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Ahead of print publication  

Steroid-free management and recent advances in antineutrophil cytoplasmic antibody-associated vasculitis

1 Department of Rheumatology; Department of Medicine, University Hospitals Limerick, Limerick, Ireland
2 Department of Medicine, University Hospitals Limerick, Limerick, Ireland

Date of Submission27-Apr-2022
Date of Acceptance07-Aug-2022
Date of Web Publication07-Oct-2022

Correspondence Address:
Fahd Adeeb,
Department of Rheumatology, UL Hospitals Group, Dooradoyle, Limerick
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_87_22


Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) represents one of the most challenging and potentially life-threatening conditions faced by rheumatologists. Part of the challenge has been the limited therapeutic options available and the substantial concern related to their toxicity, which are time dependent and dose dependent. Systemic glucocorticoids (GC) have been the cornerstone of AAV therapy since the 1950s; however, the extensive list of risks associated with its use are well described. Cyclophosphamide and rituximab have become the standard therapy for remission induction in organ or life-threatening AAV but not all patients achieve or sustain remission and many remain on long-term GC therapy. Recent attention focuses on achieving sustainable steroid-free induction and remission maintenance through transformative innovation of novel drug development or repurposing. This review sheds light on the significant advances made in similar or more effective novel innovative steroid-sparing or reduction strategies in AAV.

Keywords: Antineutrophil cytoplasmic antibody-associated vasculitis, recent advances, steroid-free management

How to cite this URL:
Malik H, Sitram R, Mahmood W, Bhutta S, Adeeb F. Steroid-free management and recent advances in antineutrophil cytoplasmic antibody-associated vasculitis. Indian J Rheumatol [Epub ahead of print] [cited 2022 Nov 29]. Available from:

  Introduction Top

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a relatively rare disease that predominantly affects the small and medium vessels, with a predilection for the lungs and kidneys. It consists of three very variable but equally potentially life-threatening primary systemic vasculitides including (1) granulomatosis with polyangiitis (GPA; also known as Wegener's granulomatosis), (2) microscopic polyangiitis (MPA), and (3) eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg-Strauss syndrome).

The risk of relapse is independently predicted by anti-proteinase 3 (PR3)-ANCA positivity[1] and/or lung involvement,[2],[3] which suggest that the prolongation of immunosuppressive therapy after remission is achieved in this cohort may be reasonable. Steroid minimization (and if possible, subsequent complete withdrawal) is critical and is one of the major current goals in the therapeutic strategies of AAV to reduce the risk of glucocorticoid (GC)-related complications.

In this narrative review, online databases including PubMed, Embase,, and Google Scholar were used to objectively identify the relevant studies related to the topic using selected keywords and search terms. We further took citation search and assessed the reference list of the relevant studies. Only article published in English were included. The relevant abstracts were initially reviewed and assessed, followed by retrieval and assessment of the full article of the selected papers. The relevant findings were summarized in this overview with all authors holding diverse and neutral views about the topic.

  Historical Use of Steroids in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Top

Après its discovery in the 1940s, albeit initial skepticism, intensive course of high dose, prolonged systemic GC appeared to be a promising therapeutic strategy in AAV in the 1950s which resulted in a significant reduction in mortality. It remained to be the most effective and mainstay of treatment for the next two decades, but it then apparently transpired that its side effects were a major problem.

The introduction of cyclophosphamide (CYC) in the 1970s dramatically improved patients' outcome, especially in a combination regime with GC; but again, its toxicity is well described in the literature. Infertility, cystitis, cytopenias, infections, and malignancy are among the most prominent concerns. It has proven extraordinarily difficult to find alternatives and these two drugs were the only available options to induce remission in organ- or life-threatening AAV for approximately 40 years until the proven successful use of rituximab (RTX).[4],[5] Limited by their adverse effects (AEs) and ability to maintain remission (with significant proportion of patients remain to be GC dependent), long-term treatment alternatives are highly needed.

Recent therapeutic focus in AAV has been on early GC elimination or exit strategy, when possible, without compromising the treatment outcome. The PEXIVAS study, which is the largest ever trial in AAV (704 patients at 95 centers in 16 countries) demonstrated that the reduced-dose regimen of oral GC was noninferior to the standard oral dose regimen for remission induction in respect of death or end-stage kidney disease, but significantly reduced the risk of serious infections at 1 year.[6] Similarly, successful use of lower GC dose with either CYC or RTX in AAV has been replicated in several other recent studies.[7],[8]

  The Role of Complement Activation Pathways Top

Activation of the alternative complement pathway is critically important in AAV, with both murine and human data supporting the pivotal role of C5 and of its receptor C5aR as drivers of inflammation in AAV.[9] Avacopan is a novel orally administered small molecule which selectively inhibits C5aR located on the surface of neutrophils, without causing immunosuppression.

Two 12-week proof-of-concept and dose-finding phase II trials were conducted to evaluate the role of avacopan in AAV induction strategies. Used as an adjunct to standard of care (SOC) with different GC regimens, the CLEAR trial was the first to demonstrate encouraging evidence suggests that it may effectively reduce or replace GC during induction, where rapid improvement was seen in the Birmingham Vasculitis Activity Score (BVAS) and urinary albumin-to-creatinine ratio at 4 weeks.[10] The CLASSIC trial evaluated two different avacopan doses (10 or 30 mg twice daily) with superiority demonstrated in achieving early remission and renal response with the 30 mg dose.[11]

A large multicenter phase III study involving 331 patients (ADVOCATE trial) demonstrated that AAV patients were effectively treated with avacopan as an alternative to GC when combined with the SOC therapy (despite the exclusion of patients with a glomerular filtration rate of <15 ml/min and pulmonary hemorrhage).[12] Notably, it led to clinically and statistically superior sustained remission at 52 weeks versus GC with better safety profile reducing the GC-related morbidity [Table 1].
Table 1: Main remission induction protocols in antineutrophil cytoplasmic antibody-associated vasculitis - A chronological

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On the basis of these data, avacopan has since been approved as an adjunct to SOC therapy in severe active AAV by both the US Food and Drug Administration and European Medical Agency in October 2021 and January 2022, respectively. The total duration and long-term optimal strategy required with avacopan however is still unclear due to the limited current available data.

  Current Treatment Strategies in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Top

Treatment for AAV is best delivered through a multidisciplinary team approach, ideally by a rheumatologist, nephrologist, pulmonologist, radiologist, and pathologist, but may extend to other specialties depending on patients' disease manifestations including ophthalmologist, otorhinolaryngologist, cardiologist, gastroenterologist, and neurologist. To optimize treatment outcome, early recognition, exclusion of possible mimics, careful correct assessment on disease severity (mild form, severe or life-threatening, and refractory) to guide therapeutic options and early treatment initiation are all equally important. In general, treatment is categorized into two phases: remission induction and maintenance.

  Remission Induction Therapy Top

Current SOC therapy for remission induction in organ or life-threatening AAV involves high-dose GC with either CYC or RTX, and prophylaxis against Pneumocystis jirovecii should be considered during this intense induction therapy. CYCLOPS trial which compared pulsed intravenous (iv) versus daily oral CYC demonstrated similar efficacy of iv CYC with the advantage of having lower toxicity profile despite higher relapse rate during a long-term follow-up.[15] Favorably, lower CYC induction regime dose (a maximum of six 500 mg fixed doses of iv CYC pulses) resulted in similar efficacy but better safety profile in elderly >65 years.[16]

Substantive scientific data indicate that RTX is effective in inducing remission in AAV. In the RITAZAREM trial, RTX in conjunction with GC achieved a remission induction rate of 90% at 4 months in previously relapsing AAV patients,[19] consistent with the previous RAVE and RITUXVAS trials demonstrating high efficacy of RTX when combined with GC in inducing remission.[4],[5]

Accumulating body of evidence support the efficacy of methotrexate (MTX) or mycophenolate mofetil (MMF) in nonorgan threatening disease, with MMF the preferred option in patients with abnormal renal function.[20] Concordantly, the updated 2015 European Alliance of Associations for Rheumatology recommendations, in conjunction with the European Renal Association-European Dialysis and Transplant Association, advised against the use of MTX or MMF in retro-orbital disease, meningeal, cardiac or mesenteric involvement, acute-onset mononeuritis multiplex, and pulmonary hemorrhage.[20]

The NORAM trial which compared MTX versus oral CYC in nonorgan- or life-threatening AAV is of clinical importance as it demonstrated similar efficacy between the two drugs for remission induction.[13],[21] Comparably, MMF in a large randomized-controlled trial (RCT) involving 140 new active nonlife-threatening AAV patients of different age groups (MYCYC trial) demonstrated non inferiority to pulsed CYC for remission induction, but with a higher relapse rate (especially in anti-PR3-positive patients).[17]

Plasma exchange (PLEX) has previously been used as one of the initial adjunct induction therapies in AAV, especially with the most severe disease manifestations. The MEPEX trial which was conducted between 1995 and 2003 involving 137 patients demonstrated that PLEX led to a higher AAV rate of renal recovery and dialysis independence compared to iv methylprednisolone, despite similar patient survival and serious adverse events (SAEs) rates.[14]

Interestingly, the more recent PEXIVAS trial which was the largest RCT ever conducted in AAV involving 704 patients did not demonstrate outcome or survival improvement when PLEX was added to SOC induction therapy, including in those with severe renal disease or pulmonary hemorrhage[4] [Table 1] and [Table 2]. It may however be useful and considered in specific subpopulations, mainly in those who are also anti-glomerular basement membrane antibody positive.[22]
Table 2: Comparison of reduced dose glucocorticoid-rituximab combination in antineutrophil cytoplasmic antibody-associated vasculitis remission induction regimens

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  Remission Maintenance Therapy Top

The risk of relapse is high in AAV;[2],[3],[23] therefore, close monitoring and adequate treatment for remission maintenance of at least 2 years is currently recommended.[20] The optimal therapy duration is unknown, but recent data suggest that prolonged therapy beyond 2 years may be necessary to improve renal survival and reduce relapse risk.[24] Azathioprine (AZA) and MTX (in preserved renal function) are well-established first-line therapeutic options (supported by previous studies including the WEGENT trial),[25],[26],[27] with MMF as a potential alternative (based on proven better outcome with AZA compared to MMF in the IMPROVE trial).[28]

In addition to remission induction, RTX also plays an important role and has gained considerable momentum in recent years as the most efficient remission maintenance therapy for patients who previously achieved remission through RTX or CYC (i.e., patients with organ- or life-threatening diseases). It has also been shown to be more cost-effective for preventing relapses compared to AZA.[29] Data from the MAINRITSAN (500 mg every 6-months) and RITAZAREM (1 g every 4 months) trials suggest that RTX is superior to AZA in maintaining remission and preventing relapses.[23],[30]

An individually tailored approach to guide RTX infusion (vs. fixed-schedule regime) for remission maintenance based on serial CD19+ B-lymphocyte levels and ANCA titer, resulted in fewer infusions but the similar clinical outcome (MAINRITSAN2).[31] Current expert recommendations suggest consideration for extended treatment of up to 5 years in patients at high risk of relapse or its consequences.[32] Hypogammaglobulinemia, infusion reactions, severe infections, and having poor outcomes in SARS-CoV-2 infection are among the notable AEs.

Leflunomide (LEF) yielded a convincing efficacy outcome in GPA with a lower relapse rate compared to MTX in a study by Metzler et al. but was associated with more AEs (LEF dose of 30 mg/day was used).[33] Similarly, Mustapha et al. demonstrated in a retrospective study that LEF was an effective therapeutic option in two-thirds of PR3 and MPO-AAV patients who failed first-line treatment (with majority requiring only low-dose GC), but less so in EGPA and with up to a fifth of patients developing gastrointestinal AEs which led to discontinuation of therapy.[34]

  Novel-Targeted Therapies Top

Recent years have witnessed unparalleled advances of novel induction and maintenance strategies in AAV. A major trend in the current treatment landscape for AAV focuses on the minimization of GC use. There is an increased appreciation of combination therapies either given sequentially or as an add-on targeting more than one mechanism to achieve remission while reducing the total cumulative GC dose.

Avacopan (C5aR-inhibitor) appears to be an effective steroid-dose reducing agent in active severe AAV when added to the SOC induction therapy of either RTX or CYC in a major breakthrough phase III study.[12] Significant improvement was seen in treatment response similar to GC in achieving BVAS of 0 and without GC use at week 26, but with superior sustained remission versus GC at week 52.[12] There is also early evidence for successful use of another C5 inhibitor, eculizumab when combined with RTX in severe relapsing AAV.[35]

There is gathering evidence documenting encouraging results of intensified combination strategies using RTX with other immunosuppressive agents in AAV. This includes the successful use of sequential RTX-CYC combination resulting in early GC withdrawal,[18],[36] with a phase III RCT currently underway (ENDURRANCE-1 trial; Identifier: NCT03942887). Infliximab (IFX), an anti-tumor necrosis factor (anti-TNF) has been shown to be effective as a GC-sparing agent in resistant orbital GPA, when given sequentially after RTX with significant long-term response.[37],[38]

The addition of another B-cell targeting therapy which inhibits B-lymphocyte stimulator (BLyS), belimumab (BEL) to RTX in active PR3-AAV is currently being evaluated (COMBIVAS trial; Identifier: NCT03967925). This is based on (1) the promising scientific evidence from the BREVAS trial where no relapse were seen in patients who received RTX for remission induction followed by BEL for maintenance therapy[39] and (2) the fact that RTX increases circulating BLyS, an important physiological mediator of B-cell homeostasis, in certain subgroups, in which BEL targets.[40]

Other B-cell-targeted therapies have also gained interest in AAV. Anti-CD20 ofatumumab and obinutuzumab demonstrated encouraging remission induction and sustained B-cell depletion, with no major long-term relapse in case series of eight and three (who developed anaphylactic reactions to RTX) AAV patients, respectively.[41],[42] A Dutch study showed that Bruton's tyrosine kinase (BTK) protein and phosphorylation levels are profoundly increased in newly emerging B cells of active GPA patients with in vitro BTK blockade greatly inhibiting B-cell effector functions.[43] Unfortunately, a phase II trial looking into blisibimod, a selective BLyS inhibitor added to MTX as induction therapy in nonsevere AAV was terminated prior to enrolment ( Identifier: NCT01598857).

Of late, there has been a growing interest in the use of immunoadsorption (IA) as rescue therapy in life-threatening AAV, where pathogenic antibodies are specifically removed without supplementation of plasma or albumin. Chu et al. recently demonstrated that IA added to SOC improved remission rates and lower the risk of death in AAV patients with severe kidney involvement.[44] An open-label interventional study comparing IA and PLEX in AAV is currently underway (CINEVAS trial; NCT NCT03635385).

The benefit of iv immunoglobulins (ivIg; a purified plasma product) including rapid improvement of disease activity and related biomarkers has been demonstrated in a meta-analysis by Shimizu et al., supporting results from a large French nationwide study which showed encouraging clinical benefit of ivIg as an adjunctive therapy, particularly in relapsing or refractory disease.[45],[46] It is also particularly useful in profoundly immunocompromised patients especially in those with recurrent infections, and may replenish Ig in hypogammaglobulinemia induced by RTX therapy. Preliminary data for the use of subcutaneous (sc) Ig as an alternative to ivIg in AAV have been encouraging.[47]

Based on recent observations, several pathophysiological pathways crucial for antibody activity have been identified to be involved in ivIg-mediated steroid-sparing immunosuppression. The central role of IgG Fc fragment in linking adaptive and innate immune systems, upregulation of the inhibitory receptor FcγRIIB, direct triggering of SIGNR1- or DC-SIGN-dependent anti-inflammatory pathways initiated by ivIg may all be key in ameliorating autoantibody-induced inflammation.[48] Furthermore, it has been demonstrated that mean sialylation ratio of anti-PR3 antibodies was significantly lower in patients with active GPA compared to patients with weakly active or inactive disease.[49] Better pathogenic understanding may provide personalized therapeutic option where recombinant sialylation Ig may potentially be useful in GPA-AAV; although most therapeutic glycoengineering approach to enhance Ig sialylation are still in preclinical stages.

The promising success of a small open-label trial of 20 nonsevere relapsing GPA patients who received iv abatacept in inducing remission and GC discontinuation has provided additional useful insights into remission induction therapy for AAV.[50] Based on this encouraging preliminary evidence, a phase III trial (ABROGATE) is currently being conducted to determine its efficacy ( Identifier: NCT02108860). Recently, Martins et al. published a small series of kidney transplant recipients with AAV receiving belatacept, a fusion protein that also target T-cell co-stimulation as maintenance therapy with low relapse rate, which could renew the interest of co-stimulation blockade in AAV.[51]

Anti-TNF monoclonal antibodies (mAbs) may have a potential role in refractory ocular AAV based on several isolated case reports.[52],[53],[54] In the RATTRAP trial, IFX was shown to be useful in some cases, despite RTX demonstrating better response and clinical remission rate.[55] In contrast, etanercept (fusion protein anti-TNF) failed to demonstrate efficacy (WGET trial),[56] while a recent French real-life study revealed low efficacy (<50%) of both anti-TNFs (IFX and adalimumab) and abatacept in refractory and/or relapsing GPA mainly with pulmonary or otolaryngeal manifestations.[57]

The use of Janus kinase (JAK)-inhibitors in AAV was suggested by previous studies implicating activation of JAK/STAT pathway in its pathogenesis.[58] Liu et al. in their pilot study reported that tofacitinib, a pan-JAK inhibitor to be effective and safe in nonorgan-threatening AAV, sparing the dose of GC.[58] Fostamatinib, a potent spleen tyrosine kinase (Syk) inhibitor, has also been shown to be extremely effective in preclinical experimental model in treating renal and pulmonary inflammation of induced MPO-AAV,[59] while tocilizumab (anti-interleukin 6 [IL6]) has been shown to successfully induce clinical remission mainly of MPO-AAV in several case reports;[60] however, both groups of drugs have yet to be investigated in controlled clinical trials.

A phase 2 European study of an anti-C5a mAb IFX-1 (vilobelimab) to reduce or replace the use of GC involving 57 patients with GPA and MPA (IXCHANGE trial) has been completed with initial data revealing positive results including similar efficacy to GC;[61] however, another phase 2 study (IXPLORE) in the US had to be terminated due to the COVID-19 pandemic ( Identifier: NCT03712345).

Selective prolonged lymphocyte depletion through alemtuzumab (anti-CD52 mAb; CAMPATH-1H) may have a role in selected refractory or relapsing AAV (and in the context of RTX failure) with careful evaluation of infection risk. In a prospective cohort study of 71 patients with relapsing/refractory AAV, 80% of patients achieved remission after receiving alemtuzumab; however, (1) more than two-third of patients relapsed (median 9.2 months) and (2) SAEs were common, with death seen in approximately half of the patients during the observation period (median survival time 106 months).[62]

A recently published phase 2b trial (ALEVIATE) of 12 refractory AAV patients that looked into two different alemtuzumab doses (30 or 60 mg every 3–6 months to a maximum of 3 courses over a trial period of 1 year) demonstrated complete remission in a third of patients at 6 months (total remission rate of 9 patients/75%; 5 patients/41.6% with partial remission). Similar high relapsed rate was observed (4 patients; 33%) at 12 months.[63] This study is however limited by short follow-up period and exclusion of patients above 60 years.

Evidence for reliable optimal treatment strategy in EGPA is currently quite limited as it is a relatively understudied disease group in AAV. Eosinophils and Th2 cells activation, together with ANCA-mediated inflammation are cardinal in its pathogenesis, with eosinophilic-dominated inflammation a characteristic feature and asthma being a near-universal picture that usually precedes vasculitis.[64] IL-5 is an important cytokine for the maturation and survival of eosinophils and is elevated in patients with EGPA.[65]

Mepolizumab (MEPO), an anti-IL-5 mAb initially used for refractory eosinophilic asthma has been demonstrated to be safe and effective for both induction and remission maintenance in refractory and relapsing EGPA.[65],[66] Four-weekly sc MEPO of 300 mg added to SOC led to significant reduction in both relapses and GC requirement in the MIRRA trial.[65] Recently, a large multicenter observational study demonstrated that both 4-weekly 100 mg and 300 mg are effective for the treatment of EGPA and suggested comparison of the two doses in a setting of a controlled trial.[66]

Other anti-IL-5 inhibitors including reslizumab and benralizumab are also currently being evaluated in EGPA, with early data from the same authors demonstrating positive outcomes of both drugs.[67],[68] Omalizumab, an anti-IgE mAb was shown in a recent systematic review to be an effective GC-sparing agent in EGPA patients with severe asthmatic manifestations; however, paradoxically, albeit from mainly case reports, limited evidence suggest that it may be implicated in EGPA pathogenesis among asthmatic patients that received it.[69] In addition, a favorable response was seen in a patient with relapsing EGPA who received imatinib, a tyrosine kinase inhibitor, supporting previous published in vitro data by Kälsch et al.[70],[71]

Several other treatment modalities are currently under evaluation for AAV in clinical trials including the use of hydroxychloroquine as an adjunct to SOC in patients with low-level disease activity ( Identifier: NCT04316494) and Vitamin D3 (cholecalciferol) supplementation in AAV patients with insufficient or deficient Vitamin D3 ( Identifier: NCT04280601), while a study assessing the therapeutic benefit of endothelin receptor antagonist BQ123 as add-on therapy in AAV has been completed and is under evaluation. These studies may potentially provide further insight and improve our understanding of the disease.

  Conclusion Top

Conventional GC use has dramatically improved the outcome of AAV; however, it is burdened with relevant AEs. There is growing body of evidence demonstrating feasible early reduction or withdrawal of GC in many AAV patients based on insights from clinical trials and preliminary data documenting successful use of novel steroid-sparing-targeted therapies. It is an exciting time for researchers and clinicians across the globe in search of new treatment paradigms which deliver high therapeutic efficacy and address the unmet need to safely assist in GC avoidance or early GC withdrawal strategy, maximizing patients' clinical outcomes.

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Conflicts of interest

There are no conflicts of interest.

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