Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) encompasses three distinct disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Historically, GPA and MPA have been studied together in clinical trials and observational studies, while cases with EGPA have been studied separately. The reasons for this become apparent when looking at disease manifestations among GPA, MPA, and EGPA: Approximately 80% of patients with MPA and 60% with GPA present with kidney disease. The frequency of kidney involvement in EGPA is considerably lower; it has been estimated around 25%, but this estimate may be influenced by recruitment bias and the true number seems to be even lower.

A diagnosis of AAV is substantiated by the presence of ANCA. Antibody testing has moved away from testing for the presence of cytoplasmic or perinuclear ANCA by immunofluorescence to specific immunoassays that allow detection of ANCA directed either against proteinase 3 (PR3) or myeloperoxidase (MPO), and these tests have higher specificity and sensitivity to support a diagnosis of AAV. PR3-ANCA is usually detected in cases with GPA, while MPO-ANCA is more frequent in MPA. Severe systemic presentation forms, such as patients with kidney disease, usually have detectable antibodies. This is different in patients with EGPA who present with ANCA-positivity in only 30% of cases. Antibody-positive patients (more often MPO-ANCA than PR3-ANCA–positive) have a higher frequency of kidney disease (29%) in comparison with those who are ANCA-negative (9%). The EGPA patient subgroup with MPO-ANCA–positivity shares a genetic association at the major histocompatibility complex (MHC) class II HLA-DQ locus with MPO-ANCA–positive MPA, thus in part explaining some of the observed similarities in presentation of MPA and MPO-positive EGPA. For further discussions in this chapter, we focus on GPA and MPA; however, kidney disease in EGPA requires the same/similar management as discussed later. Specific manifestations in proposed disease clusters, also highlighting extrarenal disease, see Table 32.2 . Major differences are encountered depending on diverse presentation forms, and kidney involvement in general is associated with poor overall prognosis.

Once a lethal disease with a 5-year mortality rate of 87% in the absence of treatment, in the more recent era (2010–2015) the 5-year mortality of AAV has decreased to below 20% and AAV has become a relapsing-remitting disease due to refined therapeutic approaches. Both GPA and MPA are systemic diseases that require intensive immunosuppressive therapy to prevent organ damage from vasculitic manifestations, such as alveolar hemorrhage, ANCA-glomerulonephritis, and neuropathy. These immunosuppressive therapies have a substantial toxicity potential, which leads to a significant risk of infections within the first year after diagnosis, and together with the sequelae of the disease, such as CKD, immunosuppressants are also drivers of an increased event rate of cardiovascular complications. ^, The burden of the disease itself, together with the detrimental effects of immunosuppression, still leads to an overall 2.3-fold higher mortality risk of patients with AAV in comparison with a matched background population. Efforts to rapidly and effectively control the disease but also limit exposure to and complications associated with immunosuppressive therapies such as glucocorticoids are therefore both necessary to reduce premature death among patients with AAV. Novel therapeutic approaches and regimens have been approved in the management of GPA and MPA and might help to achieve this goal.

Serotype Versus Phenotype for Diagnosis

There is ongoing debate whether patients should be classified on the basis of their ANCA serotype rather than their clinical phenotype. The ANCA subtypes of MPO-ANCA and PR3-ANCA correspond in high frequencies to the diagnoses of MPA and GPA, although a proportion of patients, with either a more limited disease form without kidney disease or a subset with “pauci-immune” glomerulonephritis, which is often renal limited, remains ANCA-negative. A diagnosis in ANCA-negative disease is dependent on clinical presentation and biopsy findings. The revised classification criteria for GPA and MPA assigned specific weight to the presence of ANCA (see Table 32.3 ), further complicating the path to a potential diagnosis of AAV in those with no detectable ANCA when a vasculitis is suspected.

Table 32.3

Classification Criteria for Granulomatosis with Polyangiitis and Microscopic Polyangiitis as Issued by the American College of Rheumatology and European Alliance of Associations for Rheumatology

	2022 ACR/EULAR Classification Criteria for GPA	2022 ACR/EULAR Classification Criteria for MPA
Criteria	A total cutoff of ≥5 is needed. Clinical criteria: • Nasal involvement: bloody discharge, ulcers, crusting, congestion, blockage, or septal defect/perforation (+3) • Cartilaginous involvement (inflammation of ear or nose cartilage, hoarse voice or stridor, endobronchial involvement, or saddle nose deformity) (+2) • Conductive or sensorineural hearing loss (+1) Laboratory, imaging, and biopsy criteria: • Positive test for cANCA or anti-PR3 antibodies (+5) • Pulmonary nodules, mass, or cavitation on chest imaging (+2) • Granuloma, extravascular granulomatous inflammation, or giant cells on biopsy (+2) • Inflammation, consolidation, or effusion of the nasal/paranasal sinuses, or mastoiditis on imaging (+1) • Pauci-immune glomerulonephritis on biopsy (+1) • Positive test for pANCA or anti-MPO antibodies (–1) • Blood eosinophil count ≥1 x 10 9 /L (–4)	A total cutoff of ≥5 is needed. Clinical criteria: • Nasal involvement: bloody discharge, ulcers, crusting, congestion, blockage, or septal defect/perforation (-3) Laboratory, imaging, and biopsy criteria: • Positive test for pANCA or anti-MPO antibodies (+6) • Fibrosis or interstitial lung disease on chest imaging (+3) • Pauci-immune glomerulonephritis on biopsy (+3) • Positive test for cANCA or anti-PR3 antibodies (-1) • Blood eosinophil count ≥ 1×10 9 /liter (-4)
Patients/Controls (Comparators)	Development set: 578/652 Validation set: 146/161	Development set: 149/408 Validation set: 142/414
Validation	Sensitivity of 92.5% and specificity of 93.8% in the validation cohort (ACR 1990 in same dataset: sensitivity 69.3%, specificity 75.8%)	Sensitivity of 90.8% and specificity of 94.2% in the validation cohort (No ACR classification criteria existed for MPA)

ACR, American College of Rheumatology; ANCA, antineutrophil cytoplasmic antibody; EULAR , European Alliance of Associations for Rheumatology; MPA , microscopic polyangiitis; MPO, myeloperoxidase; PR3, proteinase 3.

A meta-analysis of genetic associations of patients with ANCA-associated vasculitis revealed that 75% of the associations are more closely related to PR3 and MPO rather than the diagnosis of GPA and MPA. A clinical study focusing on pulmonary presentation forms identified that some features are exclusively observed in PR3-ANCA vasculitis, such as pulmonary nodules, and MPO-ANCA vasculitis ( Fig. 32.1 ), such as an usual interstitial pneumonia pattern, the regulation of different biomarkers, the prediction of disease relapses as patients with PR3-ANCA have a higher relapse risk than those with MPO-ANCA, and also the occurrence of certain comorbidities, with a predominance of cardiovascular mortality in MPO-ANCA–positive patients. While most clinical trials have required a clinical diagnosis of GPA or MPA to qualify for trial inclusion, the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS) trial randomized patients in a 2 × 2 factorial design (plasma exchange (PLEX) versus no-PLEX and reduced-dose versus standard-dose glucocorticoids; see discussions later) according to their ANCA serotype (historical or current positivity for MPO- or PR3-ANCA) and smaller experimental medicine studies, such as the ongoing ObiVas trial (ISRCTN13069630), a trial investigating the endpoint of nasal-associated lymphoid tissue CD19 ⁺ B cell depletion in obinutuzumab- versus rituximab-treated patients, required PR3-ANCA–positivity for inclusion. The importance of a positive ANCA-test has also been highlighted by the recent American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria for GPA and MPA: A positive PR3-ANCA (and/or cytoplasmic ANCA) and MPO-ANCA (and/or perinuclear ANCA) would be sufficient to classify a patient as having GPA and MPA in the context of suspected vasculitis. ^, On the basis of the previously mentioned considerations, it is important to report the ANCA serotype and the clinical phenotype when reporting cases of AAV ( Table 32.4 ), as has also been agreed on in the 2012 revised international Chapel Hill Consensus Conference nomenclature of vasculitides.

Different patterns of lung involvement encountered in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

Computed tomography scan images of various forms of lung injury in patients with ANCA-associated vasculitis. (A) Honeycombing and peripheral reticulation, usual interstitial pneumonitis, as exclusively observed in patients with myeloperoxidase-ANCA vasculitis. (B) Mild ground-glass opacities (diffuse) in a perivascular pattern, here in a patient with myeloperoxidase-ANCA vasculitis. (C) Diffuse alveolar hemorrhage in a patient with proteinase 3-ANCA vasculitis. (D) Two large granulomas in a patient with proteinase 3-ANCA vasculitis.

Table 32.4

Disease Manifestations in GPA, MPA, PR3-ANCA, and MPO-ANCA Vasculitis

	GPA	MPA	PR3-ANCA Vasculitis	MPO-ANCA Vasculitis
General Fever ≥38°C (100.4°F) Fatigue Weight loss ≥2 kg (4.4 lb) Arthralgia Myalgia	78% 31% 56% 35% 55% 22%	86% 40% 68% 43% 32% 24%	81% 44% (≥38.5°C [101.3°F]) — 47% (>3 kg [6.6 lb]) 56% 26%	92%
Cutaneous Petechiae or purpura	35% 17%	30% 10%	34% 18%	17%
Mucous membranes/Eyes Scleritis or episcleritis	38% 14%	13% 1%	28% 5% and 10%	10%
ENT	82%	26%	81%	2%
Respiratory Hemoptysis/DAH	63% 21%	63% 19%	68% 18%	50% 22%
Cardiovascular	11%	15%	16%	6%
Abdominal	19%	22%	11%	4%
Renal	59%	82%	58%	79%
Neurologic Neuropathy Mononeuritis multiplex Sensory neuropathy	31% 12% 5% 11%	37% 26% 9% 21%	30% 21% — —	39% 21%

The frequencies are taken as reported in 674 patients with granulomatosis with polyangiitis (GPA) and 325 patients with microscopic polyangiitis reported in the Diagnostic and Classification Criteria in Vasculitis study, an international study involving 32 countries, and 546 patients with PR3-ANCA vasculitis reported from the French Vasculitis Study Group. The cohort of patients with MPO-ANCA vasculitis ( n = 144) also comprises 6 cases with PR3-ANCA vasculitis and reported data from a single center in Germany. ANCA, Antineutrophil cytoplasmic antibody; DAH, diffuse alveolar hemorrhage; DCVAS, Diagnostic and Classification Criteria in Vasculitis; ENT, ear, nose and throat; FVSG, French Vasculitis Study Group; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PR3, proteinase 3.

The global incidence of GPA and MPA has increased over the past decades. This is in part explainable by a pronounced increase in ANCA testing, which has become available in most laboratories worldwide. In a comparison between two time periods in Denmark (2000–2004 versus 2010–2015a, while testing increased 3-fold over time, the incidence of GPA and MPA increased from 15.1 to 21.4 per million. Even higher incidence rates were reported in other studies focusing on epidemiology of the disease. In Olmsted County, Minnesota, in a time period from 1996 to 2015, the incidence of GPA was 13 cases per million and of MPA was 16 cases per million, with a slight male preponderance. Most studies reporting patients with GPA found a male predominance, while many focusing on MPA found a female preponderance. Patients with GPA were on average a decade younger as patients with MPA at the time of diagnosis. Further studies on epidemiology of AAV have been reviewed elsewhere.

Geoepidemiologic differences have been reported in AAV. In a study of 967 patients, those from Japan and China have an almost 60- and 7-times greater chance of being MPO-ANCA rather than PR3-ANCA–positive than patients from Northern Europe. In addition, differences in Europe or of individuals with European ancestry have also been observed. Patients in Southern Europe and Caucasian Americans had a 2.6-fold greater chance of MPO-ANCA–positivity than Northern Europeans. This phenomenon has been linked to northern latitudes and lower ultraviolet radiation levels, as both were associated with PR3-ANCA–positivity in a study of 1408 patients from Europe and the United States. These findings further highlighted a north-south dichotomy for patients with a positive PR3-ANCA test, but the predominance of MPO-ANCA in Eastern Asia remains largely unexplained thus far. In the European cluster analysis, patients in the MPO-kidney cluster were on average 63 years old, while those within the PR3-kidney cluster were 56 years old. The young respiratory cluster, also dominated by cases with PR3-ANCA vasculitis, were predominantly women, while the other clusters had either more men or an equivalent distribution (see Table 32.2 ).

In diverse autoimmune diseases a loss of T cell and B cell tolerance leads to autoimmunity, which precedes an inflammatory response and tissue injury. In the case of AAV, there is a loss of immunologic tolerance to the neutrophil enzymes MPO and/or PR3. Subsequently, ANCA will attach to these proteins promoting neutrophil activation. Occurrence of tissue injury is mediated by both humoral and cellular autoimmunity and involves multiple innate and adaptive components of the immune system ( Fig. 32.2 ). ANCAs are often detectable at a time before the diagnosis of AAV, often years ahead of diagnosis, was made. ^, Disease activity includes granulomatous manifestations, which are almost exclusively seen in patients with PR3-ANCA vasculitis but rarely manifest in the kidneys, and vasculitis manifestations, which frequently lead to life-threatening disease such as alveolar hemorrhage and kidney failure and seen in patients with either PR3-ANCA or MPO-ANCA.

Schematic overview of key pathogenic steps eventually leading to vasculitis.

The inflammatory environment in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized by immune cell activation, with active contribution of neutrophils, monocytes, and macrophages, which all express the C5aR1 (CD88). Alternative complement pathway activation, together with other inflammatory stimuli, leads to neutrophil priming and production of ANCA by plasma cells, among others. ANCAs bind to neutrophils, which lead to a release of reactive oxygen species and other inflammatory mediators. This leads to activation of the neutrophils and to the formation of neutrophil extracellular traps (NETs), which are key mediators of active vessel inflammation and injury. The role of NETs in antimicrobial defense is well known, but also their role in resolving neutrophil-driven inflammation in diseases such as gout. Autoantibody formation is induced by NETs in ANCA-associated vasculitis, which play a critical role in the onset of autoimmunity. Moreover, key effector cells lead to release of myeloperoxidase and proteinase 3 from granules, which are implicated in disease pathogenesis.

Multinucleated giant cell formation and development of granulomas in GPA are promoted by stimulation of monocytes by PR3, and this depends on soluble interleukin-6, monocyte MAC-1, and protease-activated receptor-2. Vasculitis is characterized by microvascular endothelial inflammation, which in turn leads to extravascular inflammation, tissue destruction, fibrotic/sclerotic lesions, and eventually loss of tissue function. Key effector cells leading to tissue destruction are neutrophils, monocytes, and macrophages, all capable of either expressing or producing the key autoantigens, namely PR3 and MPO. Key inflammatory pathways induced by both antigens lead to endothelial injury through mechanisms such as neutrophil degranulation and microparticle release from neutrophils and are major constituents of neutrophil extracellular traps (NETs), networks of fibers composed of DNA from neutrophils relevant in antimicrobial processes, and contributors to endothelial cell damage directly through induction of proinflammatory proteins and activation of the complement system.

The alternative complement pathway plays a crucial role in the pathogenesis of ANCA-GN. Activation of the complement system contributes to further neutrophil-mediated inflammation via production of anaphylatoxins, such as complement C5a. Seminal work in 2007 demonstrated that the injection of anti-MPO IgG was capable of inducing ANCA-GN in C4 ^–/– mice, while C5 ^–/– and factor B ^–/– mice were protected and did not develop cellular crescents or necrosis. These findings indicated that the alternative complement pathway is required to induce renal injury in ANCA-GN, while the classic and lectin pathways are not. Likewise, pretreatment of mice with a C5-inhibiting monoclonal antibody prevented development of crescents and fibrinoid necrosis and led to a significant reduction of influx of inflammatory cells. Further experiments provided evidence that the addition of CCX168 (now known as avacopan, a drug being used clinically) at day 1 significantly reduced the development of cellular crescents by 89.2%, which followed a dose-dependent pattern, and reduced hematuria and proteinuria in treated animals. Blockade of C5L2, the second receptor of C5a, had no relevant effect on blocking renal inflammation in this MPO-ANCA mouse model. One study induced lung injury in an animal model of MPO-ANCA vasculitis, either mimicking GPA, MPA, or EGPA. All of the animals developed crescentic GN, which was successfully inhibited by knocking out C5 or factor B, as was shown previously. However, blockade of the alternative complement pathway did not reduce the lung injury score, underlining that induction of lung injury in AAV might not depend on activation of the alternative complement pathway.

Immunofluorescence (IF) or immunohistochemistry (IHC) findings of kidney specimen in ANCA-GN are typically “pauci-immune,” which means that immune deposits are either absent or only faintly present on biopsy, although deposition of at least one immunoglobulin or complement component has been observed in over half of the renal biopsies in one series (discussed further “Histology” later).

Macrophages and monocytes play key roles in the kidney injury observed in ANCA-GN. CD163 is a high-affinity scavenger receptor for the hemoglobin-haptoglobin complex that is exclusively expressed on monocytes and macrophages. Urinary levels of soluble CD163 (sCD163) are elevated during phases of active vasculitis, and the expression levels are higher in comparison with patients with sepsis-associated acute kidney injury or patients with other forms of glomerulonephritis, indicating a dominant role of monocytes and macrophages in propagating kidney injury in ANCA-GN in comparison with other diseases leading to kidney failure. Glomerular and tubulointerstitial expression of CD163 is more pronounced in comparison with other glomerular diseases, further highlighting the relevance of CD163 in ANCA-GN. Importantly, the levels of urinary sCD163 tend to correlate with severity of kidney injury, in particular fibrinoid necrosis and cellular crescents. Sequential measurement of urinary sCD163 predicted disease relapse better than measuring proteinuria, hematuria, or repeat kidney biopsy, ^, although the specificity of urinary sCD163 was reduced when nephrotic-range proteinuria was present during remission.

Various other mediators lead to a mixed inflammatory infiltrate observed in ANCA-GN. Monocyte chemoattractant protein-1 (MCP-1; also known as chemokine ligand 2, CCL2), is a chemokine that recruits monocytes, memory T cells, and dendritic cells to sites of inflammation. CCR2 and CCR4 are two cell surface CC chemokine receptors that bind CCL2. MCP-1 was elevated in urine samples of patients with active ANCA-GN, and a reduction of urinary MCP-1 levels preceded improvement in kidney function. Longitudinal follow-up sampling of patients revealed that the addition of urinary MCP-1 to urinary sCD163 improved the accuracy of identifying subtle ANCA-GN flares. Urinary MCP-1/creatinine ratio has been tested in the phase 2 CLEAR trial, testing two different avacopan regimens (without glucocorticoids and with 20 mg prednisone) against a standard of care cohort receiving 60 mg prednisone; notably, patients received either cyclophosphamide (79.4%) or rituximab (20.6%) alongside avacopan or prednisone. Both avacopan-treated cohorts had a more rapid reduction in urinary MCP-1 levels in comparison with the prednisone arm. CC chemokine ligand 18 (CCL18), which acts through the CC chemokine receptor (CCR8) on mononuclear cells, correlated with the extent of cellular crescents, interstitial inflammation, and the degree of kidney function compromise and therefore also appears to be involved in the inflammatory response seen in ANCA-GN. Urinary levels of T cell subsets, namely CD3 ⁺ and CD4 ⁺ , are also increased in patients with ANCA-GN and corresponded to the crescentic class of the Berden classification (see later) when compared with the other classes. In the prospective PRE-FLARED study, 102 patients ANCA-GN were recruited in remission and the predictive value or urinary CD4 ⁺ T cells on renal relapses was investigated. During a median follow-up of 6 months, renal relapses occurred in 10 patients. The amount of urinary CD4+ T cells was significantly higher in patients with a subsequent relapse in comparison with those with sustained remission, with a cutoff of 490 CD4 ⁺ T cells yielding a sensitivity of 60% and a specificity of 97.8%.

Taken together, all these findings highlight the complexity of the pathophysiology of ANCA-GN. This growing knowledge provides a mechanistic basis for the immunosuppressive approach required to limit the extent of chemotaxis, the local inflammatory response, ongoing antibody production, and cellular innate responses that lead to kidney injury and perpetuate the inflammation (see Fig. 32.2 ). As our understanding grows, more targeted therapeutic approaches, with fewer risks, are becoming a reality.

A diagnosis of GPA or MPA is usually made by synthesis of information gathered from medical history, clinical evaluations, radiology, and eventually pathology results. Diagnostic delays are common, with a reported median time to diagnosis exceeding 6 months, and contribute to the accumulation of tissue injury. A high index of suspicion is required to permit early diagnosis and treatment. Symptoms differ among patients and are related to development of acute kidney disease in cases of renal-limited forms, while most patients report nonspecific symptoms such as fever/subfebrile temperatures, weight loss, and night sweats, often in combination with organ-specific symptoms (see Tables 32.2 and 32.4 ). AAV is also the leading cause of “pulmonary- renal syndrome,” which is characterized by the presence of acute glomerulonephritis and diffuse alveolar hemorrhage. Among autoimmune disorders leading to pulmonary-renal syndrome, AAV accounts for around 70% of cases.

A systemic approach is required when assessing a patient with suspected AAV in order to estimate the extent and severity of organ involvement. Importantly, because PR3-ANCA or MPO-ANCA may occur in both GPA and MPA, these diseases cannot be distinguished on the basis of ANCA specificity. Practically any organ can be affected by GPA or MPA (see Tables 32.2 and 32.4 ). AAV often presents as multisystem disease, with a particular predilection for ear, nose, and throat (ENT), lung, and skin lesions alongside kidney disease. A high level of suspicion is raised when a patient presents with hematoproteinuria and has signs of systemic inflammation and manifestations, which are in line with a potential diagnosis of AAV. Rare manifestations can be potentially life-threatening such as aneurysms (e.g., of the renal artery), can lead to sequelae significantly impacting quality of life such as orbital masses, or can mimic other diagnoses such as AAV with presenting features of giant cell arteritis. Patient care often involves several specialties in order to make a diagnosis. Tools such as the Birmingham Vasculitis Activity Score (BVAS) are helpful to assess a patient in a systematic way and to get an impression of the severity of presentation, as well as to follow-up disease activity over time.

Patients with ANCA-GN frequently exhibit an elevation of the acute phase reactants, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and platelet count during phases of active disease. Moreover, in those patients in whom the disease remains undetected for weeks to months, the eventual presentation may be with anemia of chronic disease, which might be impacted by further blood loss due to alveolar hemorrhage or gastrointestinal involvement. A systematic screen for other immunologic alterations is recommended: The presence of anti-GBM antibodies has been reported in 6% of patients with AAV, a lower baseline complement C3 correlates with poor overall and kidney survival, and low immunoglobulin G levels at baseline affect the risk of secondary acquired hypogammaglobulinemia after therapy initiation.

A special emphasis lies on determining lung involvement in the context of AAV. The ANCA serotype-based classification allows for discrimination between patients with PR3-ANCA and MPO-ANCA disease. A study performing computed tomography (CT) scans on 129 (81 with PR3-ANCA and 48 with MPO-ANCA) patients revealed that there are distinct patterns seen in each disease. MPO-ANCA vasculitis might present with peripheral reticulation and honeycombing, characteristic of a usual interstitial pneumonitis (UIP) pattern (see Fig. 32.1A ), while nodules with cavitation (see Fig. 32.1D ) and central airway disease were exclusively reported in PR3-ANCA vasculitis. A radiograph of the lungs is often not sensitive enough to detect some of the pulmonary lesions; thus a CT scan is the preferred method to detect overt pulmonary disease. If an infection or malignancy is suspected, the use of 18-fluorodeoxy-glucose positron emission tomography/CT might be a helpful additional diagnostic tool and might detect vasculitis involvement of other organs.

Upon referral to a specialist, the median time to diagnosis in patients with generalized disease including kidney involvement was 9 days in comparison with 22 days in those with more limited disease, and the difference became more apparent when patients were seen by internal medicine physicians as opposed to ENT surgeons (6 vs. 57 days). Assessment of biopsies revealed that most of the performed kidney biopsies (75%) were supportive of an AAV diagnosis, while a minority of ENT biopsies confirmed the suspected diagnosis (42%).

Positivity for either PR3-ANCA or MPO-ANCA, especially at higher titers, consolidates the suspected diagnosis of GPA or MPA in most cases. Overall, only a small proportion of patients with ANCA-GN will have a negative ANCA serology (<5%), but they exhibit a typical “pauci-immune” pattern on immunofluorescence on biopsy. In contrast, an expert center in China reported a high proportion of ANCA-negative “pauci-immune” glomerulonephritis, with a reported frequency of 33% in 85 patients. The absence of a positive ANCA despite a consistent clinical presentation continues to pose a challenge for physicians, as ANCA-negative patients have typically been excluded from the majority of randomized controlled trials (RCTs). ^, Varied hypotheses have been offered to explain ANCA-negative disease. ANCA-negative vasculitis is often found when a “limited” presentation form is diagnosed (e.g., with AAV limited to the ENT tract). Of note, localized ANCA production within the affected tissue has been considered a potential explanation in these patients. In addition, other antibodies have been reported in AAV and would be of particular importance in ANCA-negative disease, but these antibodies have not been implemented in clinical practice due to lack of replication studies or limited added value in the diagnostic path to diagnose AAV. In ANCA-negative GN, infections and malignancies are present in a significant number of patients and need to be considered if there is a lack of response to therapy. This also underlines that initial triggers of disease might be different from ANCA-positive cases.

Tissue biopsy is an important component of diagnosis in AAV. In the case of a high likelihood of kidney involvement (urinalysis revealing hematoproteinuria; deterioriating kidney function), a biopsy helps substantiate the diagnosis and has moved into the center of attention because of predicting prognosis. Crescentic glomerulonephritis is a term that refers to a pattern of glomerular injury characterized by a lesion similar to the crescent of the moon. The Latin word “crescere” is used in particular for the waxing moon and by whatever coincidence, crescents in glomeruli have a huge variety of shapes similar to the different types of “lunes.” From a historical perspective, the term crescentic glomerulonephritis was coined at a time when pathogenetic background of AAV was still largely unknown. It was the development of antibody staining for kidney tissue that first brought insight into the various types of crescentic glomerulonephritis because it was noticed that some appeared in combination with a particular staining pattern denoting the presence or absence of immune complexes or other deposits (see Table 32.1 ). Today, the most common forms of crescentic glomerulonephritis are pauci-immune ANCA-GN and anti-GBM nephritis, which are described in detail in this chapter. However, crescents can occur in many more kidney diseases such as IgA nephropathy, lupus nephritis, infectious GN, C3 glomerulonephritis, and even, more unexpectedly, in membranous nephropathy or drug-induced glomerulonephritis, which are discussed further elsewhere in this book (see Chapters 30-34 and 36).

Pauci-immune ANCA-GN is a form of crescentic glomerulonephritis characterized by a paucity of both immunoglobulins and components of the complement system in glomeruli as tested by antibody staining (immunofluorescence). The term was first used in 1989 by Jennette, Wilkman, and Falk. This form of crescentic glomerulonephritis, with its lack of immune- complex deposition, is consistent with the pathogenesis of ANCA-GN based on a type II hypersensitivity reaction in which neutrophils are activated by autoantibodies in the circulation, ultimately leading to vasculitic lesions in the absence of immune-complex deposition. Pauci-immune GN was originally defined as a staining pattern by immunofluorescence in which there was less than 2+ staining for immunoglobulins on a scale from 0 to 4, as well as for complement components. More recently, however, exclusive and strong staining for C3 in patients with ANCA-GN has been reported to occur in up to 50% of patients. Scaglioni and colleagues were the first to question whether ANCA-GN is always pauci-immune, with results demonstrating substantial deposition of IgG and/or C3 in the capillary walls and/or mesangial areas of around 25% of a study group of 48 patients. Another study of 187 kidney biopsies from patients with ANCA-GN found positivity for C3c in 42% and showed their presence by electron microscopy (EM) in both mesangial areas and along the GBM. C3 can either occur uniquely or in combination with IgG in ANCA-GN and may be associated with a slight difference in clinical presentation. In an early study, the presence of immunoglobulins in ANCA-GN has been associated with higher levels of proteinuria, whereas another study found that glomerular deposition of C3 in ANCA-GN was associated with worse renal and overall survival. Strongly positive C3 staining ( Fig. 32.3H ) in glomeruli occurs in patients with both PR3-ANCA and MPO-ANCA. In contrast, a retrospective multicenter study of 154 patients concluded that the lack of clear predictive value of C3 serum levels and the finding of similar kidney outcomes irrespective of C3 deposition on biopsy precludes the use of C3 levels or staining as biomarkers of AAV outcomes. However, in view of new therapies with complement inhibitors, it would be of interest to study whether these drugs have different outcomes in patients with or without signs of complement activation on biopsy—these data are not yet available.

Characteristic lesions in antineutrophil cytoplasmic antibody glomerulo nephritis.

(A) Fibrinoid necrosis representative of vasculitis at the level of capillary loops. (B) Crescent formation: cellular crescent around area with breaks in the GBM and small focus of fibrinoid necrosis. (C) Circumferential cellular crescent with a break in the Bowman capsule: inflammation extends into the interstitial area. (D) Necrotizing vasculitis of a small artery in kidney biopsy specimen. (E) Perigranulomatous reaction around an almost destructed glomerulus. Granulomatous reaction with palisading of histiocytes. (F) Interstitial granuloma with necrosis in its center; could represent total destruction of a glomerulus or other no longer recognizable structure. (G) Tubulitis: cytotoxic T-lymphocytes invade the tubular epithelium. (H) Immunofluorescence for C3 in a glomerulus: positivity along the GBM and in mesangial areas.

Necrotizing crescentic glomerulonephritis with a pauci-immune pattern is the most characteristic finding of ANCA-GN. Glomerular fibrinoid necrosis (see Fig. 32.3A ) is representative of small vessel vasculitis at the level of the glomerular capillary loops, which leads to crescent formation in the Bowman space (see Fig. 32.3B and 32.3C ). There may be marginally different combinations of lesions in patients with either PR3-ANCA or MPO-ANCA, where the former tend to exhibit more acute lesions and the latter more chronic lesions, but no lesions are uniquely present in either serologic group. Renal arteritis (see Fig. 32.3D ) is encountered in 13.5% of patients with ANCA-GN, and these patients are older, have a more pronounced inflammatory infiltrate, and have a worse kidney prognosis. Although a granulomatous reaction is still considered to be the essential inflammatory reaction in AAV, granulomas are almost never encountered in kidney biopsies of patients with AAV (see Fig. 32.3E and 3F ). The growing awareness of AAV among clinicians coincides with its earlier detection in recent years, which may be responsible for this. However, rupture of the Bowman capsule that may precede the granulomatous reaction around a glomerulus has recently gained interest. Necrotizing vasculitis of medium and large sized arteries is also a rare finding, present in no more than 15% of kidney biopsies in large studies. However, this is most likely related to the “skiplike” nature of these lesions leading to sampling error. Most kidney biopsies in ANCA-GN show a fair amount of acute interstitial inflammation, and some studies reported a relation between tubulitis (see Fig. 32.3G ) caused by these inflammatory infiltrates and renal outcome. Fig. 32.3 shows the most characteristic lesions of ANCA-GN.

By light microscopy, crescents in many different diseases appear to be the same and represent a common histologic endpoint. A crescent may develop where there are breaks in the glomerular capillary basement membrane, assuming that whatever caused this break is irrelevant. Breaks in the glomerular basement membrane lead to the entry of inflammatory mediators into the Bowman space that initiate the proliferation of cells lining the Bowman capsule. The proliferative nature of this process is reflected in the cytonuclear characteristics of the cells including variability in nuclear size, slightly atypical features such a rather strong chromatin density and prominent nucleoli, and an occasional mitotic figure indicative of the rapid multiplication of the epithelial cells. Besides epithelial cells, crescents have many other components, most importantly a large variety of inflammatory cells such as lymphocytes, monocytes, macrophages, and granulocytes. A number of studies have shown a relationship between urinary soluble CD163 and the presence of crescents on the kidney biopsy, suggesting that tissue changes may be reflected in the urine.

A long-standing topic of discussion has been the role and involvement of podocytes in crescent formation. Whereas epithelial cells lining the Bowman capsule are referred to as the parietal epithelial cells of the Bowman space, the podocytes are referred to as the visceral epithelial cells and these two cell types develop from the same lineage. Both cell types seem to be involved in crescentic lesions. However, there may be a difference in their contribution where, for instance, parietal epithelial cells are more prominently present in the pseudocrescents of collapsing focal segmental glomerulosclerosis (FSGS) and visceral epithelial cells are more dominant in the crescentic lesions of pauci-immune ANCA-GN. The role of podocytes in clinical manifestations of patients with ANCA-GN has not been thoroughly investigated; one study demonstrated that podocyte loss in ANCA-GN is associated with proteinuria. Interestingly, a morphometric signature of podocyte depletion in ANCA-GN was found by a deep learning-based approach for antigen-specific cellular morphometrics, showing potential for risk stratification. For more discussion on glomerular cell biology and podocytopathies, see Chapter 4 .

Kidney pathologists use varied terminologies to describe the extent of crescent formation and its development from an acute to a chronic lesion. For the latter, there is the distinction between cellular, fibrocellular, and fibrous crescents. To describe the extensiveness in a single glomerulus, the terms segmental ( Fig. 32.4A ) and circumferential ( Fig. 32.4C–4D ) are used. To give an indication of the severity of crescentic glomerulonephritis, the terms focal and diffuse are used: focal if crescents are present in less than half of all glomeruli in a biopsy, diffuse if they are present in more than half of all glomeruli in a biopsy (see Fig. 32.4 ). For detailed descriptions of the composition of crescents, slightly different definitions developed over time for different diseases. Kidney pathology working groups are currently working on the harmonization of these definitions. ^, Having the same definitions for the descriptors of the crescentic lesions in all kidney diseases will be helpful for standardization purposes. However, this unification should not withhold us from investigating whether similar patterns of crescent formation in different diseases have the same implications, for instance, with regards to outcome parameters and treatment decisions. We know that crescents have a variety of pathogenetic routes. In day-to-day diagnostics, the immunofluorescent or immunohistochemical procedures that clinical pathologists use to determine whether the crescents are representative of kidney involvement in AAV, systemic lupus erythematosus, and many other diseases reflect the enormous variability of conditions under which crescents may develop on a clinical basis alone. Therefore we cannot exclude that there is also variability in the significance of crescents for different diseases, but little is known about this. That the presence of 100% crescents in anti-GBM disease is regarded as a sign of irreversible damage not responsive to treatment is an example of how the crescentic pattern of disease is used for management purposes—but pertaining to anti-GBM disease only. The rule of thumb of more than 50% crescents in a kidney biopsy being representative of clinical RPGN is another example, perchance related to another 50% rule in the histopathologic classification for ANCA-GN commonly referred to as the Berden classification.

Stages of a crescent.

(A) Segmental cellular crescent with fibrinoid necrosis. (B) Cellular crescent showing the contribution of visceral and parietal epithelial cells. (C) Almost circumferential cellular crescent with streaks of fibrin. (D) Circumferential cellular crescent: a few collagen fibers begin to appear. (E) Fibrocellular crescent. (F) Extension of collagen fibers moving into fibrous crescent. (G) Segmental lesion probably resulting from crescent resembling FSGS. (H) Continuation of chronic lesions leads to an almost globally sclerotic glomerulus.

In order to classify patterns of disease in pauci-immune ANCA-GN that have a relation to outcome, the Berden classification established 4 histologic classes based on 50% or more glomeruli in a biopsy having no abnormalities (focal class), having cellular crescents (crescentic class), having global sclerosis (sclerotic class), or otherwise put into a mixed category (mixed class). By combining clinical and histologic parameters, a renal risk score for kidney function outcome was later developed by Brix and colleagues, the so called ANCA Renal Risk Score (ARRS, also referred to as the Brix score), recently improved as the kidney risk score (AKRiS) and now containing four risk classes in order to optimize clinicopathologic prognostication for clinical practice and trials. With the rapid development of new drugs, these two tools need to be kept up to date in order to enhance their prognostic value. Other scores used to assess biopsies of patients with ANCA-GN are the Mayo Clinic Chronicity Score (MCCS) and Percentage of ANCA Crescentic Score (PACS, Table 32.5 ). More and more kidney biopsies from patients with AAV tend to have a focal class pattern of disease in comparison with a decade ago. In kidney biopsies that lack typical glomerular lesions, it is advised to work up all of the tissue: Due to their focal distribution, lesions may not be apparent at each level. In fact, case reports of acute interstitial nephritis as the only lesion in a patient with AAV (i.e., in the absence of crescent formation) could be examples of patients in whom the number of glomeruli with crescent formation is below the level of detection in a biopsy with a moderate amount of glomeruli.

Several scenarios exist where detection of PR3-or MPO-ANCA is misleading. A single-center study from France analyzed 288 ANCA-positive patients, of whom 49 had a final diagnosis of either GPA or MPA. Titers >3.25-fold over the reference limit of a positive test had a sensitivity of 94% and a specificity of 73% to discriminate AAV from mimickers. The other 239 patients either had another autoimmune disorder (total n = 99; inflammatory bowel disease, n = 16; systemic lupus erythematosus, n = 14; non-AAV vasculitides, n = 11) or in the context of other diseases (total n = 140; infections, n = 38; myocardial infarction/stroke, n = 25; hematologic disorders, n = 13), highlighting that ANCA-positivity is frequently encountered in varied scenarios. Similar findings were reported previously in patients with MPO-ANCA–positivity. Importantly, almost 50% of these patients exhibit signs of kidney disease, either reduced estimated glomerular filtration rate (below 60 mL/min/1.73 m ² ), overt proteinuria, or microscopic hematuria. Patients with AAV on average have a higher CRP in comparison with those who present with other diagnoses but are tested ANCA–positive. A higher CRP value is certainly encountered in cases with ANCA–positivity and underlying infections. Infective endocarditis has been associated with PR3-ANCA–positivity, as approximately 20% are ANCA–positive. These patients more frequently have a longer period of infection and present with purpura, macrohematuria, proteinuria, and acute kidney injury. Some of these patients have a “pauci-immune” pattern when kidney biopsies are performed. In cases with suspected systemic infections and ANCA positivity, determining procalcitonin levels might be helpful to ease distinguishing between infections and AAV. Various viruses, bacteria, fungi, and protozoa have been associated with the formation of ANCA.

An analysis of the World Health Organization pharmacovigilance database (VigiBase) identified 483 deduplicated case records of drug-induced AAV. These patients were on average 62 years, were more frequently female (71%), and there was a delay of 9 months between introduction of the new medication and onset of disease. The three drugs with the highest disproportionate reporting and the highest number of reported cases were hydralazine as an antihypertensive agent and propylthiouracil and thiamazole as antithyroid drugs. Among antithyroid drugs, propylthiouracil has a greater potential to induce drug-induced vasculitis. Drug-induced vasculitis usually presents with MPO-ANCA or double positivity, defined as presence of MPO-ANCA and PR3-ANCA at the same time. The detection of other antibodies, such as antinuclear antibodies, is also common in drug-induced vasculitis. Management of such cases include immediate drug cessation and introduction of immunosuppression if patients present with severe disease (e.g., kidney involvement). Maintenance of remission is not required in most cases when the offending substance is withdrawn, and rechallenging of the patient with the drug implicated in inducing the vasculitis should be avoided. Other medications include allopurinol, minocycline, penicillamine, rifampicin, and sulfasalazine, among others. However, causal associations between these drugs and AAV are not well established.

Childhood AAV is rare and has a female preponderance. A rare autosomal dominant genetic disease, “Copa syndrome,” can mimic severe AAV including kidney disease and alveolar hemorrhage and typically occurs early in life with disease onset usually younger than 5 years of age and has a female predominance.

Therapeutic strategies have historically been divided into those used in the induction of remission (within the first 3–6 months of active disease) and those used to maintain remission (subsequent therapies). The aim of the induction phase of therapy is to rapidly reduce inflammation and achieve remission, which is usually defined as a BVAS of zero (according to, e.g., version 3) and has been used in most clinical trials. A change in BVAS has been proven to be repeatable, reproducible, and sensitive. The renal items of BVAS are often semiquantitative, and a maximum of 12 points is reached easily (hematoproteinuria and a form of creatinine increase) but does not always reflect the severity of kidney function impairment; that means a patient with a creatinine of 1.7 mg/dL or 8.1 mg/dL and concomitant hematoproteinuria would have the same score. An overview of key clinical trials dictating current therapeutic strategies is highlighted in Fig. 32.5 .

Timeline of relevant therapeutic developments in antineutrophil cytoplasmic antibody–associated vasculitis over the past 2 decades.

Trials testing new strategies to induce remission are given in black, while trials testing therapeutic options to maintain remission are highlighted in red.

Induction of Remission

Steroid Reduction and Steroid-Sparing Strategies

Glucocorticoids are a main pillar of therapy in ANCA-GN and are able to rapidly reduce inflammation. Thus glucocorticoids are a mainstay of therapy in AAV. However, glucocorticoid toxicity contributes to morbidity and mortality of patients with AAV by increasing the risk of infections, and among other side effects, it has an impact on cardiovascular risk factors such as blood pressure and lipids. No clinical trial has investigated whether initial therapy with high-dose methylprednisolone pulses has beneficial effects on kidney function recovery. A retrospective study of 114 patients from 5 expert centers with either a serum creatinine >500 μmol/L (5.7 mg/dL) or dialysis dependency at enrollment found that patients who received intravenous pulse methylprednisolone (followed by oral glucocorticoids) did not have higher rates of recovery of kidney function (57.7% in the methylprednisolone arm vs. 66.1% in the oral prednisolone alone arm), which was defined as either independence from kidney replacement therapy in those who presented with dialysis dependence or an improvement of kidney function in those not requiring dialysis at baseline. However, the patients receiving methylprednisolone pulses experienced more frequent serious infections by 3 months (36.5% vs. 19.4%), and more developed diabetes by 12 months (26.9% vs. 6.5%) than those who had received oral prednisolone alone. The total oral prednisolone dose was 4 g in the methylprednisolone group versus 6.8 g in the oral prednisolone group, suggesting that the initial high-dose therapy increased the risk of complications, and a special focus on prevention of infections is required when methylprednisolone pulses are used.

The first clinical trial to investigate substantial reduction of glucocorticoid exposure was the RAVE trial, which advised investigators to stop prednisone after 5.5 months, and this was part of the primary endpoint. The cumulative glucocorticoid dose by 6 months was 4.0 g in the rituximab arm and 4.4 g in the cyclophosphamide/azathioprine arm. Two further clinical trials have studied the effect of reduced doses of glucocorticoids on either the composite of kidney failure and death (PEXIVAS) or remission (LoVAS). In the PEXIVAS trial, participants receiving the reduced dose of glucocorticoids had an exposure that was <60% at 6 months of that in the standard-dose group (for regimen comparison, see Table 32.3 ). In terms of efficacy, the reduced-dose regimen was equivalent to the standard dose in terms of kidney failure and mortality, but the frequency of serious infections was reduced, as 96 patients (27.2%) in the reduced-dose arm and 116 patients (33.0%) in the standard-dose arm developed at least one serious infection (HR 0.69, 95% CI 0.52–0.93). Of note, most patients in the PEXIVAS trial received cyclophosphamide-based induction therapy, so information on rituximab induction plus reduced-dose glucocorticoids remains limited. A retrospective real-world study from France found that a combined endpoint, including progression of disease, relapse rate, kidney failure, and death, was reached more frequently in patients receiving a reduced-dose PEXIVAS regimen; however, important information on achieving the endpoints (definition of progression) and the highly imbalanced baseline characteristics are significant issues of this study.

The LoVAS trial, conducted in Japan, randomized patients to a reduced-dose or high-dose glucocorticoid regimen in addition to rituximab therapy. Most patients had MPO-ANCA vasculitis (85.8%), and the eGFR at baseline was relatively well preserved in both arms (52.0 vs. 55.3 mL/min/1.73 m ² ). The cumulative dose of glucocorticoids received in the reduced-dose group was 1.3 g, which was 68.3% lower compared with the high-dose group (cumulative exposure of 4.2 g) (see Table 32.6 for glucocorticoid dosing). Remission rates were equivalent between the two glucocorticoid groups, while less treatment toxicity and fewer serious infections (5 vs. 13 patients) were observed with the reduced-dose glucocorticoids ( P = 0.04). Longer-term follow-up showed that the reduced-dose regimen was associated with fewer serious adverse events, while the relapse rate did not differ between groups. Lower doses of glucocorticoids with exposure limited to 2 weeks only have been reported in observational studies using a combination therapy of cyclophosphamide and rituximab as induction of remission treatment (see later). Although clinical trials have provided evidence that reduction of cumulative doses and earlier withdrawal (within the first 6 months) of glucocorticoids is noninferior in terms of achieving remission and future relapses, the duration of glucocorticoid therapy is still a controversial topic.

Table 32.6

Different Steroid Tapering Regimen According to PEXIVAS, LoVAS, and ADVOCATE Trials

Trial	PEXIVAS			LoVAS			ADVOCATE
Regimen	Reduced dose	Standard dose		Low dose	High dose
Weeks	<50/50-75/>75 kg	<50/50-75/>75 kg	Weeks			Weeks	>55 kg	<55 kg
1-2	25/30/40 mg	50/60/75 mg	1-2	0.5 mg/kg	1.0 mg/kg	1	60 mg	45 mg
3-4	20/25/30 mg	40/50/60 mg	3-4	0.25 mg/kg	0.8 mg/kg	2	45 mg	45 mg
5-6	15/20/25 mg	30/40/50 mg	5-6	7.5 mg	0.7 mg/kg	3	30 mg	30 mg
7-8	12/15/20 mg	25/30/40 mg	7-8	5 mg	0.5 mg/kg	4-6	25 mg	25 mg
9-10	10/12/15 mg	20/25/30 mg	9-10	4 mg	0.4 mg/kg	7-8	20 mg	20 mg
11-12	7/10/12 mg	15/20/25 mg	11-12	3 mg	0.35 mg/kg	9-10	15 mg	15 mg
13-14	6/7/10 mg	12/15/20 mg	13-16	2 mg	15 mg	11-14	10 mg	10 mg
15-16	5/5/7 mg	10/10/15 mg	17-20	1 mg	12.5 mg	15-20	5 mg	5 mg
17-18	5/5/7 mg	10/10/15 mg	21-24	0 mg	10 mg	≥21	0 mg	0 mg
19-20	5/5/5 mg	7/7/10 mg
21-22	5/5/5 mg	7/7/7 mg
23-52	5 mg	5 mg
>52	Investigators’ local practice	Investigators’ local practice

The PEXIVAS trial did not mandate steroid withdrawal, and further reduction steps beyond 52 weeks of follow-up were based on the investigators’ local practice. The LoVAS trial assessed its primary endpoint at 6 months of follow-up, while steroid withdrawal formed the basis of both primary endpoints of ADVOCATE.

In patients with ANCA-GN, the reduced-dose PEXIVAS glucocorticoid regimen is nowadays standard and recommended by all major recommendations/guidelines. A steroid-free remission maintenance (i.e., withdrawal of glucocorticoids before 6 months) is possible and safe, especially when rituximab as maintenance agent is used, and is preferred by the authors of this chapter.

Complement Inhibition with Avacopan

Another option to reduce cumulative glucocorticoid exposure is the addition of avacopan, an oral C5aR1 inhibitor. It has been tested in animal models of MPO-ANCA vasculitis and was tested in two smaller phase 2 trials: CLEAR, a dose-finding study conducted in Europe, and CLASSIC, a safety study conducted in the United States. The phase 3 trial, ADVOCATE, was an international study and has assigned 330 patients (268; 81.2% with ANCA-GN) to either receive avacopan (30 mg twice daily, ± a short course of prednisone for a maximum of 4 weeks, maximum initial dose 20 mg) or prednisone, which was tapered off over 20 weeks (see Table 32.6 ). All patients were either receiving rituximab (4-times 375 mg/m ² , a week apart each; used in 214 patients (64.9%)) or cyclophosphamide (either intravenous as used in 102 patients [30.9%] or orally in 14 [4.2%]). An eGFR of <15 mL/min/1.73 m ² was an exclusion criterion of ADVOCATE.

Two endpoints were tested: 1. BVAS of 0 at week 26 and no glucocorticoid therapy in the previous 4 weeks and 2. sustained remission, defined as remission at weeks 26 and 52 and no receipt of glucocorticoids for 4 weeks. The first primary endpoint was observed in 72.3% and 70.1% of patients assigned to avacopan and prednisone, respectively (noninferiority), while the second primary endpoint was observed in 65.7% and 54.9%, respectively, showing superiority of an avacopan-based therapy over prednisone. Of note, relapses were less common in the avacopan arm (HR 0.46; 95% CI 0.25–0.84). Glucocorticoid toxicity was significantly reduced by the addition of avacopan. In 265 of 268 patients with ANCA-GN, eGFR at baseline was available. Kidney function improved in those with ANCA-GN over time in the avacopan and the prednisone arm but was greater in the avacopan arm with an eGFR increase of 7.3 in contrast to 4.1 mL/min/1.73 m ² in the prednisone arm. eGFR increase was recorded from a baseline eGFR of 44.6 and 45.6 mL/min/1.73 m ² in the treatment arms. Investigators focused on the 50 patients (of 330) who were recruited with an eGFR of ≤20 mL/min/1.73 m ² and observed an eGFR recovery of +16.1 and 7.7 mL/min/1.73 m ² in the avacopan and prednisone groups, respectively.

Avacopan is the first eGFR-sparing therapy in ANCA-GN and might be of particular value for those patients presenting with severely impaired kidney function at baseline. Of note, those patients with an eGFR <15 mL/min/1.73 m ² were excluded from the trial and there is no information about avacopan efficacy in patients with dialysis dependency. The substance also allows for substantial reduction of cumulative glucocorticoid exposure and thus is of relevance for those facing glucocorticoid-related side effects and toxicity. Other inhibitors of the alternative complement pathway, such as the factor B inhibitor iptacopan, are currently tested in clinical trials of AAV (NCT06388941). However, a more proximal inhibition of the complement system does involve the addition of prophylaxis against encapsulated bacteria such as meningococcal infections.

Rituximab, Cyclophosphamide, or Combination Therapy

The 2022 update of the EULAR recommendations for the management of AAV recommend that either rituximab or cyclophosphamide is used to treat organ-threatening or life-threatening disease. This recommendation is based on the publication of the RAVE trial, which randomized patients with new or relapsing disease to either rituximab (4 × 375 mg/m ² , a week apart; n = 99) or oral cyclophosphamide (2 mg/kg body weight, with adjustments; n = 98), followed by azathioprine (2 mg/kg body weight) as an agent to maintain remission. At 6 months, 64% in the rituximab arm as opposed to 53% in the control arm reached the primary endpoint, defined as BVAS/WG of 0 and a prednisone dose of 0 mg whereby rituximab achieved noninferiority. At 18 months, only 39% of those who received rituximab and 33% of controls remained in remission. In the rituximab arm, patients did not receive maintenance therapy, while the control group was maintained on azathioprine until the end of the trial. In trial participants with relapsing disease, the rates of remission were significantly different at 6 and 12 months (67% and 49% vs. 42% and 24%; for rituximab vs . cyclophosphamide/azathioprine), but a borderline significance was reported at 18 months (37% vs. 20%; for rituximab vs . cyclophosphamide/azathioprine). Relapses observed during the RAVE trial were mainly driven by individuals who had a historic or present positivity for PR3-ANCA. In patients with relapses ( n = 81), a significantly higher proportion remained in remission when assigned to rituximab. The RAVE trial excluded patients with a serum creatinine ≥4.0 mg/dL, leaving a knowledge gap from RCTs on rituximab use in those presenting with severe kidney disease. The PEXIVAS trial included 704 patients with a median serum creatinine of 3.8 mg/dL, where 109 (15.5%) trial participants received rituximab alongside plasma exchange (PLEX; n = 55) or no-PLEX ( n = 54). Fewer patients reached the composite of kidney failure and death at a median follow-up of 2.9 years when PLEX was added to rituximab and glucocorticoids, which was comparable with the overall outcome of the trial and therefore nonsignificant (see later for more details). Subanalyses focusing on kidney outcomes (kidney failure within the first year, increases in eGFR) of patients in PEXIVAS are ongoing and will shed more light on rituximab’ efficacy in patients with severe kidney disease because currently available data are limited to mainly retrospective observational data. The utility of PLEX itself is discussed in more detail later.

Combination of rituximab and cyclophosphamide has become a popular strategy for induction of remission in severe ANCA-GN. A combination of rituximab (4-times 375 mg/m ² ) and cyclophosphamide (2 scheduled infusions, 15 mg/kg body weight, adjusted) was tested in the RITUXVAS trial and found to be noninferior to 3 to 6 months of intravenous cyclophosphamide are used according to the CYCLOPS trial (see Table 32.7 ), followed by azathioprine as maintenance agent. This trial was small (33 and 11 patients) but found a nonsignificant increase in eGFR of 19 mL/min/1.73 m ² in the combination group compared with 15 mL/min/1.73 m ² in the cyclophosphamide-azathioprine arm. Further evidence that combined therapy with rituximab and cyclophosphamide is effective stems from observational studies. ^, However, the retrospective nature of these studies and lack of a comparator in some studies are limitations of these studies.

Table 32.7

Summary of Studies Reporting on Combined use of Cyclophosphamide and Rituximab

Trial/Study	RITUXVAS	Pepper et al.,	Gulati et al.,	Cortazar et al.,
Patients	33 and 11 (RCT)	49	64	129
Induction	PLEX (8 and 3 patients), RTX arm (4-times 375 mg/m 2 and 2 pulses CYC, 15 mg/kg with adjustment), CYC arm (according to CYCLOPS a ), followed by azathioprine maintenance	RTX (2-times 1000 mg) CYC (6 pulses IV, 500 mg each or 500-750 mg)	PLEX (7 sessions), RTX (2-times 1000 mg) CYC (IV, 10 mg/kg, max. 750 mg first 2 pulses, 4-times 500 mg subsequent)	PLEX (40 patients) RTX (2-times 1000 mg) CYC (oral, adjusted)
Glucocorticoids	1 g methylprednisolone (+ optional doses), oral prednisolone down to 5 mg at month 6	1-2 pulses methylprednisolone 250 mg-1 g, oral prednisolone for 1-2 weeks	2.6 g (6 months), initial dosage max. 60 mg/day	Pulse methylprednisolone (optional), oral prednisone taper over 7 months
Maintenance	CYC arm only (AZA)	AZA (first line), MMF, MTX, RTX	MMF or AZA	RTX (1000 mg every 4 months)
Serum creatinine (μmol/L) b	—	179 and 174 (2 groups)	558	—
eGFR (mL/min/1.73 m 2 )	20 and 12	28.9 and 28.3 (2 groups)	9	18.8 (75 patients with “RPGN”)
Remission (at 6 months)	76% and 82% (sustained remission)	96% (47 patients)	94% (60 patients)	84% (109 patients)
Kidney recovery	eGFR 39 and 27 mL/min/1.73 m 2 at month 12	Serum creatinine 109 μmol/L and 113 μmol/L at month 12	67% (of 30 with KRT at baseline); of non-KRT patients, eGFR improved to 45 mL/min/1.73 m 2 at 3 years	eGFR 28.9 mL/min/1.73 m 2 at month 6 (PR3 significantly better)
Mortality	6 and 2 (18% each)	3 (6.1%) of which 1 was an infectious complication	9 (14.1%), of which 5 were infectious complications (1 COVID-19)	4 (3.1%)

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