed cell infiltrates in vasculitis are the rule rather than the exception, and histopathologic patterns of vasculitis may include leukocytoclasis (degranulation and destruction of neutrophils within blood vessel walls), granulomatous findings (with or without giant cells), lymphoplasmacytic infiltrates, varying degrees of eosinophilic infiltration, necrosis, and combinations of all these findings.
TABLE 249-4
PATHOLOGIC CHARACTERISTICS OF SELECTED FORMS OF VASCULITIS
| TAKAYASU ARTERITIS | POLYARTERITIS NODOSA | GRANULOMATOSIS WITH POLYANGIITIS (WEGENER GRANULOMATOSIS) | EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS ∗ | HENOCH-SCHÖNLEIN PURPURA | CUTANEOUS LEUKOCYTOCLASTIC ANGIITIS | |
|---|---|---|---|---|---|---|
| Vessels involved | Elastic (large) or muscle (medium-sized) arteries | Medium-sized and small muscle arteries | Small arteries and veins; sometimes medium-sized vessels | Small arteries and veins; sometimes medium-sized vessels | Capillaries, venules, and arterioles | Capillaries, venules, and arterioles |
| Organ involvement | Aorta, aortic arch and major branches, and pulmonary arteries | Skin, peripheral nerves, gastrointestinal tract, and other viscera | Upper respiratory tract, lungs, kidneys, skin, eyes | Upper respiratory tract, lungs, heart, peripheral nerves | Skin, joints, gastrointestinal tract, kidneys | Skin, joints |
| Type of vasculitis and inflammatory cells | Granulomatous with some giant cells; fibrosis in chronic stages | Necrotizing, with mixed cellular infiltrate | Necrotizing or granulomatous (or both); mixed cellular infiltrate plus occasional eosinophils | Necrotizing or granulomatous (or both); prominent eosinophils and other mixed infiltrate | Leukocytoclastic, with some lymphocytes and variable eosinophils; IgA deposits in affected tissues | Leukocytoclastic, with occasional eosinophils |
Ig = immunoglobulin.
Pathophysiology
Some pathophysiologic mechanisms are common to many different forms of vasculitis, regardless of the size of the predominant blood vessels involved. Immune complex deposition, for example, is present in several types of vasculitis that involve both medium-sized and small blood vessels.
Large-Vessel Vasculitides
The pathologic process in large-vessel vasculitis appears to begin in the adventitia. In both Takayasu arteritis ( Chapter 63 ) and giant cell arteritis ( Chapter 250 ), abundant numbers of activated T lymphocytes are found within inflamed arterial walls, centering on the adventitia. In Takayasu arteritis, most of these T cells appear to be of the CD8 + subtype. Current evidence suggests that the cytotoxic functions of these cells, mediated by perforin and granzyme B, contribute to smooth muscle cell damage in this disease. CD4 + T-cell responses in Takayasu arteritis have not been well defined.
In giant cell arteritis ( Chapter 250 ), evidence suggests an antigen-driven disease, with the site of immunologic events being the adventitia. CD4 + T cells that secrete interferon (IFN)-γ appear to be recruited to the adventitia by a specific antigen(s), the identity of which remains unknown. Both the T cells that orchestrate the transmural inflammation and the inciting antigens are theorized to reach the adventitia through the vasa vasorum. Subsequently, T-cell signals from the adventitia stimulate macrophages and multinucleated giant cells to elaborate an array of downstream mediators, including metalloproteinases and platelet-derived growth factor. Interleukin (IL)-6, known to be a crucial cytokine in giant cell arteritis and probably Takayasu arteritis, is also produced by macrophages residing in the blood vessel wall. The results of this inflammatory cascade are granulomatous inflammation, destruction of the internal elastic lamina, arterial wall hyperplasia, smooth muscle cell proliferation, intimal thickening, vascular occlusion, and, in some cases, weakening of the vessel wall with subsequent dilation and aneurysm formation. Matrix metalloproteinases appear to play important roles in destruction of the internal elastic lamina, damage to other vascular tissues, and weakening of the arterial wall.
Medium- and Small-Vessel Vasculitides
Several different pathophysiologic mechanisms are operative among the medium- and small-vessel vasculitides.
Immune Complex–Mediated Vascular Injury
Immune complex–mediated tissue injury does not produce a single clinical syndrome but rather applies to many forms of vasculitis and overlaps with injuries caused by other immune mechanisms. Numerous variables influence immune complex–mediated injury, including the physical properties of the immune complexes (e.g., their size), the ability of the immune complexes to activate complement, the antigen-to-antibody ratio, and the hemodynamic features of specific vascular beds. Immune complexes participate in the pathophysiologic process of some forms of both medium- and small-vessel vasculitis, including polyarteritis nodosa, cryoglobulinemia, IgAV, cutaneous leukocytoclastic angiitis, and rheumatoid vasculitis.
Role of Antineutrophil Cytoplasmic Antibodies
Antineutrophil cytoplasmic antibodies (ANCAs) are directed against antigens that reside within the primary granules of neutrophils and monocytes. Two types of ANCA are relevant to vasculitis: (1) those directed against proteinase 3 (PR3), known as PR3-ANCA, and (2) those directed against myeloperoxidase (MPO), termed MPO-ANCA. ANCAs interact with cytokines, neutrophils, monocytes, and other elements of the immune system to amplify ongoing inflammation in certain forms of vasculitis. A striking and still unexplained feature of ANCA-associated vasculitis is that patients with primary forms of these conditions virtually never have antibodies to both PR3 and MPO. Despite the specificity of these antibodies, however, evidence for a primary role of ANCA in the etiology of human disease is still tenuous.
In granulomatosis with polyangiitis, abnormal cytokine regulation interacts with the production of antineutrophil cytoplasmic antibodies to fuel the inflammatory response. T H 1 cytokines such as interferon (IFN)-γ, interleukin (IL)-12, and tumor necrosis factor (TNF) appear to play important roles. Under the direction of IL-12, CD4 + T cells from patients with granulomatosis with polyangiitis produce elevated levels of TNF, and peripheral blood mononuclear cells secrete increased amounts of IFN-γ. Serum levels of soluble receptors for TNF are elevated in patients with active granulomatosis with polyangiitis and normalize with the induction of remission. In vitro priming of activated neutrophils with TNF markedly enhances the ability of ANCA to stimulate neutrophil degranulation. Through processes, which are promoted by a variety of cytokines, ANCA binding leads to neutrophil activation and degranulation, with the release of cytotoxic substances and activation of the alternative complement pathway.
The effectiveness of B-cell depletion for the treatment of antibody-associated vasculitis probably relates to the removal of several B-cell functions beyond their evolution into plasma cells and the production of ANCA. Such functions include the production of cytokines, the presentation of antigen, and B cell–T cell crosstalk. B-cell depletion is emerging rapidly as the treatment of choice for some forms of severe vasculitis.
Superantigen Model
The degree of immune activation in Kawasaki disease and the acute but generally self-limited nature of this illness imply a potential role for superantigens. Superantigens are proteins that are produced by microbial pathogens (e.g., Staphylococcus aureus or Streptococcus species) and that are capable of stimulating large populations of T cells in a manner unrestricted by the class II major histocompatibility complex (MHC). Superantigens bind directly to conserved amino acid residues outside the antigen-binding groove on class II MHC molecules, thereby selectively stimulating T cells that express particular β-chain variable gene segments. Through the binding of this MHC-superantigen complex to its cognate T-cell receptors, as many as 20% of circulating lymphocytes may become activated, thereby leading to a potentially enormous outpouring of cytokines. With regard to the etiology of Kawasaki disease, substantial attention has focused on toxic shock syndrome toxin 1, an exotoxin produced by S. aureus . Superantigens have also been postulated to play roles in the susceptibility to disease flares in granulomatosis with polyangiitis. Compelling laboratory and naturally occurring animal models of disease, combined with the known associations of hepatitis B virus and hepatitis C virus with vasculitis in humans, suggest that additional links between infection and systemic vasculitis may be established in the future.
Anti–Endothelial Cell Antibodies
Anti–endothelial cell antibodies can induce endothelial cell injury and lysis through either complement-mediated cytotoxicity or antibody-dependent cellular cytotoxicity. The ability of these antibodies to damage endothelial cells is an appealing argument for their potential role in forms of vasculitis in which the endothelium is the focus of the inflammation (as opposed to the more external vessel wall layers).
Diagnosis
Vasculitis is often considered in patients who have multisystem diseases or fever of unknown origin ( Chapter 259 ). The major categories of disease that can mimic vasculitis are also multisystem diseases ( Table 249-5 ).
TABLE 249-5
MAJOR DISEASE CATEGORIES IN THE DIFFERENTIAL DIAGNOSIS OF VASCULITIDES
| Other forms of vasculitis Simultaneous occurrence of common medical problems in the same patient Infections
Occlusive processes
Malignant neoplasms
Connective tissue disorders
Miscellaneous
|
Certain features of a patient’s case should raise the diagnostic suspicion for vasculitis. First, most cases of vasculitis do not begin suddenly but rather unfold subacutely during weeks or months. Second, pain is usually a prominent feature of vasculitis as a result of arthritis or arthralgias, myalgias, headaches, neuropathy, testicular infarction, digital ischemia, sinusitis, otalgia, back pain (caused by aortic inflammation), postprandial abdominal pain (caused by mesenteric vasculitis), or other disease manifestations. Third, signs of inflammation such as fever, rash, weight loss, and elevated acute phase reactants are highly characteristic. Finally, multiorgan system involvement is the rule in vasculitis.
The diagnosis of vasculitis should be established through biopsy of an involved organ whenever possible. Diagnoses based on angiography alone have many potential pitfalls, and angiographic findings that are called “consistent with vasculitis” must be interpreted in the proper context. A diverse array of other diseases, ranging from atherosclerosis to vasospasm to pheochromocytoma, may mimic the angiographic appearance of vasculitis. Systemic vasculitis can also be mimicked by two or more common medical problems or treatment complications occurring simultaneously in the same patient. Finally, high on the differential diagnosis of any individual form of vasculitis are other forms of vasculitis. For example, digital ischemia and splinter hemorrhages may be secondary to idiopathic polyarteritis nodosa. They may also be caused by polyarteritis nodosa associated with hepatitis B viral infection, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis, cryoglobulinemia, Buerger disease, or some other form of vasculitis. Because the appropriate interventions for these conditions vary widely, careful distinction among these potential etiologies is essential.
Treatment
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