ANCA-Associated Vasculitis: Core Curriculum 2020

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by inflammation and destruction of small- and medium-sized blood vessels and the presence of circulating ANCA. Clinical disease phenotypes include granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis. Serologic classification of AAV into proteinase 3–ANCA disease and myeloperoxidase-ANCA disease correlates with a number of disease characteristics. AAV has a predilection for the kidney, with >75% of patients having renal involvement characterized by rapidly progressive glomerulonephritis. The cause and pathogenesis of AAV are multifactorial and influenced by genetics, environmental factors, and responses of the innate and adaptive immune system. Randomized controlled trials in the past 2 decades have refined the therapy of AAV and transformed AAV from a fatal disease to a chronic illness with relapsing course and associated morbidity. This article in AJKD’s Core Curriculum in Nephrology series provides a detailed review of the epidemiology, pathogenesis, diagnosis, and advances in the management of AAV. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by inflammation and destruction of small- and medium-sized blood vessels and the presence of circulating ANCA. Clinical disease phenotypes include granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis. Serologic classification of AAV into proteinase 3–ANCA disease and myeloperoxidase-ANCA disease correlates with a number of disease characteristics. AAV has a predilection for the kidney, with >75% of patients having renal involvement characterized by rapidly progressive glomerulonephritis. The cause and pathogenesis of AAV are multifactorial and influenced by genetics, environmental factors, and responses of the innate and adaptive immune system. Randomized controlled trials in the past 2 decades have refined the therapy of AAV and transformed AAV from a fatal disease to a chronic illness with relapsing course and associated morbidity. This article in AJKD’s Core Curriculum in Nephrology series provides a detailed review of the epidemiology, pathogenesis, diagnosis, and advances in the management of AAV. FEATURE EDITOR:Asghar RastegarADVISORY BOARD:Ursula C. BrewsterMichael ChoiAnn O’HareManoocher SoleimaniThe Core Curriculum aims to give trainees in nephrology a strong knowledge base in core topics in the specialty by providing an overview of the topic and citing key references, including the foundational literature that led to current clinical approaches. FEATURE EDITOR: Asghar Rastegar ADVISORY BOARD: Ursula C. Brewster Michael Choi Ann O’Hare Manoocher Soleimani The Core Curriculum aims to give trainees in nephrology a strong knowledge base in core topics in the specialty by providing an overview of the topic and citing key references, including the foundational literature that led to current clinical approaches. The most widely used classification system for systemic vasculitis is that defined at the 2012 International Chapel Hill Consensus Conference (CHCC), which stratifies vasculitis according to vessel size (Box 1). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is divided into 3 clinical diseases (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA], and eosinophilic GPA [EGPA]). Each of these conditions is commonly associated with a circulating ANCA, with the major target antigens identified as proteinase 3 (PR3) and myeloperoxidase (MPO).Box 1Systemic Vasculitis NomenclatureSmall-vessel vasculitis (SVV)•Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV)⋄Microscopic polyangiitis (MPA)⋄Granulomatosis with polyangiitis (Wegener) (GPA)⋄Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA)•Immune complex SVV⋄Anti–glomerular basement membrane (anti-GBM) disease⋄Cryoglobulinemic vasculitis (CV)⋄Immunoglobulin A (IgA) vasculitis (Henoch-Schönlein) (IgAV)⋄Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis)Medium-vessel vasculitis (MVV)•Polyarteritis nodosa (PAN)•Kawasaki disease (KD)Large-vessel vasculitis•Takayasu arteritis (TA)•Giant cell arteritis (GCA)Variable vessel vasculitis (VVV)•Behçet disease (BD)•Cogan syndrome (CS)Based on 2012 International Chapel Hill Consensus Conference (see Jennette et al in Additional Readings). Small-vessel vasculitis (SVV)•Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV)⋄Microscopic polyangiitis (MPA)⋄Granulomatosis with polyangiitis (Wegener) (GPA)⋄Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA)•Immune complex SVV⋄Anti–glomerular basement membrane (anti-GBM) disease⋄Cryoglobulinemic vasculitis (CV)⋄Immunoglobulin A (IgA) vasculitis (Henoch-Schönlein) (IgAV)⋄Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis) Medium-vessel vasculitis (MVV)•Polyarteritis nodosa (PAN)•Kawasaki disease (KD) Large-vessel vasculitis•Takayasu arteritis (TA)•Giant cell arteritis (GCA) Variable vessel vasculitis (VVV)•Behçet disease (BD)•Cogan syndrome (CS) Based on 2012 International Chapel Hill Consensus Conference (see Jennette et al in Additional Readings). One of the current controversial issues in AAV is the definition of disease based on clinical phenotype (GPA vs MPA) because there is significant overlap in clinical features between these 2 diseases. It has been suggested that AAV should be classified according to ANCA specificity (PR3-ANCA disease vs MPO-ANCA disease). Relapse rates (higher in PR3-ANCA) and clinical outcomes (mortality higher in MPO-ANCA) associate better with ANCA specificity, and genetic studies segregate more closely with ANCA specificity than clinical phenotype. The CHCC 2012 advocated for adding a prefix to the clinical phenotype in a given patient with AAV (eg, PR3-ANCA GPA or MPO-ANCA GPA). A large multinational study (>6,000 patients from 136 sites in 32 countries), the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS), is currently collecting data to develop new diagnostic criteria and update the classification for systemic vasculitis. AAV is an uncommon disease with an incidence of about 20 per million population per year in Europe and North America. There is a slight male preponderance. Incidence increases with age, with a peak in the 60- to 70-year age range. AAV is more common in white and Asian populations and less common in African American populations. There is notable geographic variation, with GPA being more common in Northern Europe and Australia/New Zealand, whereas MPA is more common in Southern Europe and Asia. It is unclear whether this represents genetic differences or other environmental factors such as vitamin D levels and sun exposure. Infection with Staphylococcus aureus may trigger episodes of AAV; notably, GPA is more common in winter months, and chronic nasal carriage of S aureus has been associated with an increased risk for disease relapse. Furthermore, a double-blind placebo-controlled trial of trimethoprim in patients with GPA reported fewer respiratory tract infections and a significantly lower relapse rate. Other environmental factors include silica exposure, hydrocarbon exposure, and pesticides and medications (see Drug-Induced Vasculitis). Familial forms of AAV have been described but are rare. Two genome-wide association studies in European and North American populations have identified disease susceptibility loci in AAV. GPA is associated with single-nucleotide polymorphisms in HLA-DP, PRTN3 (encoding PR3), and SERPINA1 (encoding α1-antitrypsin, a protease acting as the major inhibitor of PR3). PR3-ANCA disease–associated variants in PRTN3 and SERPINA1 support the hypothesis that PR3-ANCA is not merely an epiphenomenon in AAV, but plays a central role in the pathogenesis of this disease. By contrast, MPA was associated with HLA-DQ polymorphisms. It is worth noting that the strength of these genetic associations was greater with respect to ANCA specificity (PR3-ANCA or MPO-ANCA) than for clinical phenotype (GPA or MPA). ►Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum. 2013;65(1):1-11. ★ ESSENTIAL READING►Lionaki S, Blyth ER, Hogan SL, et al. Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum. 2012;64(10):3452-3462.►Lyons PA, Rayner TF, Trivedi S, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367(3):214-223.►Unizony S, Villarreal M, Miloslavsky EM, et al. Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis. 2016;75(6):1166-1169. ANCAs are autoantibodies directed against cytoplasmic antigens expressed in the primary granules of neutrophils and the lysosomes of monocytes. Neutrophil primary granules contain a range of antibacterial proteins, including lysozyme, MPO, neutral serine proteinases (PR3, elastase, and cathepsin G), and acid hydrolases (cathepsin B and D). Autoantibodies may develop against any of these proteins, but the clinically relevant antibodies are directed against MPO and PR3. During the active stage of disease, ANCAs are typically immunoglobulin G (IgG), but other immunoglobulin classes (IgM and IgA) are described. Many laboratories use indirect immunofluorescence assay (IIF) as a screening test for ANCA. Although both MPO and PR3 are found in primary granules, 2 major immunostaining patterns are seen. Ethanol fixation leads to dissolution of primary granules, and the cationic MPO attaches to the negatively charged nuclear membrane giving a perinuclear pattern (pANCA), whereas PR3 remains distributed in a cytoplasmic pattern (cANCA). When a positive IIF result is identified, the target antigen is confirmed by an antigen-specific immunoassay (enzyme-linked immunosorbent assay). A 2017 international consensus statement on ANCA testing recommended initial testing for suspected AAV with immunoassays for PR3-ANCA and MPO-ANCA, rather than IIF. PR3-ANCA is most commonly associated with GPA (75%), whereas MPO-ANCA is more commonly associated with MPA (60%) or renal-limited vasculitis (80%; Table 1). Atypical ANCAs, which are not directed against either PR3 or MPO (positive IIF and negative enzyme-linked immunosorbent assay), can be found in a range of nonvasculitic conditions (inflammatory bowel disease, autoimmune disease, and malignancy). PR3-ANCA or MPO-ANCA may also be found in chronic infections (endocarditis, tuberculosis, human immunodeficiency virus [HIV], hepatitis C, and bartonellosis). The presence of both anti-MPO and anti-PR3 antibodies in the same patient is very rare and suggestive of drug-induced vasculitis.Table 1Frequency of ANCA Positivity in Different ConditionsPR3-ANCA (mostly cANCA)MPO-ANCA (mostly pANCA)OtherANCA-Associated VasculitisGPA75%20%5% ANCA negativeMPA30%60%10% ANCA negativeEGPA5%45%50% ANCA negativeRenal-limited vasculitis10%80%10% ANCA negativeDrug-induced vasculitis10%90%Often high titer, dual positivity for MPO and PR3Nonvasculitis ConditionsSystemic lupus2%10%10% atypical ANCAEndocarditis15%5%Inflammatory bowel diseaseNegativeNegativeAtypical ANCA, various antigens: ulcerative colitis (50%-67%), Crohn disease (6%-15%)Primary sclerosing cholangitisNegativeNegativeAtypical ANCA, various antigens: 60%-80%Cystic fibrosisNegativeNegativeAtypical ANCA pattern, directed against BPI (90%)Abbreviations: ANCA, antineutrophil cytoplasmic antibody; BPI, bactericidal/permeability-induced protein; cANCA, cytoplasmic antineutrophil cytoplasmic antibody; EGPA, eosinophilic granulomatosis with polyangiitis; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; pANCA, perinuclear antineutrophil cytoplasmic antibody; PR3, proteinase 3. Open table in a new tab Abbreviations: ANCA, antineutrophil cytoplasmic antibody; BPI, bactericidal/permeability-induced protein; cANCA, cytoplasmic antineutrophil cytoplasmic antibody; EGPA, eosinophilic granulomatosis with polyangiitis; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; pANCA, perinuclear antineutrophil cytoplasmic antibody; PR3, proteinase 3. A subgroup (∼10%) of patients with clinical features and pathology consistent with AAV remain ANCA negative on testing. Although these patients may have a similar clinical course and response to treatment, ANCA-negative patients are more likely to have renal-limited disease or less severe systemic disease. In some of these ANCA-negative patients, epitope mapping by a highly sensitive epitope excision/mass spectrometry approach led to the discovery of a pathogenic MPO-ANCA that is reactive to a restricted epitope. The detection of this specific MPO-ANCA using standard assays is masked by ceruloplasmin, a natural inhibitor of MPO. ►Bossuyt X, Cohen Tervaert JW, Arimura Y, et al. Position paper: revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nat Rev Rheumatol. 2017;13(11):683-692. It is unclear why autoantibodies to neutrophil self-antigens develop because both MPO and PR3 are sequestered from the immune system in primary granules, and following neutrophil degranulation at sites of tissue injury, are rapidly eliminated by specific inhibitors (α1-antitrypsin [PR3] and ceruloplasmin [MPO]). Defective neutrophil apoptosis, or impaired clearance of apoptotic cell fragments, may lead to prolonged exposure of these antigens to the immune system. Infection may also play a role through molecular mimicry, in which antibodies to microbial antigens cross-react with neutrophil antigens, or possibly through the development of antibodies to complementary peptides and subsequent host immune response to these anti-complementary PR3 antibodies. Experimental and clinical data provide evidence that ANCAs are not only biomarkers of AAV, but play an important role in pathogenesis. This was first demonstrated in a series of experiments using a passive transfer model of anti-MPO crescentic glomerulonephritis (GN). MPO-deficient mice immunized with mouse MPO produce high-titer anti-MPO antibodies, and when these antibodies were injected into wild-type mice, the animals developed crescentic GN and pulmonary hemorrhage. Notably, neutrophil depletion abrogated the disease in these mice, confirming the central role of neutrophils. In a second animal model, WKY rats immunized with human MPO developed MPO-ANCA and necrotizing renal and pulmonary vasculitis. A human case of transplacental transfer of anti-MPO antibodies from mother to fetus with subsequent neonatal pulmonary hemorrhage and GN has been described in a premature infant born at 33 weeks. Notably, attempts to develop an animal model for vasculitis caused by PR3-ANCA have not been successful. This has been attributed to differences in the biology of PR3-ANCA in humans and experimental animals. Neutrophils are the main mediators of vessel injury. In response to infection or inflammation, neutrophils exposed to inflammatory cytokines (tumor necrosis factor α and interleukin 1), lipopolysaccharide or complement C5a become primed with movement of MPO and PR3 from primary granules to the neutrophil surface. In this primed state, ANCAs may bind to these autoantigens on the cell surface, resulting in robust cellular activation. Activated neutrophils alter the expression of adhesion molecules and bind to vascular endothelium. Neutrophil degranulation results in the release of reactive oxygen species and proteases mediating tissue injury. Activated neutrophils also undergo a specific form of cell death (NETosis) in which neutrophil extracellular traps (NETs) are extruded from the cell containing entrapped MPO, PR3, and complement components in a chromatin web. NETs can mediate direct injury to endothelium, transfer MPO/PR3 to vascular endothelium and dendritic cells for antigen presentation, and activate the alternate pathway of complement. Chemokines and tissue deposition of PR3 and MPO result in the recruitment of autoreactive T cells and monocytes augmenting tissue injury (Fig 1). Historically it was considered that complement played a limited role in AAV due to the paucity of complement deposition seen on kidney biopsy and the absence of hypocomplementemia. Recent evidence from the anti-MPO model in a variety of complement-deficient mice has demonstrated a role for the alternate pathway of complement, and specifically, the anaphylatoxin C5a and C5a receptor (CD88) seems central to this process. An amplification loop has been proposed in which activated neutrophils release properdin, promoting the alternate pathway and generating the anaphylatoxin C5a, which binds to C5a receptors on neutrophils, leading to further neutrophil priming and activation (Fig 2). Recent studies of humans support these findings, with the demonstration of alternate pathway activation in the circulation and tissue deposition of complement components of the alternate pathway more commonly recognized. Elevated circulating and urinary C5a levels have been described in active AAV, and low levels of circulating C3 (found in 5%-20% of patients) are associated with worse outcomes. Most excitingly, early clinical studies using the C5a receptor antagonist avacopan have supported an important role of C5a in AAV. ►Hutton HL, Holdsworth SR, Kitching AR. ANCA-associated vasculitis: pathogenesis, models, and preclinical testing. Semin Nephrol. 2017;37(5):418-435.►Prendecki M, Pusey CD. Recent advances in understanding of the pathogenesis of ANCA-associated vasculitis. F1000Res. 2018;7;doi:10.12688/f1000research.14626.1. The pathologic hallmark of ANCA-associated GN is necrotizing and/or crescentic GN without significant immune complex deposition that is detectable using immunofluorescence or electron microscopy. The areas of necrosis may be small and segmental or may be more extensive with large circumferential crescents (Fig 3A and B ). Occasionally, these can rupture the Bowman capsule, provoking a brisk tubulointerstitial inflammatory response. If there is no other underlying kidney disease, the unaffected glomeruli and non-necrotic lesions in segmentally affected glomeruli look unremarkable. Less commonly, patients may show extraglomerular renal vasculitis (Fig 3C and D). Although pauci-immune, small amounts of IgG or C3 may be seen and if present, have been associated with more severe disease. Neutrophil-rich inflammation of medullary vessels (medullary angiitis) may also be seen, sometimes in isolation and in other instances concurrent with renal cortex involvement by GN and vasculitis (Fig 3D). In contrast to GPA and MPA, EGPA is characterized by prominent eosinophil-rich inflammation in granulomas surrounding necrotizing vasculitis of interlobular-sized and larger vessels. Case 1: A 60-year-old woman with nasal crusting for 6 months presents with fever, migratory arthralgia, progressive fatigue, and a 20-lb weight loss over 3 months. Physical examination is notable for purpura in the lower extremities. Laboratory data are significant for increased levels of inflammatory markers, a subacute increase in serum creatinine (Scr) level from a baseline of 1.0 mg/dL to 2.2 mg/dL, and proteinuria and hematuria seen on urinalysis. Serologic tests are positive for PR3-ANCA at a titer of 63 U/mL. Antinuclear antibody is positive at 1:40, and serum C3 and C4 levels are normal. MPO-ANCA and anti–glomerular basement membrane (anti-GBM) are negative. Computed tomography (CT) of the chest reveals lung nodules. Skin biopsy reveals findings consistent with a leukocytoclastic vasculitis with absence of immune deposits on direct immunofluorescence. A kidney biopsy is performed.Question 1: What is the most likely diagnosis?a)GPAb)MPAc)EGPAd)Systemic lupus erythematosusFor the answer to the question, see the following text. Case 1: A 60-year-old woman with nasal crusting for 6 months presents with fever, migratory arthralgia, progressive fatigue, and a 20-lb weight loss over 3 months. Physical examination is notable for purpura in the lower extremities. Laboratory data are significant for increased levels of inflammatory markers, a subacute increase in serum creatinine (Scr) level from a baseline of 1.0 mg/dL to 2.2 mg/dL, and proteinuria and hematuria seen on urinalysis. Serologic tests are positive for PR3-ANCA at a titer of 63 U/mL. Antinuclear antibody is positive at 1:40, and serum C3 and C4 levels are normal. MPO-ANCA and anti–glomerular basement membrane (anti-GBM) are negative. Computed tomography (CT) of the chest reveals lung nodules. Skin biopsy reveals findings consistent with a leukocytoclastic vasculitis with absence of immune deposits on direct immunofluorescence. A kidney biopsy is performed. Question 1: What is the most likely diagnosis?a)GPAb)MPAc)EGPAd)Systemic lupus erythematosus For the answer to the question, see the following text. A typical presentation of GPA is characterized by constitutional symptoms, chronic sinusitis, arthralgia, leukocytoclastic skin rash, lung nodules, acute kidney injury from biopsy-proven necrotizing and crescentic pauci-immune GN, and PR3-ANCA positivity. The absence of immune complex deposition in skin and kidney excludes lupus nephritis. Thus, the answer to question 1 is (a). Although there is significant overlap in the clinical features of GPA and MPA, MPA is distinguished from GPA clinically by the lack of granulomatous manifestations and serologically by its more frequent association with MPO-ANCA type (Table 2). EGPA is similar to GPA in that it is characterized by granulomatous inflammation and necrotizing vasculitis involving small- and medium-sized vessels but is distinguished from GPA by the presence of eosinophilia and asthma. ANCA is positive in only ∼50% of patients of EGPA, typically MPO-ANCA. Renal involvement occurs in 20% of patients with EGPA, but only the ANCA-positive group develops a necrotizing crescentic GN.Table 2Comparison of Clinical Features by ANCA SpecificityPR3-ANCAMPO-ANCADemographics50-70 y60-80 y (mean, 10 y older than PR3-ANCA)GeographyNorthern Europe, North AmericaSouthern Europe, AsiaGenetic risk allelesHLA-DP, PRTN3, SERPINA1HLA-DQPathologyNecrotizing vasculitis, granulomatous inflammationNecrotizing vasculitis, no granulomatous inflammationRenalMore acute presentationMore common, more chronic injury on biopsy, may have a slow indolent course, more likely renal limited, isolated interstitial kidney disease (rare), usually MPO-ANCARespiratory involvementMore common; nodules, cavitation, and central airway disease more specific to PR3Less common; may be chronic lung fibrosis, peripheral reticulation, honeycombing and usual interstitial pneumonia more specific to MPOUpper airway diseaseMore common, destructive lesions (nasal perforation, saddle nose)RareOutcomesMore likely to have resistant diseaseWorse long-term survival (more chronic injury)Relapse rateHigherLowerTreatmentMay respond better to rituximab than cyclophosphamideSimilar response to rituximab and cyclophosphamideAbbreviations: ANCA, antineutrophil cytoplasmic antibody; MPO, myeloperoxidase; PR3, proteinase 3. Open table in a new tab Abbreviations: ANCA, antineutrophil cytoplasmic antibody; MPO, myeloperoxidase; PR3, proteinase 3. Kidney disease is common in AAV and is the most important predictor of mortality. Those who present with glomerular filtration rates (GFRs) < 50 mL/min have a 50% risk for death or kidney failure at 5 years. The typical renal presentation is that of a rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months. Kidney biopsy typically reveals a pauci-immune focal necrotizing crescentic GN. In patients with MPO-ANCA, a more long-term presentation may be found, with features of irreversible kidney injury (glomerulosclerosis and interstitial fibrosis) and poor response to immunosuppression. Although the necrotizing crescentic GN is typically pauci-immune, evidence of immune complex deposition is found in >50% of biopsies and is associated with higher levels of proteinuria and higher percentage of glomerular crescents. Rarely, interstitial nephritis in the absence of glomerular involvement may be found secondary to vasculitis of the vasa recta. Granulomatous inflammation presenting as a renal mass is a rare presentation in GPA. Timely initiation of therapy is critical to prevent kidney progression to kidney failure regardless of GFR at presentation. Remission of kidney disease is defined as stabilization or improvement in Scr level and resolution of hematuria. Proteinuria can be present during remission, reflecting structural damage from vasculitis. Age, MPO-ANCA, low GFR at entry, lower percentage of normal glomeruli, and higher degree of tubular atrophy are all correlated with poor outcomes. Relapse of renal vasculitis is another important predictor of kidney failure and in the absence of a reliable biomarker for renal relapse, close monitoring for an increase in Scr level and recurrence of hematuria remains an integral component of long-term management of patients with AAV. However, the value of ANCA monitoring in predicting relapse is controversial. In patients with renal involvement at baseline, ANCA level increase during serial monitoring has been demonstrated to predict relapse. Given the pathogenic role of macrophages and T cells, urinary biomarkers of activation of these cells may predict disease activity. Levels of macrophage-derived urinary soluble CD163 and serum and urinary CD25 have recently been shown to predict renal relapse. Constitutional symptoms (fatigue, myalgia, and fevers) are prominent and may be present for several months before presentation. The lungs are more commonly involved in GPA, and pulmonary necrotizing granulomatous lesions may produce cavitation or nodular lesions seen on CT. Upper respiratory tract disease may present as rhinitis, sinusitis, otitis media, or granulomatous inflammation leading to septal perforation and nasal collapse. Upper respiratory tract involvement is less common in MPA and lung involvement in MPA typically presents as alveolar hemorrhage and may be associated with pulmonary fibrosis. Hearing loss or scleritis/uveitis may occur. A purpuric rash on the lower extremities is common, secondary to a leukocytoclastic vasculitis. Cutaneous nodular lesions may be seen in GPA. Peripheral neuropathy, typically mononeuritis multiplex, occurs but central nervous system involvement is rare. Mesenteric vasculitis may present with abdominal pain and blood in the stool. Rarely, vasculitis in liver or pancreas can mimic hepatitis or pancreatitis. Cardiac involvement with myocarditis or heart block is rare. Venous thrombosis can occur in the active phase of vasculitis and may be associated with anti-plasminogen antibodies. A number of therapeutic agents are associated with small-vessel vasculitis, including hydralazine, propylthiouracil, minocycline, and anti–tumor necrosis factor agents. Drug-induced vasculitis is often characterized by high-titer MPO-ANCA and the presence of other autoantibodies such as antinuclear antibodies. Hydralazine-associated vasculitis can be severe, with predilection for the kidney. Cocaine adulterated with levamisole causes a distinct type of ANCA vasculitis characterized clinically by prominent necrotic skin lesions in addition to vasculitic involvement of major organs and serologically by dual positivity for PR3-ANCA and MPO-ANCA. A subset of patients with crescentic GN have dual-positive disease characterized by the presence of both ANCAs and anti-GBM antibody. Copresentation of ANCA and anti-GBM antibody occurs at a higher frequency than anticipated by chance alone. About 10% to 40% of patients with anti-GBM disease test positive for ANCA, almost exclusively to MPO, and 5% to 14% of patients with AAV have circulating anti-GBM antibody. The mechanism of this association is speculative, although it has been shown that ANCAs may be detected first and the glomerular inflammation induced by ANCAs could expose sequestered epitopes in the GBM, triggering anti-GBM antibodies. Clinically, these patients have severe disease at presentation with early morbidity and mortality similar to patients with anti-GBM, while their long-term course is characterized by disease relapses similar to patients with AAV. Case 2: A 48-year-old woman with a history of PR3-ANCA GN at age 45 years presents to the emergency department with progressive fatigue, night sweats, and fever for 2 months, and 3 days of worsening dyspnea and hemoptysis. Her laboratory data are notable for increased erythrocyte sedimentation rate, C-reactive protein level, and acute kidney injury (Scr of 3.5 mg/dL); urinalysis shows proteinuria and hematuria. PR3-ANCA is positive at a titer of 190 U/mL. Anti-GBM is negative. CT of the chest shows bilateral ground glass infiltrates and kidney biopsy reveals a pauci-immune GN.Question 2: What is the preferred treatment regimen for this patient?a)Pulse methylprednisolone followed by oral prednisoneb)Cyclophosphamide and glucocorticoidsc)Rituximab and glucocorticoidsd)Plasmapheresis, cyclophosphamide, and glucocorticoidsFor the answer to the question, see the following text. Case 2: A 48-year-old woman with a history of PR3-ANCA GN