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INTRODUCTION
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune rheumatic disease composed of three discrete diagnoses of microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA) [1,2]. MPA, GPA, and EGPA are distinguished mainly based on the pattern of involved organs and the expression of ANCAs against myeloperoxidase (MPO) or proteinase 3 (PR3); however, pathologic confirmation is also important for accurate diagnosis [3]. Among various rheumatic diseases encountered in practice, AAV reportedly has a higher rate of adverse outcomes [4]. Observations from the European Vasculitis Study Group (EUVAS) reported that 12% and 22% of patients with AAV died in a 1-year and 5-year period, respectively [5]. In addition, the long-term renal outcomes of patients with AAV were unfavorable based on integrated analyses of the EUVAS inception clinical trials, in which 13% of the patients progressed to end-stage renal disease (ESRD) [6]. Furthermore, findings from the Glomerular Disease Collaborative Network inception cohort indicated that a 5-year survival and ESRD-free rate of patients with AAV with renal disease was 72% and 54%, respectively [7]. The heightened risks of mortality and ESRD in patients with AAV appear to be consistent in an Asian population. Outcome analysis from a Japanese AAV cohort showed that 11.0% and 10.8% of the patients experienced death and ESRD, respectively, during follow-up [8], and analysis of the national health insurance database in Republic of Korea revealed increased mortality and ESRD development in patients with AAV, with an estimated rate of 26.8% and 8.2%, respectively [9]. Furthermore, disease aggravation during the disease course was common in AAV, with a 5-year disease relapse rate reaching as high as 89%, although large variation was reported in clinical settings [10]. Especially, MPA and GPA are recognized as major AAV subtypes that have a greater risk of poor clinical outcomes of mortality and ESRD, whereas the prognoses of EGPA appears to be relatively favorable [11]. Due to the high rate of negative patient outcomes, an essential component in management of AAV is implementation of optimal therapeutic strategies. In the present review, the recent AAV treatment guidelines are presented to provide key guidance to physicians for managing this complicated disease.
MAIN SUBJECTS
Important considerations when selecting therapeutic agents for AAV
Administration of appropriate immunosuppressive agents is important in management of AAV. Two key issues should be considered prior to selection of treatment for AAV.
1) Assessment of disease stages
An essential component in treating AAV is assessing the stage and activity of underlying disease. In the European League Against Rheumatism (EULAR) recommendation for conducting clinical studies and/or clinical trials in systemic vasculitis (Table 1), the EUVAS group categorized clinical subgroups into “Localized,” “Early systemic,” “Generalized,” “Severe,” and “Refractory” according to the presence of systemic vasculitis outside ears, nose, throat and lungs, threatened vital organ function, other definitions, and serum creatinine [12]. Conversely, Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group separated clinical subgroups into limited and severe disease. The definition for limited disease provided by the WGET research group refers to a patient who fulfills the American College of Rheumatology (ACR) criteria for GPA diagnosis, but in the absence of disease that has a potential to threat either a critical individual organ or to the patient's life [13]. Detailed descriptions for this are (1) no red blood cell casts in the urine; (2) serum creatinine ≤1.4 mg/dL and no evidence of serum creatinine rise of more than 25% above the baseline levels; (3) Circumscribed pulmonary involvement of room air partial pressure of oxygen >70 mmHg or room air oxygen saturation by pulse oximetry >92%; (4) and no disease in critical organs such as the gastrointestinal tract, eyes, and central nervous system, without the immediate requirement of maximal therapy that may compromise organ function and/or patient life. Severe disease, which is not classified as limited disease by definition, is a stage that is particularly important to note because it indicates the need to start intensified remission induction therapy. Therefore, for management of AAV, a thorough systematic evaluation via physical examination, imaging study, and laboratory testing is necessary to guide treatment decisions.
2) Defining disease activity status
Next, the activity state of AAV should be evaluated. The EULAR defines activity states as remission, response, relapse, refractory disease, or low-activity disease state (Table 2) [14]. Remission is defined as the absence of disease activity attributable to active disease qualified by need for ongoing stable maintenance immunosuppressive therapy. In addition, relapse (recurrence or new onset of disease attributable to active vasculitis) can be divided into major or minor based on the potential threat to organs or life. Refractory disease is an unsatisfactory response to a sustained duration of appropriate therapy. Accurate determination of disease status is crucial in AAV because the goal of treatment is clinical remission, and disease relapse should be managed effectively using glucocorticoids (GCs) and/or immunosuppressive agents per treatment recommendations.
Available guidelines for management of AAV
The pharmacologic agent-specific recommendations proposed by the British Society for Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) guideline for the management of adults with AAV, EULAR/European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) recommendation for the management of AAV, 2021 ACR/Vasculitis Foundation Guideline for the Management of AAV, and Kidney Disease: Improving Global Outcome (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases are summarized and presented in Tables 3~5. Furthermore, recommendations for medication dosage, if described in the guidelines, and other recommendations are outlined in Tables 6 and 7.
1) BSR and BHPR guideline for management of adults with AAV
In the BSR and BHPR guideline released in 2014, selection of treatment regimens is based on a purpose of remission induction, maintain remission, in relapsing or refractory diseases during follow-up [15]. In addition, five principles of management are emphasized: rapid diagnosis; rapid initiation of treatment; early induction of remission to prevent organ damage; maintenance of remission with the aim of eventual drug cessation; and prevention of drug toxicity. In the BSR and BHPR guideline, the use of GCs and intravenous (IV) cyclophosphamide (CYC) or rituximab (RTX) should be considered in newly diagnosed AAV patients. Methotrexate (MTX) and mycophenolate mofetil (MMF) are alternative drugs for disease remission induction in patients with evidence of low disease activity and no risk of organ damage based on the Birmingham Vasculitis Activity Score (BVAS). However, the use of MMF is considered as an alternative for MTX [16,17]. In contrast, in the presence of severe renal failure or other life-threatening conditions, the guideline recommends that plasma exchange (PLEX) should be considered. High-dose GC, used in combination with CYC or RTX, is also required in the induction phase, although rapid tapering is necessary.
For maintenance therapy, azathioprine (AZA) or MTX is typically considered, although MMF or leflunomide (LEF) as well as RTX also are options. The duration of maintenance is not specified but is recommended to continue for at least 24 months after achieving disease remission and may be lengthened in patients with GPA or with continuously positive PR3-ANCA. In addition, when remission is successfully maintained for at least one year on maintenance therapy, GC can be tapered, and when GC is successfully withdrawn, other immunosuppressive agents may be stopped after six months. Furthermore, for relapsing diseases, the degree of relapse should be considered. For example, minor relapse is recommended to be treated with increased GC dosage and optimization of immunosuppression. However, major relapse may require RTX or CYC treatment with GC dose increment, and PLEX could be considered as adjunct therapy. Finally, in the case of refractory diseases, RTX is more effective than CYC and should be the first choice for a patient not previously treated with RTX. In both relapsing and refractory diseases, the cause should be investigated.
Other general recommendations in the BSR and BHPR guideline include regular assessment and monitoring of disease status using instruments such as the BVAS, Vasculitis Damage Index, 36-item short form, laboratory testing of ANCAs, and detection and prevention of potential adverse effects following treatment. In addition, active patient involvement, education, and a collaboration of specialists is also underscored.
2) EULAR/ERA-EDTA recommendation for management of AAV
The 2016 EULAR/ERA-EDTA recommendations [18] are an update of the 2009 EULAR recommendations for management of primary small- and medium-vessel vasculitis [19] proposed the overarching principle of shared decision making between the patient and their specialist, as well as presenting 15 recommendations based on level of evidence. The recommendation stresses the importance of patient care with close collaboration with or at centers of expertise and of pathologic confirmation. In the EULAR/ERA-EDTA guideline, new-onset organ- or life-threatening AAV is recommended to be treated with a combination of GCs and either CYC or RTX; non-organ-threatening disease can be treated using a combination of GCs with MTX or MMF treatment. Major relapses that are either organ- or life-threatening are recommended to be treated as new-onset organ- or life- threatening AAV, and PLEX should be considered in AAV with serum creatinine ≥500 μmol/L as a result of rapidly progressive glomerulonephritis and can be considered in severe diffuse alveolar hemorrhage. For remission-maintenance, a combination of low-dose GCs with AZA, RTX, MTX, or MMF is recommended for at least 24 months of sustained remission. In disease refractory to remission-induction therapy, it is recommended to switch CYC to RTX or RTX to CYC.
Other statements in the recommendation include a structured clinical assessment instead of ANCA testing and investigation of hematuria in patients exposed to CYC, testing for immunoglobulin levels prior to each cycle of RTX and in patients with recurrent infection, assessment of cardiovascular risk and comorbidities, and consultation with the patient concerning the disease nature, treatment, and outcomes.
3) 2021 ACR/Vasculitis Foundation Guideline for the Management of AAV
Although EGPA is included as a disease subtype of AAV, it usually confers a good prognosis compared with GPA/MPA, has a distinct pathogenetic mechanism, and may respond differently to immunosuppressive therapy [20]. Thus, the ACR/Vasculitis Foundation Guideline, published in 2021, provides recommendations for AAV management after subtyping AAV as GPA/MPA and EGPA [21,22]. Unfortunately, lack of randomized control trials restrict the recommendations; therefore, there are conditional and ungraded position statements in the guideline. Notably, in the ACR/Vasculitis Foundation Guideline, RTX is conditionally recommended over CYC for remission induction in active, severe GPA/MPA considering efficacy, safety, and patient preference. In addition, reduced GC dose is conditionally recommended over a standard GC dose regimen in active, severe GPA/MPA. Furthermore, using RTX instead of MTX or AZA for maintenance is conditionally recommended in patients with severe GPA/MPA in remission after CYC or RTX treatment, and IV immunoglobulin therapy is conditionally recommended in patients with GPA/MPA refractory to remission induction treatment. In the ACR/Vasculitis Foundation Guideline, simultaneous use of GC and MTX is conditionally recommended over GC+RTX, GC+CYC, GC+AZA, GC+MMF, or GC alone for active non-severe GPA. Regarding active, severe EGPA, either IV pulse GC or high-dose oral GC as well as CYC or RTX may be prescribed as initial therapy or for remission induction. Especially for EGPA patients, the therapeutic option of mepolizumab (MEP), a humanized monoclonal antibody against interleukin-5 [23], has been included in remission induction for active, non-severe disease as well as for maintenance and relapsing disease. These significant changes likely represent the results of clinical studies published in recent years, indicating that selection of immunosuppressive agents could be outlined in more detail for patients with AAV in the following years. Furthermore, for patients with EGPA, treatment based on the Five-Factor Score is conditionally recommended in the guideline [24,25]. However, no promising results have been achieved for the oral C5a receptor inhibitor avacopan because the ACR/Vasculitis Foundation Guideline encompasses only therapeutic agents approved by the U.S. Food and Drug Administration (FDA) [26].
4) KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases
Although the KDIGO guidelines primarily focus on management of AAV that results in kidney inflammation manifesting as necrotizing and crescenticglomerulonephritis, general management strategies for AAV not limited to the kidney are also described and summarized as practice points [27]. For induction of remission, GC+CYC or RTX could be used, which is similar to other guidelines. MMF and MTX, in the absence of irreversible tissue damage, could be considered if there is no organ-threatening involvement. PLEX combined with an induction regimen is recommended for patients with creatinine >500 μmol/L requiring dialysis, diffuse alveolar hemorrhage with hypoxemia, and an overlap of AAV and anti-GBM antibodies. Several noticeable practices introduced include immediate initiation of active treatment in active deteriorating kidney disease, the recommendation to consider combined RTX and CYC in markedly reduced or rapidly declining kidney function (typically serum creatinine >354 μmol/L), proposal of a protocol-based reduction of GC dosage in accordance with the PEXIVAS trial [28], and a specific description of immunosuppressive dosing.
5) 2022 Update of the EULAR Recommendations on the Management of AAV
The 2022 update of the EULAR recommendations on the management of AAV presented at the EULAR Congress 2022 in Copenhagen, proposed four overarching principles and 17 recommendations (Table 8). In addition to the main overarching principles that highlighted holistic and multidisciplinary approach in patient care, noticeable changes in these recommendations compared to the former recommendations included testing for both PR3- and MPO-ANCA using high-quality antigen-specific assay as a primary method under the suspicion of AAV, an emphasis on RTX in remission maintenance for GPA/MPA, and remission induction of non-organ- or life-threatening GPA/MPA using RTX. Furthermore, a specific dose defined upon GC initiation (starting at a dose of 50~75 mg prednisolone/day according to body weight) with a stepwise reduction into a prespecified target was proposed. On the other hand, PLEX was suggested to be considered in those with serum creatinine >300 μmol/L and active glomerulonephritis, and a routine application in alveolar haemorrhage were no longer recommended. In addition, treatment for both GPA/MPA and EGPA are separately provided - with an emphasis on using MEP in EGPA - consistent with the recent ACR/Vasculitis Foundation Guideline; however, consideration of avacopan combination with RTX or CYC for GC dose reduction in GPA/MPA was included, which was absent in the 2021 ACR/Vasculitis Foundation Guideline (Table 8).
6) Novel therapeutic agents for AAV
Although significant advances have been achieved in management of AAV, due to the heterogeneous manifestations and rarity of disease [29], evidence is insufficient to support certain treatments as more effective than others [30]. In addition, although observations from clinical trials of patients with AAV increased the understanding of the therapeutic benefits/limitations of immunosuppression, the outcomes in AAV patients, especially for GPA/MPA, remained unfavorable. Moreover, there are also substantial toxic effects of current immunosuppressive treatments. Therefore, there is a continuous need for novel therapeutic agents for disease management [31]. In this context, the recently demonstrated therapeutic efficacy of avacopan in GPA/MPA is encouraging. Combination of avacopan in a background treatment of CYC (followed by AZA) or RTX regimen resulted in a higher rate of sustained remission at week 52 compared with prednisone tapering with an acceptable safety profile [26]. Because GC use is associated with significant toxic effects and minimizing the use of GC is of increased interest in rheumatology, the role of avacopan in the treatment of patients with AAV remains unclear. Next, omalizumab, a recombinant, humanized, monoclonal antibody against human immunoglobulin E (IgE) approved for treatment of various allergic diseases [32], could have benefit in the management of EGPA [33]. However, no specific recommendations supporting the use of omalizumab in EGPA are present in the ACR/Vasculitis Foundation Guideline, even in subjects with high serum IgE level. Data from future large, randomized, control trials are warranted.
CONCLUSION
AAV is a potentially lethal disorder associated with significantly increased rate of adverse clinical outcomes. Because appropriate treatment is essential to improve patient outcomes, the updated information provided in the guidelines for AAV will contribute to clinicians’ medical decisions. Furthermore, novel therapeutic guidelines are expected to be released continuously based on the results from clinical trials. Finally, research investigating the pathogenesis of AAV will also enhance the understanding of disease and aid in development of optimal management recommendations for patients with AAV.
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