Antineutrophil Cytoplasmic Autoantibody (ANCA)-Associated Vasculitis and Anti-Glomerular Basement Membrane (Anti-GBM) Disease

Katti Woerner

Jason Kidd

ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIS

Introduction/General Considerations

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a necrotizing vasculitis without immune deposits affecting small blood vessels and is associated with antibodies to myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).¹ ANCAs are present in more than 90% of patients with pauci-immune glomerulonephritis.

AAV is classified on the basis of both clinicopathologic phenotypes and by the antigen specificity of ANCA. The clinicopathologic variants include microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (formerly called Wegener granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA) (formerly called Churg-Strauss syndrome), and renal-limited vasculitis (RLV).¹ AAV may be drug induced and can manifest as any ANCA clinical phenotype.²

MPA is a multiorgan, pauci-immune small vessel vasculitis without granulomatous inflammation or asthma. Patients with MPA often have necrotizing glomerulonephritis and may have pulmonary capillaritis. Patients with GPA have necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, as well as kidney or multiorgan vasculitic lesions indistinguishable from those of MPA. EGPA has eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, as well as asthma and peripheral eosinophilia. Kidney involvement is a less common manifestation with EGPA. AAV confined to a single organ may occur, most commonly limited to the kidneys.

Patients with PR3-AAV are more likely to present with rapidly progressive glomerulonephritis (RPGN) and have a relapsing/remitting course, especially those with pulmonary and sinus manifestations when compared to patients with MPO-AAV.³ Nasal carriage of Staphylococcus aureus may be associated with a higher risk of relapse. Patients with MPO-AAV are more likely to present with a smoldering disease course and RLV. Once in remission, these patients are less likely to relapse.

AAV is rare and mainly occurs in adulthood. The incidence increases with age and is more common in White populations. It is likely underdescribed in patients of African descent. It is a common cause of glomerulonephritis in older adults.

The development of AAV in children is rare and can have an aggressive presentation. A recently published series noted that the most common presentation of AAV in children is RPGN, and almost a third of patients develop kidney failure.⁴

Pathogenesis

The pathogenesis of AAV is complex, but substantial experimental and clinical evidence point to a pathogenic role of ANCA.⁵ Neutrophils can be primed by cytokines, resulting in the translocation of a small amount of the ANCA autoantigens to their cell surface. Primed neutrophils adhere to endothelial surfaces. In the presence of circulating ANCA (either MPO- or PR3-ANCA), the interaction of the autoantibodies with their target antigens leads to full activation of neutrophils and their degranulation on the surface of small vessel endothelial cells. This results in necrotizing vascular injury and triggers a cascading inflammatory process. This process is amplified by the release of inflammatory mediators, including alternative complement pathway-activating factors, and complement-derived chemotactic factors such as C5a.¹

Histopathology

A kidney biopsy is critical for both the diagnosis and management of patients with AAV. On light microscopy, necrosis and crescents are predominant findings. Crescents can be seen at varying stages of activity. Arteries may show fibrinoid necrosis with associated inflammation. Tubular injury can be substantial, and intratubular red blood cell (RBC) casts are seen. On immunofluorescence microscopy, there is a paucity of staining for immunoglobulins (Igs). No deposits are present on electron microscopy (Figure 13.1).

Light microscopic findings of AAV and anti-glomerular basement membrane (anti-GBM) nephritis may be indistinguishable, although patients with anti-GBM disease generally have more cellular crescents and are differentiated from patients with AAV based on immunofluorescence findings.

Fibrous crescents along with significant tubular atrophy and interstitial fibrosis may be seen because patients with AAV can have a relapsing and remitting course. These chronic changes are not commonly seen in anti-GBM nephritis because of the fulminant nature of its presentation.

FIGURE 13.1: A, Periodic acid-Schiff (PAS)-stained light microscopy showing crescentic glomerulonephritis along with intense interstitial inflammation and tubular injury in a patient with myeloperoxidase-ANCA-associated vasculitis. B, Small artery with fibrinoid necrosis and perivascular inflammation seen on PAS staining in the same patient. (Image courtesy of Selvaraj Muthusamy MBBS, Ph.D.)

Clinical Findings

Patients with AAV typically present with early symptoms of fatigue, myalgias, arthralgias, diminished appetite/weight loss, and, potentially, fever. This prodrome can occur weeks to months before seeing evidence of organ involvement. Symptoms will vary depending on the extent of organ involvement, and patients may evolve from single-organ to multiorgan involvement throughout their disease course:

Constitutional: malaise, fevers, weight loss
Ear, nose, throat (ENT): nasal crusting, nasal ulcers, rhinorrhea, sinusitis, epistaxis, hearing loss, saddle nose deformity. Nasal involvement more common with GPA than with MPA
Neurologic: foot drop, peripheral neuropathy, headache, confusion, stroke
Pulmonary: cough, hemoptysis, wheeze, tracheal stenosis—more common with PR3-ANCA
Kidneys: hematuria, proteinuria, swelling
Abdomen: pain, hemorrhage
Cutaneous: ulcers, necrosis, livedo reticularis, palpable purpura (Figure 13.2)
Ophthalmic: episcleritis, sudden vision loss

Venous thrombosis and pulmonary emboli are common complications in patients with vasculitis and are more likely to occur when the disease is active. The mechanism leading to thrombosis is unclear.

Disease activity can be assessed using the Birmingham Vasculitis Activity Score (BVAS). This assessment is in its third version, validated in 2008 as an assessment of systemic vasculitis.⁶ The scoring consists of an assessment of the following potential symptoms: general; cutaneous; mucous membranes/eyes; ENT; chest; and cardiovascular, abdominal, renal, and nervous systems. Scores are weighted depending on whether they are persistent or new/worse and also weighted on the specified finding.

Laboratory Testing

Evaluation for vasculitis includes laboratory and urine evaluation as well as directed imaging/evaluation per clinical picture. Typical findings will include elevation in creatinine, active urine sediment (hematuria with dysmorphic red cells/RBC casts), proteinuria (generally subnephrotic), elevated erythrocyte sedimentation rate/C-reactive protein, and, typically, an elevated ANCA level.

FIGURE 13.2: A, Vasculitic rash in a patient with proteinase 3-ANCA-associated vasculitis (PR3-AAV). B, Bywaters lesions (vasculitic nail fold lesions) in a patient with PR3-AAV. (Image courtesy of Jason Kidd.)

ANCA testing is either by indirect immunofluorescence (IIF) assay or antigen-specific enzyme-linked immunosorbent assay (ELISA) for PR3 and MPO. In the setting of suspected AAV, ELISA testing for PR3-ANCA and MPO-ANCA is recommended over IIF testing alone. If pulmonary involvement is suspected, a chest radiograph or computed tomography (CT) scan should be obtained (Table 13.1).

Differential Diagnosis

RPGN is a clinical syndrome defined by the rapid loss of kidney function, presence of glomerular hematuria/proteinuria, and histopathologic evidence of crescentic glomerulonephritis. Patients are hypertensive. The differential diagnosis of RPGN can be classified into the following categories:

AAV (GPA, MPA, RLV)
Anti-GBM disease
Immune complex-mediated disease (including but not limited to)
- Systemic lupus erythematosus
- Cryoglobulinemic vasculitis (most often caused by hepatitis C)
- IgA nephropathy (limited to the kidneys) or IgA vasculitis (formerly called Henoch-Schönlein purpura) with systemic involvement
- Infection-related glomerulonephritis

Prompt recognition is essential and empiric treatment must not be delayed because fibrosis develops rapidly in untreated patients.

Patients who present with pulmonary hemorrhage along with RPGN can be classified as having pulmonary-renal syndrome. AAV is the most common cause of pulmonary-renal syndrome. Anti-GBM disease can also lead to pulmonary-renal syndrome. Patients with lupus, cryoglobulinemic vasculitis, or IgA vasculitis rarely present with pulmonary hemorrhage. Owing to the rarity of this condition, other conditions should be considered, including pulmonary embolism and pneumonia.

Patients with kidney involvement due to AAV do not always present with RPGN but, instead, can present with a progressive decline in kidney function with dysmorphic RBCs on urinalysis and subnephrotic-range proteinuria. Careful history and physical examination should occur to screen for other signs of systemic
involvement. Serologic studies are important in confirming diagnosis, but kidney biopsy is necessary in most cases and guides therapy. Patients with a known history of GPA, MPA, and EGPA who develop acute kidney injury or kidney failure should be evaluated for glomerulonephritis.

TABLE 13.1 Patterns of Antineutrophil Cytoplasmic Autoantibodies

MPO-ANCA	More commonly associated with MPA (75%) or renal-limited vasculitis (80%)
PR3-ANCA	More commonly associated with GPA (60%); pulmonary involvement; more granulomatous inflammation; high risk of relapse
Atypical ANCAs	Positive IIF but negative ELISA findings; can be found in IBD, autoimmune disease, malignancy
ANCA-negative vasculitis	In ˜10%, ANCA test findings can be negative
ANCA, antineutrophil cytoplasmic autoantibody; ELISA, enzyme-linked immunosorbent assay; GPA, granulomatosis with polyangiitis; IBD, inflammatory bowel disease; IIF, indirect immunofluorescence; MPA, microscopic polyangiitis; MPO-ANCA, myeloperoxidase-antineutrophil cytoplasmic autoantibody; PR3-ANCA, proteinase 3-antineutrophil cytoplasmic autoantibody.

Risk Factors/Predispositions

Genome-wide association studies have found significant differences between patients with GPA and MPA, as well as for MPO-ANCA versus PR3-ANCA. Several genes are associated with increased susceptibility to AAV, including α-1-protease inhibitor (α-1-antitrypsin) and PR3 among patients with PR3-ANCA.⁷

Hydralazine, minocycline, propylthiouracil, antitumor necrosis factor agents, sulfasalazine, and levamisole-adulterated cocaine have been implicated as potential causative agents of drug-induced vasculitis. Patients with hydralazine-associated vasculitis are generally positive for both MPO-ANCA and antihistone antibodies. Patients with vasculitis related to levamisole-adulterated cocaine are often dual positive for PR3- and MPO-ANCA, and may have hypocomplementemia, whereas dual ANCA positivity and hypocomplementemia are rare in patients with “primary” AAV. Treatment should consist of immediate withdrawal of the offending agent. These patients may also require systemic immunosuppression.²

Treatment

The treatment of AAV can be separated into two major components: induction and maintenance of remission. The initial approach to patients should be further tailored depending on the severity of their initial presentation and ANCA specificity.

Induction (Table 13.2)

Glucocorticoids

The initial therapy for patients with organ-threatening disease includes high-dose glucocorticoids (methylprednisolone 500 mg intravenous [IV] for 3 days) followed by a prednisone taper. There is no significant kidney benefit to continuing glucocorticoids beyond 6 months.⁸ Recently, the plasma exchange and glucocorticoids in severe ANCA-associated vasculitis (PEXIVAS) study showed noninferiority of a lower dose steroid regimen when compared to standard of care, although treatment with prednisone 5 mg was continued for a total of 52 weeks.⁹

Cyclophosphamide

Oral cyclophosphamide, an alkylating agent, in combination with glucocorticoids, was the standard for the treatment of ANCA-related disease beginning in the 1970s. This regimen played a significant role in improving vasculitis outcomes but at the cost of cyclophosphamide toxicity. The pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis (CYCLOPS) trial compared IV dosing of cyclophosphamide to daily oral dosing and showed no difference in time to remission with around half of the cumulative dose of cyclophosphamide. Long-term follow-up in this cohort noted a higher risk of relapse with pulse dosing; however, no difference was detected in patient survival or kidney function.¹⁰ The dosing interval and regimen of cyclophosphamide differs between clinicians, but most commonly, patients are treated for a total of 3 to 6 months. Cyclophosphamide remained the main induction therapy choice until the more recent rituximab trials.

TABLE 13.2 Induction Therapy Dosing

Methylprednisolone	500 mg IV Daily for 3 d
Prednisone^a	Week	Standard Dosing			Reduced Dosing
		<50 kg	50-75 kg	>75 kg	<50 kg	50-75 kg	>75 kg
	1 2 3-4 5-6 7-8 9-10 11-12 13-14 15-16 17-18 19-20 21-22 23-52	50 50 40 30 25 20 15 12.5 10 10 7.5 7.5 5	60 60 50 40 30 25 20 15 10 10 7.5 7.5 5	75 75 60 50 40 30 25 20 15 15 10 7.5 5	50 25 20 15 12.5 10 7.5 6 5 5 5 5 5	60 30 25 20 15 12.5 10 7.5 5 5 5 5 5	75 40 30 25 20 15 12.5 10 7.5 7.5 5 5 5
Cyclophosphamide	IV dosing	15 mg/kg every 2 wk × 3 doses, then every 3 wk until remission with additional 3 months Maximum dose of 1,200 mg/pulse Decrease dose by 2.5-7.5 mg/kg based on patient’s age and if eGFR <30/mL/min/1.73 m² CBC checked on days 10 and 14 post infusion. Dose reduced 20% if leukocyte nadir of 2-3 × 10⁹/L and 40% if nadir of 1-2 × 10⁹/L.^b Alternative dosing: 0.75 g/m²q 3-4 wk Decrease dose to 0.5 g/m²if age >60 years or GFR <20 mL/min/1.73 m². Adjust subsequent doses to achieve a 2-wk nadir leukocyte count >3,000/mm³.^c
	Oral dosing	2 mg/kg/d Dose reduced/adjusted based on age and leukocyte count^b
Rituximab	375 mg/m² weekly for 4 doses^d 1,000 mg IV every 14 d for 2 doses has been used as an alternative treatment regimen.
Avacopan	30 mg orally twice daily Used with cyclophosphamide- or rituximab-based induction treatment with reduced dose or no prednisone^e
CBC, complete blood count; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; IV, intravenous; q, every.^aTable adapted from Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med. 2020;382(7):622-631. ^bDosing as used by de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150(10):670-680. ^cDosing as previously reported in Rovin BH, Adler SG, Barratt J, et al. KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100(4):S1-S276 (Table S30). doi: 10.1016/j.kint.2021.05.021. ^dDosing as used by Stone J, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363:221-232. ^eJayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021;384:599-609.

Rituximab

Rituximab is an anti-CD20 chimeric monoclonal antibody. In pursuit of finding an alternative effective therapy for induction treatment, rituximab was studied in comparison to cyclophosphamide. The Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial found rituximab was noninferior to oral cyclophosphamide in patients with newly diagnosed or relapsed AAV. Patients with severe kidney dysfunction were not included in this study¹¹ (Visual Abstract 13.1).

The Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis (RITUXIVAS) trial compared a combination of rituximab and two doses of IV cyclophosphamide to 3 to 6 months of IV cyclophosphamide. The groups had similar rates of remission and serious adverse event at 12 months; patients with severe kidney disease were included in this study.¹²

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