Necrotizing Arteritis and Small-Vessel Vasculitis

C H A P T E R

65 Necrotizing Arteritis and Small-Vessel Vasculitis Marco A. Alba1, J. Charles Jennette1 and Ronald J. Falk2 1

Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States 2Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

O U T L I N E Historical Background Necrotizing Arteritis Purpura and Small-Vessel Vasculitis

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Polyarteritis Nodosa Definition Epidemiology Clinical Features and Disease Association Pathological Features Pathogenesis Autoimmune Features Environmental Influences and Genetic Features Animal Models Diagnostic Procedures Treatment

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Kawasaki’s Disease Definition Epidemiology Clinical Features and Disease Associations Pathological Features Pathogenesis Autoimmune Features Genetic Features and Environmental Influences Animal Models Diagnostic Procedures Treatment

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Antineutrophil Cytoplasmic Autoantibody Vasculitis Definition

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The Autoimmune Diseases, 6th. DOI: https://doi.org/10.1016/B978-0-12-812102-3.00065-8

Epidemiology Clinical Features and Disease Associations Pathological Features Pathogenesis Autoimmune Features Genetic Features and Environmental Influences Animal Models Diagnostic Procedures Treatment

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Cryoglobulinemic Vasculitis Definition Epidemiology Clinical Features and Disease Associations Pathological Features Pathogenesis Autoimmune Features Genetic Features and Environmental Influences Animal Models Diagnostic Procedures Treatment

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IgA Vasculitis (Henoch
Scho¨nlein Purpura) Definition Epidemiology Clinical Features and Disease Associations Pathological Features Pathogenesis Autoimmune Features Genetic Features and Environmental Influences

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Copyright © 2020 Elsevier Inc. All rights reserved.

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Animal Models Diagnostic Procedures Treatment

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Concluding Remarks—Future Prospects

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References

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HISTORICAL BACKGROUND Vasculitis is inflammation of blood vessel walls (Jennette et al., 2013a). Major categories of systemic vasculitides are based on the predominant type of vessels involved (and the pattern of initial injury), that is, large-vessel vasculitis (chronic granulomatous arteritis), medium-vessel vasculitis (necrotizing arteritis), and small-vessel vasculitis (necrotizing polyangiitis) (Fig. 65.1 and Box 65.1). Necrotizing arteritis was first recognized because of the grossly discernible segmental inflammatory nodular lesions that occur along major arteries (Kussmaul and Maier, 1866). Small-vessel vasculitis (SVV) was first recognized because of the palpable purpura that is caused by inflammation of dermal venules (Willan, 1808).

Necrotizing Arteritis Kussmaul and Maier (1866) provided the first definitive pathologic and clinical description of a patient with necrotizing arteritis. They reported the case of a 27-year-old journeyman tailor, who developed a fulminant disease characterized by fever, anorexia, muscle weakness, paresthesias, myalgias, abdominal pain, and oliguria. Kussmaul and Maier (1866) introduced the term periarteritis nodosa (PAN) as a reference to the major findings identified during this patient’s autopsy, that is, multiple inflammatory nodules affecting medium-sized arteries. For years after the original description, the generic term PAN was given to any patient with necrotizing vasculitis

FIGURE 65.1 Major categories of systemic vasculitis include large-vessel vasculitis, medium-vessel vasculitis, and small-vessel vasculitis. A substantial overlap with respect to arterial involvement can be observed in all three major categories. The aorta, a large artery, medium artery, small artery/arteriole, capillary, venule, and vein are shown from left to right. Source: Reprinted with permission from Jennette, J.C., Falk, R.J., Bacon, P.A., Basu, N., Cid, M.C., Ferrario, F., et al., 2013a. 2012 Revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 65 (1), 1
11.

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HISTORICAL BACKGROUND

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BOX 65.1

N A M E F O R VA S C U L I T I D E S P R O P O S E D B Y T H E 2 0 1 2 I N T E R N AT I O N A L C H A P E L H I L L C O N S E N S U S C O N F E R E N C E O N T H E N O M E N C L AT U R E O F VA S C U L I T I D E S • Large-vessel vasculitis (LVV) • Takayasu arteritis (TAK) • Giant cell arteritis (GCA) • Medium-vessel vasculitis (MVV) • Polyarteritis nodosa (PAN) • Kawasaki’s disease (KD) • Small-vessel vasculitis (SVV) • Antineutrophil cytoplasmic antibody (ANCA)associated vasculitis (AAV) • Microscopic polyangiitis (MPA) • Granulomatosis with polyangiitis (Wegener’s) (GPA) • Eosinophilic granulomatosis with polyangiitis (Churg
Strauss) (EGPA) • Immune complex SVV • Antiglomerular basement membrane (anti-GBM) disease • Cryoglobulinemic vasculitis (CV) • IgA vasculitis (Henoch
Scho¨nlein) (IgAV) • Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis)

• Variable vessel vasculitis (VVV) • Behc¸et’s disease (BD) • Cogan’s syndrome (CS) • Single-organ vasculitis (SOV) • Vasculitis associated with systemic disease • Lupus vasculitis • Rheumatoid vasculitis • Others • Vasculitis associated with probable etiology • Hepatitis C virus
associated cryoglobulinemic vasculitis • Hepatitis B virus
associated vasculitis • Drug-associated immune complex vasculitis • Drug-associated ANCA-associated vasculitis • Cancer-associated vasculitis • Others Modified from Jennette, J.C., Falk, R.J., Bacon, P.A., Basu, N., Cid, M. C., Ferrario, F., et al., 2013a. 2012 Revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 65 (1), 1
11.

(Jennette and Falk, 1997). The name later evolved into the more pathologically correct term of PAN, as it became clear that the inflammation arose in the walls of arteries rather than in the perivascular tissue. By the 1950s, distinction of PAN and a microscopic form of the disease was gradually recognized (Chung and Seo, 2010). Although Wohlwill (1923) described a variant of PAN that was characterized by the involvement of small-vessels, Davson and Zeek were probably the first to suggest the separation of PAN into different disorders based on the presence of widespread glomerular inflammation (glomerulonephritis, GN) (Davson et al., 1948; Zeek et al., 1948). Today, the microscopic form of PAN is designated as microscopic polyangiitis (MPA) (Jennette et al., 1994). In 1931, medical student Heinz Klinger published the first case of a patient with granulomatosis with polyangiitis (GPA) (Klinger, 1931). The detailed features of this multisystemic disorder were provided initially by the German pathologist Friedrich Wegener (Wegener, 1939). A few years later, the diagnostic triad of Wegeners granulomatosis was identified, that is, systemic necrotizing angiitis, necrotizing inflammatory involvement of the respiratory tract, and necrotizing GN (Godman and Churg, 1954). Churg and Strauss (1951) described a series of 13 patients with asthma, eosinophilia, necrotizing vasculitis, and granulomatous inflammation. Three years later, Godman and Churg (1954) concluded that this disease, now designated as eosinophilic GPA (EGPA), the microscopic form of periarteritis (MPA), and Wegener’s granulomatosis (GPA), were all pathologically and clinically distinct from PAN and probably have a related etiology and pathogenesis. This concept has been borne out by the discovery that GPA, MPA, and EGPA are associated with, and are probably caused by, antineutrophil cytoplasmic autoantibodies (ANCAs), whereas PAN is not (Jennette and Falk, 1997; Jennette et al., 2013a). Kawasaki (1967) discovered an additional form of necrotizing arteritis that was associated with the mucocutaneous lymph node syndrome. This disease has been called infantile polyarteritis nodosa because it almost always occurs in young children (Magilavy et al., 1977); however, the clinical, pathologic, and pathogenetic features of Kawasaki’s disease (KD) are clearly distinct from those of PAN (Jennette et al., 2013a).

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Purpura and Small-Vessel Vasculitis Purpura was the first manifestation of SVV that was described in the medical literature. The term probably derives from the Greek porphyra, which refers to the purple color produced by the mollusk Purpura lapillus (Jones and Tocantins, 1933). English dermatologist Willan (1808) was one of the first to separate purpura caused by systemic febrile infections from noninfectious purpura, which were was associated with systemic diseases. Scho¨nlein (1837) and Henoch (1868) described the occurrence of purpura in children in association with arthralgias and arthritis, abdominal pain, nephritis, and small visceral hemorrhages (Henoch, 1868; Scho¨nlein, 1837). Osler (1895, 1914) recognized that peripheral neuropathy, pulmonary hemorrhage, epistaxis, iritis, and rapidly progressive renal disease were all symptoms caused by necrotizing inflammation of small vessels (Jennette and Falk, 1997; Osler, 1914). In 1919 Goodpasture reported a patient with pulmonary hemorrhage and rapidly progressive GN (pulmonary
renal syndrome) who had hemorrhagic alveolar capillaritis and vasculitis of glomerular capillaries as main pathology findings (Goodpasture, 2009). By the 1950s, the pathologic features in SVV of extensive acute inflammation with numerous neutrophils and conspicuous leukocytoclasia had been well described (Jennette and Falk, 1997). Similarity of these findings with the injury pattern of the Arthus reaction in addition to the association of some cases of necrotizing vasculitis with serum sickness or exposure to certain drugs led to the suggestion of a possible “hypersensitivity” or allergic cause for vasculitis (Alarcon Segovia and Brown, 1964; Winkelmann, 1958; Zeek et al., 1948). In the 1960s, the widespread application of immunofluorescence microscopy revealed that certain forms of SVV had substantial vascular localization of immunoglobulins and complement, suggesting an immune complex pathogenesis. Landmark discoveries using this technique include the identification of linear deposits of immunoglobulin along glomerular and pulmonary capillary basement membranes in a subset of patients with pulmonary
renal syndrome (Sturgill and Westervelt, 1965), later shown to be pathogenic autoantibodies directed against basement membrane collagen (Lerner et al., 1967); the demonstration of granular deposits of IgM, IgG, and complement in vessels walls of patients with cryoglobulinemic vasculitis (CV) (Meltzer and Franklin, 1966; Meltzer et al., 1966), and the finding of deposits of IgA and C3 in dermal venules and glomerular capillaries of children with Henoch
Scho¨nlein purpura (now termed IgA vasculitis) (Faille-Kuyper et al., 1976). By the end of the 1970s, there was a widespread belief that most if not all SVV was mediated by immune complexes (Fauci et al., 1978). However, evaluation of a wide range of vasculitides failed to identify substantial vessel wall deposition of immunoglobulins or complement. This was especially true in cases of GPA, MPA, and EGPA (Ronco et al., 1983; Weiss and Crissman, 1984). Davies et al. (1982) reported a new type of autoantibody that reacted with neutrophil cytoplasm in eight patients with pauci-immune necrotizing GN and SVV. Three years later, van der Woude et al. (1985) identified these autoantibodies in patients with GPA and suggested its value as a diagnostic and prognostic marker. Numerous subsequent studies documented that ANCAs were closely associated with GPA, MPA, and EGPA. The two major antigen specificities in patients with ANCA vasculitis were described by Falk and Jennette (1988), and Niles et al. (1989), that is, antimyeloperoxidase (MPO) ANCA (MPOANCA) and antiproteinase 3 (anti-PR3) (PR3-ANCA) (Falk and Jeneette 1988; Jennette and Nachman, 2017; Niles et al., 1989). In addition to the diagnostic value of these autoantibodies there is now strong evidence that ANCA participate in disease pathogenesis by direct activation of neutrophils (Jennette et al., 2013a).

POLYARTERITIS NODOSA Definition PAN is a systemic necrotizing arteritis of medium-sized or small arteries without GN or vasculitis in arterioles, capillaries, or venules. PAN is typically not associated with ANCAs (Jennette et al., 2013a).

Epidemiology The annual incidence of PAN in European countries is approximately 2
10 cases per million population. Prevalence has been estimated between 2 and 31 cases/million (Mahr et al., 2004; Mohammad et al., 2007; Watts and Scott, 2004). The peak incidence occurs in the sixth decade of life (Mahr et al., 2004; Mohammad et al., 2007; Watts and Scott, 2004).

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Clinical Features and Disease Association Presentation includes constitutional symptoms, such as fever, weight loss, arthralgia, and myalgia (30%
93% of the cases); tender erythematous nodules, livedo reticularis, and ulcers caused by dermal and subcutaneous arteritis (28%
49%); peripheral neuropathy (e.g., mononeuritis multiplex) caused by arteritis in epineural arteries (38%
74%); and gastrointestinal manifestations, that is, abdominal pain, bowel bleeding, or perforation (14%
38%) (Hernandez-Rodriguez et al., 2014; Pagnoux et al., 2010). Kidney involvement is observed in 15% of the patients and is the result of tissue infarction or rupture of renal arterial aneurysms rather than GN. Signs and symptoms of renal involvement are renal insufficiency, new-onset hypertension, hematuria, or low-level proteinuria (Agard et al., 2003; Pagnoux et al., 2010). Less common complications of PAN include myocardial infarction, orchitis, and ischemic retinopathy. A PAN-like disease caused by deficiency of adenosine deaminase 2 (DADA2) has been described. DAD2 is a monogenic autoinflammatory disorder characterized by early-onset polyarteritis, recurrent ischemic or hemorrhagic strokes, livedo reticularis, fever, elevation of acute phase reactants, and in some cases peripheral neuropathy, gastrointestinal ischemic symptoms, and hypogammaglobulinemia (Navon Elkan et al., 2014; Zhou et al., 2014).

Pathological Features The hallmark of PAN is transmural inflammation and necrosis of muscular arteries (Fig. 65.2). The vascular inflammation initially contains predominantly neutrophils, but within a few days, the infiltrates contain predominantly monocytes, macrophages, and T-lymphocytes (Jennette, 2002). Typically, lesions are observed at arterial branching sites with acute necrotizing vasculitis usually coexisting with chronic vascular fibrotic changes. Segmental inflammation and necrosis may produce pseudoaneurysms by eroding through the vessel wall into the surrounding tissue. Thrombosis can cause acute ischemia, including infarction. Rupture of pseudoaneurysms results in hemorrhage, which may be severe and life threatening. The histopathological features of newly described DADA2 are indistinguishable from those of classic PAN (Caorsi et al., 2016).

Pathogenesis The pathogenesis of PAN remains poorly understood. It is probable that both humoral and cellular inflammatory systems participate in the development of necrotizing arteritis (Ozen, 2017). In a particular subset of patients, that is, those with hepatitis B virus
associated PAN (HBV-PAN), deposition of immune complexes is believed to play a role (Fig. 65.2). When arterial wall immune complexes are present, they cause inflammation by activating the complement, kinin, plasmin, and coagulation humoral systems, and the neutrophil, mononuclear phagocyte, lymphocyte, and platelet cellular systems. This complex interplay between the innate and adaptive immune systems results in the influx of inflammatory cells (especially neutrophils), necrosis, and sometimes thrombosis. ADA2 acts as a growth factor for endothelial and hematopoietic cells and also participates in monocyte proliferation and macrophage differentiation (Zavialov et al., 2010). In this sense deficiency of this enzyme has been associated with compromised vascular endothelial integrity and with defects in the differentiation of M2 antiinflammatory monocytes, leading to an increased polarization of M1 proinflammatory cells (Caorsi et al., 2016; Zhou et al., 2014). In addition DADA2 may lead to an increased neutrophil activation (Caorsi et al., 2016; Zhou et al., 2014). FIGURE 65.2 Left panel: Light microscopy of necrotizing arteritis consistent with PAN in the wall of the small intestine (hematoxylin and eosin). The muscular media of the artery has been destroyed and replaced by fibrinoid material with admixed leukocytes and leukocyte nuclear debris (leukocytoclasia). Right panel: Direct immunofluorescence photomicrograph demonstrating granular IgG deposits in an artery from the subcutaneous tissue of a patient with hepatitis B
associated polyarteritis nodosa, showing granular vessel wall staining for C3. PAN, periarteritis nodosa.

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Autoimmune Features Most patients with PAN do not have recognized evidence for an autoimmune pathogenesis. Exceptions are the few patients with systemic lupus erythematosus (SLE) who have a vasculitis that is pathologically similar to idiopathic PAN (lupus arteritis) (Korbet et al., 1984). ANCAs are typically absent in PAN patients (Jennette et al., 2013a).

Environmental Influences and Genetic Features There is a strong association between PAN and HBV, as approximately one-third of PAN cases are secondary to this infectious disease (Guillevin et al., 2005; Pagnoux et al., 2010). In comparison with the idiopathic form of this vasculitis HBV infected patients usually exhibit a more severe phenotype, frequently involving the gastrointestinal and peripheral nervous system and the heart (Pagnoux et al., 2010). Anecdotal reports of PAN-like vasculitis associated with hepatitis C virus (HCV), human immunodeficiency virus (HIV), parvovirus B19, cytomegalovirus, Mediterranean fever, and hematological neoplasias have been published (Hasler et al., 1995; Ozen et al., 2001). There is no evidence that genetic factors play a substantial role in the development of classic PAN neither than genetic features of HBV correlates with the induction of the disease. In contrast DADA2 is clearly associated with a genetic defect, that is, loss-of-function homozygous or compound heterozygous mutations in CECR1 gene (Caorsi et al., 2017).

Animal Models Pearl Zeek, who was one of the pioneers in delineating the clinical and pathologic features of PAN, studied an animal model of systemic arteritis that resembled PAN and that was induced by implanting pieces of silk in the perirenal tissue of rats (Zeek et al., 1948). More recently, necrotizing inflammation of mesenteric, pancreatic, and testicular arteries has been reported to occur spontaneously in certain rodent strains and in transgenic rats carrying the env-pX gene of human T-cell leukemia virus type I (Fugo et al., 2002; Yoshiki, 2002). The relevance of these models to PAN in patients in not clear because these experimental animals often have involvement of small-sized vessel (e.g., GN), as well as the presence of several pathogenic autoantibodies that are not observed in most patients with PAN (e.g., anti-DNA and antinuclear antibodies) (Fugo et al., 2002).

Diagnostic Procedures Biopsies from muscle, peripheral nerve, or skin (subcutaneous tissue) may document necrotizing arteritis. Conventional angiography is an alternative to biopsy (Hernandez-Rodriguez et al., 2014; Pagnoux et al., 2010). Typical findings include multiple aneurysms (pseudoaneurysms), and stenosis of mesenteric, renal, and hepatic arteries. The diagnosis PAN is supported by the serologic identification of HBV (Agard et al., 2003; Janssen et al., 2004). The diagnosis of PAN in a patient with necrotizing arteritis requires the exclusion of other diseases with arteritis, such as KD or ANCA vasculitis (Agard et al., 2003; Jennette et al., 2013a; Mahr et al., 2004). In this sense the presence of GN, alveolar capillaritis, or positive MPO-ANCA or PR3-ANCA rule out a diagnosis of PAN and indicate some form of SVV, for example, MPA or GPA (Agard et al., 2003; Jennette et al., 2013a).

Treatment Patients with nonorgan and non-life-threatening disease may be treated with glucocorticoids (GC) alone. A recent clinical trial showed that the addition of azathioprine to GC for remission-induction of nonsevere PAN did not improve remission rates or lower the relapse risk of these patients (Puechal et al., 2017). Under this category are included those who present with constitutional symptoms, mild cutaneous involvement or those who lack any of the poor prognostic variables described in the five factor score (FFS), that is, renal insufficiency, proteinuria .1 g/day, cardiac involvement, central nervous system involvement, or gastrointestinal involvement. Half of these patients will require an additional immunosuppressant for remission-maintenance (Samson et al., 2014). Moderate or severe manifestations, that is, one or more features of the FFS, presence of mononeuritis multiplex, or limb ischemia, are treated with high-dose GC in combination with cyclophosphamide (Gayraud et al.,

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KAWASAKI’S DISEASE

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2001; Guillevin et al., 1995). Cases with HBV-associated PAN should receive antiviral therapy with interferon (IFN)-α or lamivudine in addition to immunosuppressive agents (Guillevin, 1999; Han, 2004; Janssen et al., 2004). Experience treating DADA2 is limited. High-dose GC, tumor necrosis factor (TNF)-blockers, and enzymatic replacement therapy have all reported to be of benefit (Caorsi et al., 2016).

KAWASAKI’S DISEASE Definition KD is an acute vasculitis of childhood associated with the mucocutaneous lymph node syndrome that predominantly affects medium and small arteries. Coronary arteries are often involved (Jennette et al., 2013a).

Epidemiology In the United States, the estimated incidence of KD among children ,5 years of age is in the range of 19
25 cases per 100,000 (Watts and Scott, 2004). Incidence varies by race, being markedly more frequent in East Asia, particularly in Japan. Approximately 90% of the patients are between ages 6 months and 5 years, with a male-tofemale ratio of 1.5:1 (Yanagawa et al., 1995). In children from developed countries KD is the leading cause of acquired heart disease (Newburger and Fulton, 2004).

Clinical Features and Disease Associations Major clinical manifestations (also considered diagnostic criteria) include persistent fever in combination with (1) extremity changes (50%
85% of the cases), that is, erythema and edema of the palms and soles, periungual desquamation; (2) nonexudative bilateral conjunctivitis (70%
90%); (3) cutaneous involvement (70%
90%), that is, maculopapular eruption, diffuse erythroderma, or erythema multiforme-like rash; (4) oral mucosal lesions (90%), that is, erythema and cracking of the lips, “strawberry tongue,” or erythema of pharyngeal mucosa; and (5) cervical lymphadenopathy (25%
70%) (Fukushige et al., 1994; Kawasaki, 1967; McCrindle et al., 2017; Newburger and Fulton, 2004; Ozdemir et al., 2010). Cardiovascular complications, the major determinant of longterm prognosis, include coronary artery aneurysms, myocardial infarction, myocarditis, and valvular abnormalities (McCrindle et al., 2017).

Pathological Features The vasculitis of KD involves medium-sized and small arteries, most notably the coronary arteries. KD arteriopathy usually evolves from an acute necrotizing arteritis, characterized histologically by segmental mural necrosis with infiltration by predominantly mononuclear leukocytes with less conspicuous neutrophils, to a subacute vasculitis with infiltration of lymphocytes, plasma cells, and eosinophils, that is followed by myofibroblastic proliferation that may result in narrowing of the lumen, arterial stenosis, and ischemia (Jennette, 2002; McCrindle et al., 2017). Pseudoaneurysms are most common in the proximal coronary arteries and may be occluded by thrombus, resulting in myocardial infarction. In addition to the coronary arteries, renal, iliac, mesenteric, hepatic, and peripancreatic arteries may be involved (Cohen and Sundel, 2016). In comparison with PAN less fibrinoid material, more edema, and more macrophages are observed in necrotizing lesions of KD (Jennette, 2002).

Pathogenesis As in PAN, activation of both the innate and adaptive immune systems may play a role in KD. Previous studies have demonstrated a marked increase in serum concentration of proinflammatory cytokines IL-1β, IL-6, IL-8, IL17, and TNF-α during the acute phase of KD (Franco et al., 2010; Matsubara et al., 2005; Sohn et al., 2003; Wang et al., 2013). In addition KD patients have a deficit of regulatory T cells and increased activity of CD4 1 Tlymphocytes (Hirabayashi et al., 2013; Sohn et al., 2011). Although not fully verified, antiendothelial cell antibodies have been incriminated in the pathogenesis of vascular injury in patients with KD (Grunebaum et al., 2002; Kaneko et al., 2004; Leung et al., 1986a, 1986b, 1989).

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Autoimmune Features Autoantibodies that react with activated endothelial cells and cardiac myosin have been identified in patients with KD (Cunningham et al., 1999; Grunebaum et al., 2002; Kaneko et al., 2004; Leung et al., 1986a, 1986b, 1989). The relevance of this finding is still to be determined.

Genetic Features and Environmental Influences Infectious, environmental, and genetic factors have been implicated in the development of KD. An infectious etiology of KD has been suggested on the basis of the temporal clustering and seasonality of reported cases and the similarity of clinical presentation with childhood febrile exanthems. Although several microorganisms have been incriminated, that is, coxsackie virus, cytomegalovirus, parainfluenza virus, novel RNA viruses, or bacterial superantigens, none has been confirmed (Burns et al., 2005). Proposed associations with environmental factors include dust mites or pollen exposure, residence near standing water, and large-scale wind currents originating from Asia (Cohen and Sundel, 2016; McCrindle et al., 2017; Rodo et al., 2011). A role for genetic factors in the pathogenesis of KD is supported by the observation that children of parents who had KD in childhood are at greater risk for developing the disease (Uehara et al., 2003). In addition a child is at 10-fold greater risk of developing the disease within 1 year of onset of the disease in a sibling (Fujita et al., 1989). Genome-wide association studies (GWAS) and family linkage studies have identified an increased susceptibility for the development of KD in the presence of single-nucleotide polymorphisms of several genes that are involved in the regulation of immune response, that is, BLK, CD40, ITPKC, CASP3, and FCγR2A (Lee et al., 2012; McCrindle et al., 2017; Onouchi et al., 2008, 2012).

Animal Models Takahashi et al. (2004) have developed an animal model of vasculitis that has a remarkable pathologic similarity to the arteritis of KD. They injected a Candida albicans extract intraperitoneally for 5 consecutive days into a variety of mouse strains. Arteritis developed in 66% of the CD-1 mice and most often affected the coronary arteries and aortic root close to the orifice of coronary arteries. The gross distribution and histologic pattern of injury closely mimics coronary arteritis in patients with KD. Not all strains of mice developed disease, indicating a genetic susceptibility in certain strains. Duong et al. (2003) have described a similar mouse model of coronary arteritis induced by the injection of Lactobacillus casei cell wall extract.

Diagnostic Procedures Diagnosis of KD and incomplete (atypical) forms is based on clinical criteria and exclusion of other systemic vasculitis and infectious conditions (McCrindle et al., 2017). Leukocytosis, anemia, and raised erythrocyte sedimentation rate (ESR) and C-reactive protein are common during the first days of disease. Echocardiography of coronary arteries should be performed in all patients (McCrindle et al., 2017). Until now, no autoantibodies have been recognized that can be used for routine diagnosis of KD (Newburger and Fulton, 2004).

Treatment Management of KD is aimed to prevent the development of coronary aneurysms. Recommended initial treatment includes the administration of a single dose of intravenous gamma-globulin (IVIg, 2 g/kg) in addition to high-dose aspirin (Furusho et al., 1984; McCrindle et al., 2017; Nagashima et al., 1987; Newburger and Fulton, 2004). After normalization of fever and in the absence of coronary aneurysms, low-dose aspirin should be continued for 4
6 weeks. Patients who are refractory to initial IVIg dose (10%
20% of the cases) have an increased risk of developing aneurysms. For these children, options include a repeated infusion of IVIg, infliximab, GC, cyclosporine, cyclophosphamide, or plasma exchange (McCrindle et al., 2017).

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ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY VASCULITIS

ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY VASCULITIS Definition ANCAs are autoantibodies specific for antigens located in the cytoplasmic granules of neutrophils and lysosomes of monocytes (Jennette and Nachman, 2017). The main autoantigen targets of ANCAs are MPO (MPOANCA) and PR3 (PR3-ANCA). ANCA vasculitis is characterized by necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels, that is, capillaries, venules, arterioles, and small arteries (Jennette et al., 2013a). ANCA vasculitis has three major clinicopathologic expressions, that is, GPA (formerly called Wegener’s granulomatosis), MPA, and EGPA (formerly Churg
Strauss syndrome) (Jennette et al., 2013a) (Box 65.1). GPA has necrotizing granulomatous inflammation superimposed on the vasculitis. EGPA has asthma, eosinophilia, and granulomatous inflammation in addition to the vasculitis. MPA has only the vasculitis, without granulomatous inflammation, asthma, or eosinophilia (Jennette et al., 2013a).

Epidemiology The overall incidence and prevalence of ANCA vasculitis has been estimated at 13
23 cases/million adults per year and 46
184 cases/million, respectively (Mohammad et al., 2007, 2014; Watts et al., 2015; Watts and Scott, 2004). The annual incidence in 1,000,000 adults ranges from 2 to 12 for GPA, from 3 to 12 for MPA, and from 1 to 3 for EGPA (Watts et al., 2015). Reported prevalence of GPA is 24
160 cases/million inhabitants, between 9 and 94 for MPA, and 2 and 38 for EGPA (Mohammad et al., 2007, 2014; Watts et al., 2015; Watts and Scott, 2004). GPA is more prevalent in Nordic countries, whereas MPA is the most common ANCA vasculitis in Southern Europe and Japan (Ntatsaki et al., 2010). Mean age at disease onset is 45
60 years for GPA, 55
74 for MPA, and 38
52 for EGPA (Guillevin et al., 1999; Smyth et al., 2004).

Clinical Features and Disease Associations Constitutional symptoms such as fever and arthralgias are observed in a large majority of patients (Agard et al., 2003). Small vessels in any organ or tissue can be affected (Table 65.1). Frequent examples include vasculitis affecting dermal venules causing palpable purpura; necrotizing arteritis in small dermal and subcutaneous arteries causing ulcers, and nodules; vasculitis affecting small epineural arteries and arterioles causing peripheral neuropathy (usually mononeuritis multiplex or sensory neuropathy); vasculitis of the small vessels of the eye causing scleritis and uveitis; and vasculitis in small vessels in the gastrointestinal mucosa and submucosa causing abdominal pain and blood in the stool (Jennette and Nachman, 2017). Inflammation of glomerular capillaries causes focal and segmental, necrotizing, crescentic GN, and pulmonary capillaritis causes pulmonary hemorrhage (Jennette and Falk, 1997). Vasculitis of small vessels in the upper respiratory tract, present in approximately 90% of the GPA patients, causes sinusitis, otitis, bloody nasal discharge, or collapse of the nasal septum causing saddle nose deformity (Hoffman et al., 1992). A smaller proportion of MPA patients have upper respiratory tract inflammation that is less destructive than that of GPA. Patients with GPA may have clinical manifestations of necrotizing granulomatous inflammation, that is, pulmonary nodules and cavities, subglottic stenosis, orbital masses, and nasolacrimal duct obstruction (Hoffman TABLE 65.1

Differential Diagnostic Features of Several Forms of Small-Vessel Vasculitis (SVV). MPA

GPA

EGPA

IgAV

Cryo V

PAN

SVV signs and symptoms

Yes

Yes

Yes

Yes

Yes

No

IgA-dominant deposits

No

No

No

Yes

No

No

Cryoglobulins

No

No

No

No

Yes

No

Necrotizing granulomas

No

Yes

Yes

No

No

No

Asthma and eosinophilia

No

No

Yes

No

No

No

All these SVVs can manifest any or all of the shared features of SVV, such as purpura, nephritis, abdominal pain, peripheral neuropathy, myalgias, and arthralgias. Each is distinguished by the presence, and just as importantly the absence, of certain specific features. Both ANCA vasculitis and PAN can cause arteritis, but PAN lacks features of SVV and ANCA. GPA and EGPA are distinguished from MPA by granulomatous inflammation, and EGPA is distinguished by asthma and blood eosinophilia. ANCA, Antineutrophil cytoplasmic autoantibody; GPA, granulomatosis with polyangiitis; EGPA, eosinophilic granulomatosis with polyangiitis; PAN, periarteritis nodosa.

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et al., 1992), whereas those with EGPA may suffer from organ damage associated with eosinophilic infiltration, for example, cardiomyopathy, or gastroenteritis (Comarmond et al., 2013). The frequency of different organ system involvement, and the clinical signs and symptoms of disease, are influenced by the ANCA antigen specificity (serotype), that is, whether the patient has MPO-ANCA or PR3-ANCA (Lionaki et al., 2012). As noted earlier, this also is influenced by geography. Fig. 65.3 demonstrates the correlation of organ system involvement with ANCA serotype in a cohort of patients from the southeastern United States (Jennette and Nachman, 2017). Note that patients with renal-limited disease have predominantly MPO-ANCA, whereas patients with evidence for destructive upper respiratory tract disease have predominantly PR3-ANCA.

Pathological Features Patients with all clinicopathologic expressions of ANCA vasculitis share a common pathologic manifestation of small-vessel inflammation (Jennette, 1991, 2002). The acute vascular lesion is similar in all vessels and is characterized by mural fibrinoid necrosis with karyorrhexis and infiltrating leukocytes (Fig. 65.4) (Jennette et al., 2013b). Neutrophils predominate in early lesions and are later replaced by inflammation with a

FIGURE 65.3 Frequency of PR3-ANCA and MPO-ANCA positivity in ANCA-positive patients with a particular organ system involvement in an inception cohort of 502 ANCA vasculitis patients with MPA, GPA, or RLV evaluated at the University of North Carolina Kidney Center (excluding patients with EGPA). Organ groupings are not mutually exclusive. ‘No lung and no ENT’ has vasculitis in some other organs. Plus means there is vasculitis in an additional organ. ANCA, antineutrophil cytoplasmic autoantibody; EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear, nose, and throat; GI, gastrointestinal tract; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PR3, proteinase 3; RLV, renal-limited vasculitis. Source: Modified from Jennette, J.C., Nachman, P.H., 2017. ANCA glomerulonephritis and vasculitis. Clin J. Am. Soc. Nephrol. 12 (10), 1680
1691, with permission. FIGURE 65.4 (A, left panel) Necrotizing arteritis in a small artery and (B, right panel) necrotizing glomerulonephritis in a patient with microscopic polyangiitis. The artery and glomerulus have bright red staining for fibrinoid necrosis with a Masson trichrome stain. The artery and adjacent tissue are infiltrated by neutrophils and mononuclear leukocytes. The glomerulus has a cellular crescent on the left and segmental fibrinoid necrosis on the right.

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predominance of monocytes, macrophages, and T-lymphocytes. Late-stage lesions have fibrotic scars (Jennette et al., 2013b). Acute and chronic vasculitic lesions usually coexist in tissue samples as a result of ongoing waves of new acute lesions superimposed on earlier lesions. Focal segmental necrotizing GN with crescent formation is a frequent lesion in patients with ANCA vasculitis (Fig. 65.4). By immunofluorescence microscopy, the absence or paucity of staining for immunoglobulin distinguishes ANCA GN from immune complex GN. In addition to SVV, GPA is characterized by the presence of necrotizing granulomatous inflammation that most often affects the upper and lower respiratory tract (Jennette et al., 2013a). Earliest granulomatous lesions are histologically characterized by the presence of a neutrophil-rich inflammatory infiltrate that resembles abscess formation (Gaudin et al., 1995; Travis et al., 1991). As the lesion progresses, geographic necrosis, palisading elongated macrophages, and scattered multinucleated giant cells are observed (Travis et al., 1991). More chronic lesions have extensive fibroblastic proliferation and interstitial deposition of collagen. In contrast to GPA the necrotizing granulomas of EGPA have more intense infiltration of eosinophils along with neutrophils.

Pathogenesis The leading theory of the pathogenesis of vascular inflammation in ANCA vasculitis proposes that interaction of ANCAs with antigens (PR3 and MPO) expressed at the surface of cytokine-primed neutrophils causes full neutrophil activation [through both FcR engagement and F(ab0 )2 attachment to antigens] with generation of proinflammatory cytokines, oxygen radicals, destructive enzymes, and extrusion of neutrophil extracellular traps, in addition to the activation of the alternative complement pathway, resulting in the attachment to, injury and death of vascular endothelial cells, and other vessel wall components (Fig. 65.5) (Jennette and Nachman, 2017). Extensive in vitro evidence supports this scenario (Jennette and Falk, 1998; Rarok et al., 2003; Williams et al., 2005). Incubation of ANCA IgG with primed neutrophils induces the release of toxic reactive oxygen species and lytic granule enzymes (Falk et al., 1990b). Neutrophil priming, as occurs with exposure to certain cytokines, results in the expression of small amounts of ANCA antigens at the surface of neutrophils where they can interact with ANCA (Falk et al., 1990b). In vitro ANCA-activated neutrophils are able to kill primed endothelial cells (Ewert et al., 1992; Savage et al., 1992). Also, exposure to ANCA IgG causes rolling neutrophils to adhere to endothelial cells in culture through integrin-mediated adhesion (Radford et al., 2000). Further, it has been demonstrated that MPO-ANCA and PR3-ANCA antigens may become planted in vessel walls by a charge-dependent mechanism, allowing their interaction with ANCA to form immune complexes in situ (Vargunam et al., 1992). If the latter occurs in vivo, the magnitude of vessel wall immune complex formation must be substantially less than in conventional immune complex disease because of the absence or paucity of staining for immunoglobulin in vessel walls in ANCA SVV. In addition to in vitro experimental data, clinical observations and in vivo models (see the “Animal models” subsection of “Antineutrophil cytoplasmic autoantibody vasculitis” section) strongly support the pathogenic potential of ANCAs (Jennette and Falk, 2014). Clinical evidence include the report of a neonate who developed pulmonary hemorrhage and nephritis following transplacental transfer of maternal MPO-ANCA IgG; the presence of ANCA in the circulation and the correlation in some patients of ANCA titers with disease activity and recurrences of disease; the efficacy of anti-B-cell therapy (rituximab) and plasma exchange; and the induction of ANCA and pauci-immune SVV by drug exposure (Bansal and Tobin, 2004; Falk and Jennette, 2010; Han et al., 2003; Kallenberg et al., 1994). In addition it is interesting to note that approximately 90% of the patients report a “flu-like illness” shortly before the onset of the signs and symptoms of ANCA vasculitis (Falk et al., 1990a). An inflammatory process, such as a viral respiratory tract infection, may cause increased levels of circulating cytokines, which in turn prime neutrophils to interact with circulating ANCAs to induce vasculitis (Jennette and Falk, 1998). Experimental support for this hypothesis is provided by the observation that injection of bacterial lipopolysaccharide (LPS) into mice prior to induction of GN with anti-MPO IgG causes more severe injury (Huugen et al., 2005). The pathogenic mechanisms involved in the development of extravascular granulomatous lesions observed in GPA are unknown. One hypothesis proposes that these lesions are consequence of an exaggerated antigenindependent innate response, that is, activation of primed-neutrophils by ANCAs located in the extravascular compartment results in an intense localized necrotizing inflammation that attract an influx of mononuclear cell, later evolving into more typical granulomatous inflammation (Jennette and Falk, 2014; Jennette et al., 2013b). An alternative proposal suggest that ANCA granulomatosis is induced by an antigen-specific T-cell immune response directed against PR3 or MPO (Lamprecht and Gross, 2007).

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FIGURE 65.5 Putative pathogenic mechanisms for ANCA-induced vasculitis. ANCA antigens (granule proteins) that are normally within the cytoplasm of neutrophils are transferred to the surface by cytokine priming, where they can interact with ANCAs. Some antigens also are released and can bind to endothelial cells and other vessel wall structures. These free and bound antigens can also react with ANCAs. The interaction of neutrophils with ANCAs, especially Fc receptor engagement, induces full activation with respiratory burst and degranulation, which releases factors from ANCA-activated neutrophils that activate the alternative pathway of complement activation. The resultant inflammation causes vascular injury (vasculitis). The response to this injury results in chronic inflammation and scarring. ANCA, antineutrophil cytoplasmic autoantibody. Source: Reproduced with permission from Jennette, J.C., Nachman, P.H., 2017. ANCA glomerulonephritis and vasculitis. Clin J. Am. Soc. Nephrol. 12 (10), 1680
1691.

Autoimmune Features Over 90% of the patients with active untreated GPA or MPA, and approximately 45% of the EGPA have circulating ANCAs (Falk and Jennette, 2010; Finkielman et al., 2007; Jennette and Falk, 1997). Standard methods for the detection of ANCAs include indirect immunofluorescence (IIF) microscopy and enzyme-linked immunosorbent assays (ELISA) (Lim et al., 1999; Savige et al., 1999). When detected by IIF using alcohol-fixed neutrophils as substrate, the two major antigen specificities cause two different staining patterns: cytoplasmic (C-ANCA) and perinuclear (P-ANCA) (Fig. 65.6). The perinuclear pattern is an artifact of substrate preparation caused by diffusion of antigens from the cytoplasm to the nucleus (Charles et al., 1989). When analyzed by specific immunoassays, the most frequent C-ANCA antigen specificity is for PR3 (PR3-ANCA) (Goldschmeding et al., 1989; Jennette et al., 1990; Niles et al., 1989), and the most frequent P-ANCA specificity is for MPO (MPO-ANCA) (Jennette and Nachman, 2017). ANCA specificity is a major determinant of clinical presentation, independently of the clinicopathologic variant (Lionaki et al., 2012) (Fig. 65.3); therefore a diagnosis for ANCA vasculitis should include both the serotype as well as the phenotype, for example, PR3-ANCA MPA. It is important to realize that a minority of patients with typical clinicopathologic features of ANCA vasculitis are ANCA-negative using clinical serologic assays (Eisenberger et al., 2005). This may change with the

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FIGURE 65.6 Indirect immunofluorescence microscopy photomicrograph of (A) C-ANCA and (B) P-ANCA
staining patterns on alcoholfixed human neutrophils; produced, respectively, by PR3-ANCA and MPO-ANCA. C-ANCA, cytoplasmic antineutrophil cytoplasmic autoantibody; MPO, myeloperoxidase; P-ANCA, perinuclear antineutrophil cytoplasmic autoantibody; PR3, proteinase 3.

development of more sensitive and activity-specific assays. For example, using an epitope-specific assay, Roth et al. were able to detect MPO-ANCA with very restricted epitope specificity in many patients who were ANCAnegative by conventional clinical assays (Roth et al., 2013). In addition they identified three categories of MPOANCA epitope specificity: (1) epitope specificity confined to ANCA-associated vasculitis patients with active disease, (2) epitope specificity detected in patients with active disease and in remission, and (3) epitope specificity that was seen is patients as well as in very low titer in healthy controls (natural ANCA) (Roth et al., 2013). Approximately 5%
15% of the ANCA-vasculitis patients have concurrent antiglomerular basement membrane (anti-GBM) antibodies (Jennette, 2003; McAdoo et al., 2017; Rutgers et al., 2005). When both autoantibodies are present, a patient is at risk for manifesting vasculitic features of ANCA-associated disease that do not occur with anti-GBM disease alone, such as cutaneous, skeletal muscle, or gut vasculitis. In addition these patients have a worse prognosis than those with ANCA alone (Jennette, 2003; McAdoo et al., 2017; Rutgers et al., 2005). The presence of antiplasminogen antibodies is associated with venous thrombotic events in patients with PR3-ANCA vasculitis (Bautz et al., 2008). In addition antibodies directed against lysosomal membrane protein 2 have been reported in some patients with ANCA-necrotizing GN (Kain et al., 2008).

Genetic Features and Environmental Influences The precise etiology of the autoimmune response that causes pathogenic ANCAs is unknown, but evidence suggests that multiple environmental and genetic factors may play a relevant role in this process (Jennette et al., 2013b). Several infections have been implicated in the induction of ANCA vasculitis, for example, Ross River virus, Entamoeba histolytica, and Staphylococcus aureus (Stegeman et al., 1996). Some authors suggest that molecular mimicry between microbial proteins and self-antigens is responsible for the induction of the autoimmune ANCA response (Kain et al., 2008). Another theory proposes that pathogens can initiate an autoantibody response through induction of an appropriate antibody response to microbial proteins that have an amino acid sequence that mimics the antisense sequence (complementary sequence) of the autoantigen (Pendergraft et al., 2004). These antibodies to the complementary peptide in turn induce antiidiotypic antibodies that cross-react with the autoantigen (i.e., are autoantibodies). In support of this theory patients with PR3-ANCA disease have circulating antibodies that react with peptides that have an amino acid sequence that is complementary to PR3, and these antibodies react with anti-PR3 antibodies as an antiidiotypic pair. Further, immunization of mice with a complementary PR3 peptide induces not only an antibody response to the complementary PR3 peptide but also to native PR3. Interestingly, S. aureus, Ross River virus, and E. histolytica, which have been associated with PR3-ANCA disease, contain proteins with amino acid sequences that mimic complementary peptides of PR3 (Pendergraft et al., 2004).

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ANCA disease can also be caused by a variety of drugs, including propylthiouracil, allopurinol, minocycline, hydralazine, or cocaine contaminated with levamisole (Choi et al., 2000; Pendergraft and Niles, 2014). Other environmental exposures that have been associated with the development of ANCA vasculitis include silica, mercury, and lead exposure (Albert et al., 2004; Hogan et al., 2001; Lane et al., 2003). A GWAS of a large cohort of European patients has revealed a genetic influence on ANCA disease that correlated best with MPO-ANCA and PR3-ANCA autoantigen specificity rather than clinicopathologic phenotype (Lyons et al., 2012). In this study PR3-ANCA was associated with the human leukocyte antigen (HLA)-DP and genes encoding α1-antitrypsin (SERPINA1) and PR3 (PRTN3). MPO-ANCA was associated with HLA-DQ. Similar results were recently obtained in a North American cohort of GPA/MPA patients, where additionally a gene variant of PTPN22 was associated with an increasing susceptibility to ANCA disease (Merkel et al., 2017). The predilection for the disease in white persons and the low prevalence in African Americans suggests that a genetic background contributes to disease induction. A previous study showed that African Americans with PR3-ANCA ANCA vasculitis had 73.3-fold higher odds of having HLA-DRB1 15 alleles than healthy controls. Interestingly, DRB1 1501 protein binds with high affinity to amino acid sequences of both sense-PR3 and antisense (complementary) PR3, suggesting that the major histocompatibility complex (MHC) antigen binding site is important in disease induction (Cao et al., 2011). Epigenetic factors can also influence ANCA pathogenesis. Epigenetic modification of ANCA autoantigenencoding genes results in aberrant overexpression of PR3 and MPO in neutrophils of ANCA patients (Ciavatta et al., 2010).

Animal Models Xiao et al. (2002) described the first convincing animal model of ANCA-induced SVV. This model is based on the passive transfer of purified anti-MPO IgG or splenocytes, obtained from MPO-deficient mice immunized with murine MPO, into wild-type or immunodeficient Rag22/2 mice (lacking functional T and B cells) (Xiao et al., 2002). Over the course of 6 days, all mice that received anti-MPO developed necrotizing and crescentic GN that closely mimic human disease. In addition some mice exhibited extrarenal systemic SVV, for example, pulmonary capillaritis or necrotizing granulomatous inflammation, leukocytoclastic angiitis in the skin, or necrotizing arteritis in multiple viscera (Fig. 65.7). Studies using this model, or its variants, have demonstrated that (1) MPOANCA antibodies alone, in the absence of functional T cells, are sufficient to cause acute disease, (2) neutrophils are the mainstay effectors of disease induction, (3) bone marrow
derived cells are sufficient and necessary to induce ANCA GN, (4) genetic background plays an important role in the susceptibility and severity of disease, (5) circulating proinflammatory cytokines are able to exacerbate ANCA disease, (6) FC receptors are involved in pathogenesis and disease modulation, and (7) activation of alternative complement pathway is required to induce ANCA-associated GN (Huugen et al., 2005; Schreiber et al., 2006; Xiao et al., 2002, 2005, 2007, 2013).

FIGURE 65.7 Necrotizing arteritis in a small artery in the dermis of a mouse 6 days after intravenous injection of mouse antimyeloperoxidase IgG. There is a central area of deeply eosinophilic fibrinoid necrosis surrounded by leukocytes with leukocytoclasia (H&E stain).

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TABLE 65.2 Clinicopathologic Phenotypes (RLV 5 Renal Limited Vasculitis, MPA 5 Microscopic Polyangiitis, GPA 5 Granulomatosis With Polyangiitis) and Serotypes [MPO-ANCA (AntineutrophilCytoplasmic-Autoantibody
Myeloperoxidase), PR3-ANCA (Proteinase-3
Antineutrophil-CytoplasmicAutoantibody)] of 502 ANCA-Positive Patients From an Inception Cohort Evaluated at the University of North Carolina Kidney Center (Excluding Patients With Eosinophilic Granulomatosis With Polyangiitis, EGPA) Phenotype

MPO-ANCA (%)

PR3-ANCA (%)

RLV (n 5 121)

81

19

MPA (n 5 264)

59

41

GPA (n 5 117)

26

74

Serotype

RLV (%)

MPA (%)

GPA (%)

All (n 5 502)

24

53

23

MPO-ANCA (n 5 283)

35

55

11

PR3-ANCA (n 5 219)

10

50

40

Diagnostic Procedures Diagnosis of ANCA vasculitis is based on a combination of compatible clinical manifestations, positive laboratory test results, supportive radiology findings, and, when possible, the pathology confirmation of SVV (Table 65.2) (Jayne, 2009). As an SVV, ANCA vasculitis must be distinguished from other forms of SVV that can cause similar signs and symptoms, and have similar pathologic lesions by light microscopy. Immunopathologic features in tissue and serum are important is distinguishing among different forms of SVV (Table 65.1). ANCA vasculitis can involve arteries causing lesion that are indistinguishable histologically for the arteritis of PAN; however, PAN does not cause venulitis and capillaritis and is not associated with ANCA. Laboratory workup for suspected ANCA vasculitis must include serum creatinine levels and urinalysis in all cases, in addition to determination of ANCA, antinuclear, and anti-GBM antibodies. Although one approach to ANCA testing is to first perform a screening by IIF and if positive (or inconclusive) to test for MPO-ANCA/PR3ANCA by ELISA (Bossuyt et al., 2017; Savige et al., 1999), there is increasing evidence that high-quality immunoassays may be used for the primary screening, without the categorical need of IIF (Csernok et al., 2016; Damoiseaux et al., 2017). In addition epitope-specific assays may be a future option for the diagnosis and followup of these patients (Roth et al., 2013). Serology alone cannot make the distinction between MPA, GPA, EGPA, or isolated pauci-immune crescentic GN because each syndrome can be associated with either C-ANCA (PR3-ANCA) or P-ANCA (MPO-ANCA) (Lim et al., 1999; Savige et al., 1999). However, the relative frequencies of ANCA specificities vary among the disease variants. For example, most patients with GPA have C-ANCA (PR3-ANCA), and most patients with renallimited disease or MPA have P-ANCA (MPO-ANCA) (Table 65.2). Dual positivity is usually observed in druginduced ANCA vasculitis (Savige et al., 2000). Diseases other than pauci-immune SVV can be associated with ANCAs, especially with ANCAs that are not specific for MPO or PR3, for example, autoimmune hepatitis, rheumatoid arthritis, ulcerative colitis, or sclerosing cholangitis (Bartunkova et al., 2002; Jennette and Falk, 1993). Radiologic evaluation of the chest, orbits, brain, or ear, nose, and throat (ENT) structures may add diagnostic information and may be useful during follow-up. Computed tomography is preferred for evaluation of ANCAassociated lung disease. Typical findings include multiple, bilateral nodules, masses, and cavitations in cases of GPA and ground-glass opacities, usually reflecting alveolar hemorrhage, in patients with MPA (Cordier et al., 1990). Pulmonary fibrosis may be observed in approximately 7%
10% of these patients, particularly those with MPO-ANCA (Alba et al., 2017). Additional procedures may be performed if clinically indicated, for example, nerve-conduction studies, bronchoscopy, or ophthalmologic examination.

Treatment Treatment of ANCA vasculitis is composed of a remission induction phase with administration of highly potent immunosuppressants followed by a remission-maintenance period that aims to prevent relapses, still present in 40%
50% of the patients, and accrual of damage associated with vasculitis activity (Yates et al., 2016).

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Remission-induction therapy of organ- or life-threatening disease consists in a combination of high-dose GC and either rituximab or cyclophosphamide (de Groot et al., 2009; Stone et al., 2010). Plasma exchange needs to be considered in patients with rapidly progressive GN and serum creatinine level .5.6 mg/dL, concomitant anti-GBM autoantibodies, or in those with severe diffuse pulmonary hemorrhage (Jayne et al., 2007; Klemmer et al., 2003; Yates et al., 2016). Methotrexate and mycophenolate mofetil are alternatives for less severe disease, for example, GPA with limited ENT involvement or patients with cutaneous or articular involvement (De Groot et al., 2005; Han et al., 2011). EGPA patients with nonorgan or life-threatening manifestations are usually managed with GC alone (Groh et al., 2015). The addition of IL-5 antagonist mepolizumab is effective in relapsing/refractory EGPA disease (Wechsler et al., 2017). Current therapy strategies achieve remission of approximately 80%
90% of the patients, usually within 3
6 months after the initiation of treatment (Holle et al., 2011). Once remission is induced, patients are switched to maintenance therapy with low-dose GC in combination with rituximab, azathioprine, or methotrexate (Jayne et al., 2003; Pagnoux et al., 2008, 2015). The optimal duration of this phase is unknown. Ideally, extent of maintenance therapy should be individualized and should take into account aspects such as age, previous morbidity, or the presence of factors that have been associated with a relapsing course, for example, ANCA-PR3 seropositivity, lung or ENT involvement, or a clinical diagnosis of GPA (Hogan et al., 2005). Despite the efficacy of immunosuppressive therapy, morbidity remains common in ANCA vasculitides. Patients are at increased risk of cardiovascular events and malignancy in addition to development of end-stage renal disease or treatment-associated adverse effects, for example, osteoporosis or opportunistic infections (Westman et al., 2015).

CRYOGLOBULINEMIC VASCULITIS Definition Cryoglobulins are circulating immunoglobulins that precipitate at cold temperatures and dissolve with rewarming. CV is defined as vasculitis with cryoglobulin immune deposits that affects small vessels (predominantly capillaries, venules, or arterioles) with associated serum cryoglobulins (Jennette et al., 2013a).

Epidemiology CV is more common in southern Europe than in northern Europe or North America and is closely associated with HCV infection (Ferri et al., 2004). Cryoglobulins are detected in 12%
50% of the HCV-infected patients, although less than 30% develop overt systemic vasculitis. HCV antibodies and RNA are detected in the serum of 75%
95% of the patients with vasculitis and GN caused by mixed cryoglobulins (D’Amico and Fornasieri, 1995; Ferri et al., 2004; Ramos-Casals et al., 2012). CV is most frequent in middle-aged individuals, predominantly women (female-to-male ratio 3:1) (Ferri et al., 2004).

Clinical Features and Disease Associations The clinical picture of CV may overlap with those of other systemic SVV (Table 65.1) and ranges from mild involvement of the skin and joints to potentially life-threatening disease, for example, alveolar hemorrhage. Patients with type I cryoglobulinemia (see the “Autoimmune features” subsection of “Cryoglobulinemic Vasculitis” section) may develop symptoms of vascular occlusion, for example, acrocyanosis, livedo reticularis, skin necrosis, digital gangrene, or manifestations suggestive of hyperviscosity syndrome, that is, blurred vision, mucosal bleeding, headache, confusion, hearing loss, or heart failure (Harel et al., 2015; Terrier et al., 2013). Features of mixed CV (type II/III cryoglobulinemia) include constitutional symptoms (weakness, fever), palpable purpura, cutaneous ulcers, arthralgia/arthritis, mononeuritis multiplex, or distal sensory peripheral neuropathy; and kidney involvement, which usually presents as microscopic hematuria with proteinuria and less frequently as acute renal failure, nephrotic syndrome, or systemic hypertension. Sicca syndrome and abnormal liver function tests are common in HCV-associated CV.

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1301

FIGURE 65.8 Cryoglobulinemic vasculitis affecting a small artery in the kidney. The deeply acidophilic material in the vessel probably is a mixture of thrombus, fibrinoid necrosis, and aggregated cryoglobulins. The vessel wall and adjacent tissue are infiltrated by leukocytes with leukocytoclasia.

Pathological Features CV is characterized pathologically by inflammation in small vessels that is associated with deposits of cryoglobulins and complement in vessel lumens and walls (Fig. 65.8). CV affects vessels of many types, including postcapillary venules (e.g., in the dermis), capillaries (e.g., glomerular and rarely pulmonary alveolar capillaries), arterioles, and rarely small arteries (Ferri et al., 2004). Immunofluorescence microscopy reveals granular deposits of immunoglobulins and complement in vessel walls, and sometimes lumenal aggregates of cryoglobulins and complement. Type I membranoproliferative GN is observed in 70%
80% of the kidney biopsies; highly cellular glomerular infiltrates, thickening of GBM, hyaline intraluminal thrombi (precipitated cryoglobulins), and subendothelial dense deposits are typical features (D’Amico et al., 1989; Sinico et al., 1988).

Pathogenesis The pathogenic effect of cryoglobulins is the result of two different mechanisms, that is, immunoglobulin precipitation in the microcirculation, and deposition of mixed cryoglobulins in small vessels (Ramos-Casals et al., 2012). In the latter acute inflammation of blood vessels develops when immune complexes, composed of mixed cryoglobulins, activate the complement cascade, particularly the classic pathway (Sansonno et al., 2009). Of interest, it has been previously reported that immune complexes in HCV-associated CV contain nonenveloped nucleocapsid proteins and whole HCV virions (Sansonno and Dammacco, 2005). In this regard although mechanisms of cryoglobulin induction by HCV are not fully elucidated, one hypothesis proposes that infection of B cells by HCV triggers the production of polyclonal and monoclonal rheumatoid factors (RFs) that participate in cryoglobulin formation (D’Amico and Fornasieri, 1995). Another proposes that HCV lipoprotein induces an IgM response that is initially reactive with a virus-self complex but subsequently mutates to have RF activity (Agnello, 1995).

Autoimmune Features Cryoglobulins are divided into three major types: monoclonal (type I, either IgM or IgG), mixed monoclonal
polyclonal (type II, monoclonal IgM in combination with polyclonal IgG), and polyclonal (type III) (Brouet et al., 1974). Type I cryoglobulinemia (6% of the cases) is associated with B-cell lymphoproliferative disorders. Type II cryoglobulinemia (62% of the cases) is almost always caused by chronic HCV infection, although HBV and HIV are detected in a small percentage. Type III cryoglobulinemia (32% of the cases) is caused by HCV, lymphoproliferative malignancies or autoimmune diseases such as Sjo¨gren syndrome or SLE (Monti et al., 1995). Monoclonal cryoglobulins are not effective activators of inflammatory mediator systems and, therefore, rarely cause overt vasculitis, and morbidity is primarily by precipitation within vessels with the resultant occlusion (Muchtar et al., 2017). In contrast mixed cryoglobulins are immune complexes that are capable of activating inflammatory mediators and, therefore, characteristically cause systemic vasculitis (Muchtar et al., 2017). Most type II/III cryoglobulins contain autoantibodies directed against immunoglobulins, that is, RFs (Ferri et al., 2004; Sansonno and Dammacco, 2005).

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Genetic Features and Environmental Influences As described previously, there is a strong association between CV and HCV infection, though not all patients with HCV develop cryoglobulinemia (D’Amico and Fornasieri, 1995; Ferri et al., 2004; Sansonno and Dammacco, 2005). The likelihood of developing circulating cryoglobulins is closely linked to the duration of HCV infection and the presence of certain HLA polymorphisms (Amoroso et al., 1998; Congia et al., 1996).

Animal Models The production of high titers of IgG-RF by secreting hybridomas was the base of two experimental mouse models of CV (Gyotoku et al., 1987; Kikuchi et al., 2002). In the first model investigators established monoclonal IgG-RF-secreting hybridomas from MRL/lpr mice (Gyotoku et al., 1987). These monoclonal RF antibodies were capable of forming cryoglobulins, and, when injected into normal mice, caused peripheral vasculitis and GN resembling that seen in patients with mixed cryoglobulinemia. In an alternative model mice were implanted with a hybridoma that secreted an IgG3 anti-IgG2a RF. These animals developed circulating cryoglobulins, acute GN, and cutaneous leukocytoclastic vasculitis (Kikuchi et al., 2002).

Diagnostic Procedures Classification criteria for CV have been proposed (De Vita et al., 2011). The laboratory hallmark of CV is the detection of cryoglobulins in the circulation (Table 65.2). Blood collection for cryoglobulin identification should be performed in prewarmed tubes. The type of cryoglobulins is later identified by immunoelectrophoresis and immunofixation (Ferri, 2008). Hypocomplementemia, characteristically low C4 but normal or near normal C3, is typically observed in mixed cryoglobulinemia as is the presence of high titers of RF (Ferri, 2008). Evaluation for possible HCV infection is mandatory. Additional work-up in selected cases may include HBV and HIV testing and determination of antinuclear, anti-DNA, and anti-Ro/La antibodies (Ramos-Casals et al., 2012). Tissue samples of the skin, peripheral nerve, or kidney may confirm the presence of a SVV.

Treatment Treatment of type I cryoglobulinemia is directed against the underlying lymphoproliferative disease (Muchtar et al., 2017). In patients with hyperviscosity syndrome plasma exchange may be of benefit. Management of noninfectious mixed cryoglobulinemia consists in the administration of high-dose GC and rituximab (Terrier et al., 2012). In organ- or life-threatening disease combination of intravenous methylprednisolone, rituximab (or cyclophosphamide), and plasmapheresis is recommended (D’Amico and Fornasieri, 1995). Suppression of vascular inflammation and clearance of HCV are necessary in patients with HCV-associated CV. In these cases GC and rituximab are used in combination with pegylated IFN-ribavirin or preferentially, direct-acting antiviral agents, for example, sofosbuvir, simeprevir, or daclatasvir (Gragnani et al., 2016; Saadoun et al., 2017; Sise et al., 2016; Sneller et al., 2012). The choice of hepatitis C antiviral therapy should follow international guidelines (2016).

¨ NLEIN PURPURA) IgA VASCULITIS (HENOCH
SCHO Definition IgA vasculitis is a systemic vasculitis with IgA-dominant vascular immune deposits affecting small vessels. The disease occurs commonly in children and often involves the skin, the gastrointestinal tract, and the kidneys (Jennette et al., 2013a).

Epidemiology IgA vasculitis is the most common form of vasculitis in children. The disease has an incidence of 13
20 per 100,000 and is observed more frequently in patients of 4
7 years old (Gardner-Medwin et al., 2002). Male-to-

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female ratio is about 1.5
1.8 to 1 (Gardner-Medwin et al., 2002; Hocevar et al., 2014). IgA vasculitis is less common in adults, that is, annual incidence of 3.4 new cases per million inhabitants (Watts et al., 1998).

Clinical Features and Disease Associations The classic manifestations of IgA vasculitis include palpable purpura, abdominal pain, arthritis/arthralgia, and nephritis. Purpura is typically symmetric and involves the lower extremities and buttocks. In adults purpura may show necrotic or hemorrhagic areas (Audemard-Verger et al., 2017). Arthritis of IgA vasculitis is typically nonerosive, migratory, and oligoarticular. Gastrointestinal involvement may present as nausea and vomiting, abdominal pain, bleeding, or, uncommonly, perforation or intussusception. Renal involvement is usually manifested as microscopic hematuria with low-level proteinuria, although nephrotic-range proteinuria, hypertension, and renal failure may occur. In contrast to the excellent overall prognosis observed in children 10%
30% of the adult patients suffer from more severe kidney involvement that may progress to end-stage renal disease (ESRD) (Coppo et al., 2006; Pillebout et al., 2002; Shrestha et al., 2006). In addition approximately 20% of adult patients have chronic relapsing disease (Coppo et al., 2006; Pillebout et al., 2002; Shrestha et al., 2006). As in other SVV, alveolar hemorrhage and peripheral neuropathy may be observed.

Pathological Features IgA vasculitis predominantly affects capillaries, venules, or arterioles (Jennette et al., 2013a). Immunofluorescence microscopy of dermal venules and renal glomeruli reveals granular vessel wall deposits of predominantly IgA1 and C3, with variable amounts of IgG and IgM, supporting a pathogenic mechanism that involves IgA-dominant immune deposits and activation of the alternative pathway of the complement system (Heineke et al., 2017).

Pathogenesis IgA vasculitis is an immune-mediated vasculitis that probably results from a dysregulated mucosal immune response, possibly initiated by environmental or infectious stimuli in a genetically predisposed individual (Heineke et al., 2017). IgA1-dominant immune complex deposits in vessel walls are the putative mediators of the inflammation. The IgA1 deposits may contain predominantly self-aggregated IgA1 or IgA1 complexed with antiIgA1 autoantibodies (Heineke et al., 2017). Human IgA1 has an O-glycosylated hinge region not present in other immunoglobulin classes, and this hinge region has reduced galactosyl residues in patients with IgA nephropathy and IgA vasculitis (Allen et al., 1998; Heineke et al., 2017; Lau et al., 2007; Suzuki et al., 2009). This reduced galactosylation may be due to a functional defect in plasma cell β-1,3-galactosyltransferase. The abnormal glycosylation alters IgA1 structure and function, resulting in IgA1 aggregation, greater affinity for matrix proteins in vessel walls (including glomerular mesangium), and greater complement activation, which could result in localization of pathogenic IgA1-dominant deposits in vessel walls with resultant complement activation and vasculitis. Increased serum levels of IgA antiphospholipid antibodies (APA) directed against cardiolipin and β2-glycoprotein have been reported in some patients (Kawakami et al., 2006; Yang et al., 2000, 2012). These antibodies are able to induce complement-dependent lysis of endothelial cells (Heineke et al., 2017).

Autoimmune Features Several antibodies have been detected in the serum of children and adults with active IgA vasculitis nephritis and IgA nephropathy, for example, antibodies directed against abnormally glycosylated IgA1, IgA anti-α-galactosyl, IgA antiendothelial cell antibodies, and APA (Davin et al., 1987; Heineke et al., 2017; Kawakami et al., 2006; Yang et al., 2000, 2012). The precise role of these antibodies in the pathogenesis of this vasculitis remains uncertain.

Genetic Features and Environmental Influences IgA vasculitis has a multifactorial etiology in which both genetic and environmental factors are probably involved. An infectious etiology of IgA vasculitis has long been suspected due to the seasonal pattern of the

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65. NECROTIZING ARTERITIS AND SMALL-VESSEL VASCULITIS

disease, and the finding that approximately 40%
50% of the affected children suffered from an upper respiratory tract infection near the time of disease onset (Gonzalez-Gay et al., 2004; Masuda et al., 2003; Saulsbury, 2002; Ting and Hashkes, 2004). In this sense group A Streptococcus, methicillin-resistant S. aureus, and Helicobacter pylori have all been implicated as potential triggers for IgA vasculitis. In addition anecdotal cases have reported the association of this vasculitis with certain drugs, vaccination, and malignancy (Podjasek et al., 2014). Infections and other mucosal immune stimuli may be able to incite the production of pathogenic IgA1 that is not dependent on an antigen-specific immune response. There is evidence from family studies that there may be a genetic predisposition for having circulating potentially pathogenic abnormally glycosylated IgA1 (Boyd and Barratt, 2011; Kiryluk et al., 2011). More importantly, a recent GWAS performed in 308 European patients identified that polymorphisms of HLA-DRB1 gene were associated with IgA vasculitis susceptibility (Lopez-Mejias et al., 2017). These findings are in line with previous studies that reported an increased prevalence of HLA-DRB1 and IL-1 allele polymorphisms in IgA vasculitis patients (Amoli et al., 2004).

Animal Models There is no good animal model for IgA vasculitis, although there are several animal models of IgA nephropathy, which is the glomerular lesion of IgA vasculitis. Many of these involve oral or nasal immunization with dietary or infectious antigens (Amore et al., 2004). Uteroglobin gene knockout and uteroglobin antisense transgenic mice develop pathologic features of human IgA nephropathy, but the relevance of this to human disease is unclear (Coppo et al., 2002; Lin et al., 2015; Zheng et al., 1999). Okazaki et al. (2012) used ddY mice as a model of spontaneously developing IgA nephropathy and have shown that aberrant IgA glycosylation influences the progression of kidney disease.

Diagnostic Procedures The immunohistologic identification of IgA-dominant immune deposits in vessels is currently the only accepted diagnostic marker for IgA nephropathy and is a defining feature of IgA vasculitis (Table 65.1) (Jennette et al., 2013a). Although a kidney biopsy may confirm the diagnosis, these are reserved for patients (usually adults) with nontypical presentations or those with severe involvement. The amount of circulating abnormally glycosylated IgA1 or IgG autoantibodies specific for abnormally glycosylated IgA1 may become a useful diagnostic marker in the future (Heineke et al., 2017). Differential diagnosis of IgA vasculitis includes other SVV, viral infections, thrombocytopenic purpura, and SLE. Patients with SVV that has vascular IgA-dominant immune deposits who have unusually aggressive vasculitis or GN should be evaluated for concurrent ANCA disease.

Treatment In children, IgA vasculitis usually is a mild, self-limited, vasculitis that does not warrant corticosteroid or cytotoxic therapy (Heineke et al., 2017; Robson and Leung, 1994). Some patients will require symptomatic relief of articular or abdominal pain with nonsteroidal antiinflammatory drugs. Colchicine and dapsone may be used in cases with chronic purpuric lesions (Audemard-Verger et al., 2015). Approximately 5% of the IgA vasculitis patients will develop organ- or life-threatening disease, for example, rapidly progressive GN, significant gastrointestinal bleeding or severe central nervous system (CNS) disease. In these cases high-dose methylprednisolone should be administered; cyclophosphamide, cyclosporine, rituximab, or plasmapheresis may be tried as adjuvant therapy (Audemard-Verger et al., 2015; Gedalia, 2004; Niaudet and Habib, 1998; Pillebout et al., 2010; Tarshish et al., 2004; Ting and Hashkes, 2004).

CONCLUDING REMARKS—FUTURE PROSPECTS A variety of pathogenic immunologic mechanisms, including autoimmune processes, mediate necrotizing arteritis and SVV. Clinically, and even pathologically, identical disease can be produced by distinctly different etiologies and pathogenic mechanisms, and a given etiology can produce more than one clinical and pathologic pattern of vasculitis. Because different organs can be affected in different patients, the clinical manifestations of

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even relatively specific types of vasculitis are extremely variable among patients. Therefore the diagnosis of systemic vasculitis, including autoimmune vasculitis, is difficult and requires knowledgeable and skillful integration of clinical, pathologic, and laboratory data. Although difficult, precise diagnosis is essential for proper management, because the prognosis and appropriate treatment vary substantially among different categories of vasculitis. As knowledge of pathogenic immunologic mechanisms and inflammatory mediator systems increases, more effective treatments for autoimmune-mediated vasculitis will emerge, which will make precise diagnosis even more important.

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VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES