Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune necrotizing small vessel vasculitides that causes potentially life-threatening ischemic and inflammatory organ damage (1–3). The three subsets of AAV are granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Patients with GPA predominantly have ANCA directed against proteinase 3 (PR3), whereas, in MPA, 60 – 80% of patients have ANCA specific for myeloperoxidase (MPO) (4, 5). In EGPA, MPO-ANCA are detected in 30 – 40% of patients, whereas PR3-ANCA are rare. GPA is the most common AAV subtype with a global incidence of 9 per million person-years (6). Due to the distinct nature and genetic background of EGPA, it is often excluded from AAV clinical trials and will not be discussed in this paper.

Treatment of AAV with cytotoxic agents, immunosuppressive therapies, and biologics (particularly the monoclonal anti-CD20 antibody rituximab) have improved prognosis by effectively addressing active disease which, if untreated, can lead to impaired organ structure and/or function (organ damage) (7, 8). Although AAV is associated with premature mortality relative to the general population (9, 10), treatment-related improvements in survival together with a greater awareness of AAV leading to improved diagnosis have led to a rise in the overall prevalence of AAV (6, 11, 12).

These conditions, which were once fatal in nearly all patients, are now considered as chronic relapsing disorders with peaks and troughs in disease activity (13). Although relapses (defined as the return of active disease after remission) are common and can be clinically significant, it is not possible to reliably predict when they will occur. Re-establishing control of disease activity (re-induction) promptly in patients with relapse is important to prevent or minimize organ damage. However, the optimal treatment for AAV relapse remains to be determined (14).

This paper summarizes the risk factors for AAV relapse, evaluates the effectiveness of available and exploratory biomarkers for predicting relapse, explores factors that might help inform relapse prevention strategies, and assesses the available treatment options for re-inducing remission.

Immune dysfunction is fundamental to the development of characteristic inflammatory lesions in blood vessels and affected organs in AAV (2, 3). In patients with impaired immunological self-tolerance and a genetic predisposition, the production of ANCA plays a key role in AAV pathogenesis by promoting inflammatory responses (4, 15, 16). The binding of ANCA to MPO and PR3 exposed on neutrophils primed by complement fragment C5a and cytokines enhances leukocyte-endothelial interactions triggering neutrophil extracellular trap (NET) formation (17) as well as a strong inflammatory response. This process is part of a broader immune dysfunction which exacerbates endothelial injury, with C5a further amplifying inflammation by enhancing the generation of antibodies and the activation of phagocytic cells (18). Complement activation thus plays a key role in disease pathogenesis and therefore in the development of organ injury (19–22). Of note, pathophysiological studies in AAV have historically not distinguished between the mechanisms driving disease onset and those involved in relapse. Although these processes are likely to overlap, definitive evidence supporting this assumption is currently lacking.

AAV can develop at any time, but incidence increases with age (23). This complex disease has heterogenous phenotypes resulting in different treatment priorities in different patients ( Figure 1 ).

The early stages of AAV typically present with a range of non-specific symptoms suggestive of chronic inflammation, including fatigue, weight loss, fever, myalgia, and polyarthralgia (23). Patients with more advanced disease may show signs and symptoms of damage to the ears, nose and throat (ENT) (e.g., chronic rhinosinusitis, nasal bleeding and hearing loss (23, 24)), lung fibrosis (e.g., persistent cough and breathlessness (23)), and/or chronic kidney disease (CKD) (e.g., microscopic hematuria and reduced estimated glomerular filtration rate [eGFR] (23)). In addition, prolonged active disease can result in inflammation-related comorbidities, such as cardiovascular disease (25, 26). The longer AAV remains undiagnosed and untreated, the greater the risk of AAV-related comorbidities and irreversible organ damage.

AAV is a relapsing-remitting disease making increases in disease activity part of the natural disease course. However, there is considerable variability in the duration of remission between relapses (27, 28), with some patients never experiencing a relapse. These disparities may be partly explained by differences between patients in immune system characteristics and response to immunosuppressive treatment (29, 30).

Each relapse increases the risk of potentially fatal organ damage due to increased inflammatory disease activity and the use of higher-dose (more toxic) re-induction treatments (31). Mortality is also affected by treatment-related toxicities (in particular serious infections) and comorbidities, including cardiovascular disease (26). Although treatment effectively improves survival in most patients, survival rates are typically lower in older patients and in those with more severe kidney involvement and more active disease (32). Despite improvements in survival rates over recent decades, mortality remains approximately 2.7 times higher in patients with AAV than in the general population (26).

The aim of AAV treatment is to control active disease whilst limiting treatment-related toxicities, thereby preventing or minimizing the risk of tissue damage. Treatment includes intensive induction therapy (typically high-dose glucocorticoids with rituximab or cyclophosphamide) to gain rapid disease control and, once this is achieved, less toxic maintenance strategies to sustain remission (14).

The choice of treatment is not straightforward and may be restricted by the presence of disease-induced organ damage and co-morbidities. Treatments should ideally be tailored according to disease activity, risk factors, age, and existing comorbidities, e.g., CKD and lung disease (14, 33). The risk of treatment-induced comorbidities, such as infertility, diabetes, osteoporosis and infections, must also be considered. Ongoing monitoring of risk factors and signs of relapse is recommended throughout remission, as relapse risk can fluctuate over time due to inherent factors and cumulative events. The ideal scenario would be to have reliable tools for predicting relapses so, where necessary, treatment can be intensified early.

Over the last 30 years, expanding AAV treatment options have led to a shift from high-dose glucocorticoids supplemented with cyclophosphamide to less toxic approaches (34–36). For example, cyclophosphamide is often replaced or supplemented with rituximab to reduce the cumulative dose (14, 33). The current consensus is that rituximab is the most effective treatment for maintaining remission (37–39), and a combination of rituximab and glucocorticoids is recommended for the treatment of relapsing disease in most settings (14, 33). According to treatment guidelines, once remission is established, glucocorticoids should be tapered to the lowest effective dose (typically ≤5 mg/day within 4 to 5 months) or completely withdrawn to limit treatment toxicity (14, 33).

Recent studies, including the phase 3 randomized controlled ADVOCATE trial (40), demonstrate that the complement 5a receptor 1 (C5aR1) antagonist, avacopan, can improve remission rates, sustain remission over time, and (in patients with ANCA-associated glomerulonephritis) improve kidney function in patients with new-onset or relapsing AAV treated with rituximab or cyclophosphamide and reduced glucocorticoid exposure (37, 39–44). The use of avacopan with a low-dose glucocorticoid regimen is associated with a lower incidence of toxicities, including serious infections, than standard (non-avacopan) treatment (45). Based on results from the ADVOCATE trial (40), EULAR and KDIGO guidelines recommend using avacopan to reduce glucocorticoid exposure in patients receiving standard treatment for GPA or MPA (14, 33).

The optimal maintenance regimen has yet to be defined for patients achieving remission. Based on results from the MAINRITSAN trial ( Table 1 ) (39), the recommended regimen includes pre-emptive rituximab doses of 500 mg every six months for 24 months (14, 53). However, the RITAZAREM trial found that a rituximab-based regimen of 1000 mg every 4 months was also effective in patients with relapsing disease (51) leading guidelines to suggest using the higher dose in patients who relapse on the 500 mg regimen (14).

Defining the optimal duration of rituximab treatment is particularly challenging due to the increased risk of adverse effects, including infection, hypogammaglobulinemia, and impaired vaccine response. The recommended duration of rituximab therapy varies between guidelines, with EULAR guidelines recommending continuing treatment for 24 to 48 months (14) and KDIGO guidelines recommending 18 to 48 months (33). Of note, the MAINRITSAN-3 trial demonstrated fewer relapses in patients receiving rituximab for 36 months versus 18 months (50). Although subsequent pooled analyses failed to show an improvement in relapse-free survival with extended dosing (8), results suggest that extending maintenance therapy may be beneficial in some contexts (54).

Rituximab maintenance treatment is generally effective in sustaining remission and is typically well-tolerated. However, this is not the case for all patients and several factors may limit its’ use. These include a reduced response to rituximab in some patients, which may be a consequence of high interpatient variability of serum rituximab levels due to genetic polymorphisms and/or (in patients with repeated rituximab exposure) neutralization of rituximab activity by anti-rituximab antibodies (55–57). Furthermore, the use of rituximab is associated with an increased risk of infection, as demonstrated by both the MAINRITSAN and RITAZAREM trials ( Table 1 ) (39, 52). The observation that infection rates improved using an individually tailored approach with reduced rituximab exposure (49) raises the question of whether decisions abouts re-dosing and the duration of maintenance treatment should always be pre-emptive or whether they should be reduced in people with low relapse risk (e.g., those who remain MPO-ANCA negative or experience sustained B-cell depletion after rituximab treatment) ( Table 2 ) (62, 63).

The risk of infection tends to increase in patients with hypogammaglobulinemia during the first year of rituximab induction. This is more prevalent among patients with low baseline IgG levels and is primarily linked to older age and glucocorticoid dose (72–75). Although hypogammaglobulinemia is not definitively linked to an increased risk of infection during maintenance treatment, patients receiving re-induction therapy after relapse may experience further decreases in IgG levels due to repeated rituximab administration (75, 76). Similarly, the diminished response to vaccines in patients undergoing B-cell depletion—a common phenomenon in rituximab-treated patients —may have important clinical implications, potentially heightening the risk of infection (77, 78).

The high risk of severe infections and other complications with glucocorticoids, even at low doses, means their use requires careful risk-benefit assessment, particularly in terms of co-morbidities (31). Whilst pre-rituximab data suggest that the extended use of glucocorticoids is associated with fewer relapses (79), a retrospective study in rituximab-treated patients found that extending the use of high-dose glucocorticoids for more than six months increased the risk of severe infection and other adverse effects (e.g., diabetes and cardiovascular complications) without reducing relapse risk (80). The long-term use of low-dose glucocorticoids for the prevention of relapse has not been specifically evaluated in randomized controlled trials. However, the TAPIR trial found that the risk of major relapse in rituximab-treated patients with GPA remained low irrespective of whether patients received low-dose or no glucocorticoids and that the benefits of low-dose glucocorticoids to prevent minor relapses were only observed among patients treated with non-rituximab-based regimens (81). This suggests that maintenance treatment with rituximab and little or no glucocorticoids may be possible in some patients.

Relapse is classified according to the level of disease activity and the extent of organ involvement, assessed using the Birmingham Vasculitis Activity Score (BVAS) Version 3 (14, 82) or the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS-WG) (83). A relapse is typically deemed major if it affects key organs, such as the neurological system or the kidneys. Minor relapses are usually characterized by constitutional symptoms either in isolation or in association with non-life or non-organ-threatening manifestations. However, classification is often complicated by limitations in assessing disease activity. For example, kidney disease relapse does not have a generally accepted and shared definition, and there is no standardized modality for assessing kidney disease activity in patients with relapsing AAV.

ANCA testing is a central component of AAV diagnosis and is increasingly used to help define disease status, including remission and relapse. A negative serum ANCA assay characterizes serological remission while ANCA return suggests serological relapse. However, since ANCA titers do not necessarily reflect AAV activity, they are an imperfect indicator of relapse (78).

In the pre-rituximab era, the likelihood of relapse within the first five years was 40%–55% (82, 84). While the use of rituximab as maintenance therapy has significantly reduced this risk, relapse rates are not negligible and tend to increase significantly after maintenance treatment is withdrawn (8).

Health-related quality of life (HR-QoL) is often lower in patients with AAV compared to the general population, with many patients reporting depression, anxiety, unemployment, fatigue and pain (26, 108, 121). As expected, patient-reported outcomes (PRO) tend to worsen during periods of active disease and improve with remission (121). A post-hoc analysis of PRO data from the ADVOCATE trial demonstrated improvements in HR-QoL from baseline to weeks 26 and 52 in patients with AAV treated with rituximab or cyclophosphamide alongside glucocorticoids (108). Improvements in 36-Item Short Form Health Survey (SF-36) summary scores were greater in patients receiving avacopan versus prednisone taper at weeks 26 and 52, while EuroQoL 5-Dimensions 5-Level Questionnaire (EQ-5D-5L) summary scores showed greater improvements for avacopan versus prednisone taper only at week 52 (108). Whether this is directly due to the effects of avacopan, the impact of lower cumulative glucocorticoid exposure, or a combination of both remains to be established in future studies. Either way, results suggest that patient-reported HR-QoL should be taken into account when choosing a treatment regimen.

EULAR guidelines for the treatment of AAV stress the importance of effective communication and shared decision-making between physicians and patients (14). However, results from an online survey completed by 170 healthcare professionals (HCP) and 69 patients suggest that HCPs and patients have different perspectives on treatment aims, with HCPs prioritizing treatment efficacy and clinical outcomes, while patients focus more on long-term outlook, mental health, and functional impact (122). Patient perspectives may also be shaped by individual experiences and disease history. For example, a survey of 470 patients with AAV from 13 countries found that patients with prior exposure to dialysis or plasma exchange were more likely to favor plasma exchange for relapse management than patients without prior dialysis or plasma exchange (123). This highlights the need for a more patient-centered approach to AAV management.

Future studies are required to evaluate optimal dosing strategies and new combinations of immunosuppressants in patients with AAV. Ongoing studies include the COMBIVAS trial, in which patients with AAV are treated with rituximab in combination with the anti-BAFF agent, belimumab (55, 124, 125). The rationale for this study is that the increased BAFF levels reported in some patients with AAV may hinder the efficacy of rituximab. It is hoped that the distinct mechanisms of action for rituximab and belimumab will enhance B-cell targeting, especially as belimumab appears to mobilize CD27+ memory cells making them available to the cytotoxic effect of rituximab (126). Similarly, since activated CD4 T-cells are involved in the pathogenesis of AAV and are likely central in mediating kidney damage, a therapy that inhibits T-cell activation could help control disease activity (127, 128). However, the ABROGATE trial did not demonstrate reduced relapse rates in patients with GPA treated with abatacept (129). Data from patients with other indications suggest that obinutuzumab may achieve greater tissue B-cell depletion than rituximab (130). The OBIVAS trial is comparing the effects of obinutuzumab and rituximab on B-cell depletion and sustained remission in patients with AAV, with completion expected in late 2025 (131). Over time, the options for re-induction are likely to expand enabling further reductions in glucocorticoid use.

Effective relapse prevention and/or treatment is critical to minimizing tissue damage and glucocorticoid exposure in patients with AAV. Treatment choices are not straightforward due to interpatient variability in response and the high proportion of patients with significant comorbidities, many of which may be AAV-induced or treatment related. Balancing the benefits of treatment against individual risk factors, treatment toxicities, and organ damage is key to optimizing outcomes.

There is no definitive biomarker for predicting AAV relapse; however, monitoring ANCA titers and (in rituximab-treated patients) B-cell repopulation may help identify patients with a high risk of relapse, thereby guiding preventative dosing. When relapse prevention fails, early treatment re-introduction or intensification will help minimize the effects of active disease on tissue damage and optimize long-term outcomes. Rituximab effectively maintains remission and re-induces remission after relapse. Adjunctive therapy with avacopan can help minimize glucocorticoid exposure while improving kidney function and achieving lower relapse rates than a prednisone-based regimen aimed at corticosteroid withdrawal (40).

Further studies are required to investigate the effects of re-induction treatments specifically in patients with AAV relapse. Although specific data are lacking, it is likely that the pathogenetic mechanisms underlying new-onset AAV and AAV relapse are similar. Importantly, clinical evidence to date supports the comparable efficacy of the same therapeutic approaches in both settings. In both scenarios, reducing the risk of organ damage by minimizing disease activity whilst limiting treatment toxicity remains a top priority.