[Nephrol Dial Transplant, 2023, 0, 2-12 Thup:/dokog/10 1093)ndughod257 ‘Advance access publication date. November 2023 ANCA-associated vasculitis—treatment standard Aglaia Chalkia @®"* and David Jayne? ‘Depart of Medicine, nest of Canis, Cambridge, UK Canespandence te: Dandy Email soem suk ‘Oh wc he ie of is conibation ahp/ncademicoup.cmindpages/uthor vides ABSTRACT ‘Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are characterized by small-vessel necrotizing inflamma- ‘ton, and prior to the advent of immunosuppressive therapy frequently had a fatal outcome. Treatment has transformed AAV into a relapsing/remitting dicease with increaced drug-related toxicities and organ damage. The use of placacortcoids, cyclophosphamide fand immunosuppressives (including azathioprine, mycophenolate and methotrexate) was optimized through @ sequence of clinical tials establishing a standard of cave against which subsequent targeted therapies could be developed. Improved understanding of pathophysiology has supported the development of B-cell depietion and complement inhibition in granulomatosis with polyangitis ‘and microscopic polyangitis, and interleukin $ inhibition for eosinophilic granulomatosis with polyangits, leading to the approval lof newer agents for these conditions. There has been an increased attention on minimizing the adverse effects of treatment and on “understanding the epidemiology of comorbidities in AAV. This review wil facus on ecent evidence from clinical trials, especially with respect to glucocorticoids, avacopan, plasma exchange, rituximab and mepolizumab, and ther interpretation in the 2022 management recommendations by the European League of Associations of #heumatology. Keywords: ANCA-associated vascults, diagnosis, pathophysiology, prognosis, treatment Ina nutshell 41. Induction treatment of Lfe/organcthreatening anti- »eutrophil cytoplasmic antibody-associated vascultisis a combination of ghicocorticoids and ritaximab or oy- clophosphamice, with rituximab the preferred choice in relapsing granulomatosis with polyangitis/micrascopic pelyangits 2A rapidly reducing glucocorticoid regimen is now preferrad—the Plasma Exchange ané Glucocortico:es tm Severe ANCA-Astociated Vasculitis (PEXIVAS) Teal schedulevhich reduces risk of sevious infection with= ‘out loss of efficacy Although plasma exchange did not improve the combined endpoint of deat and/or end stage Kidney disease (=SKD), a meta-analysis concluded that plasma exchange results in reduced risk of ESKD at 2months and should be considered in patients present ing with a serum creatinine »300 wml f maintenance of remission treatment, Gxed-intervall epeat-dose rituximab for 24-48 months is more effec- tive than azathioprine or methotrexate and permits glu- cocarticoid discontinuation within § months of start cof therapy, Relapse risk increases after stuns with Grawal An understanding ofthe risks and consequences of elapse and che sks of secondary immunodefciency ‘with ntuximab informs the physicians decision on treat- sient duration, 4. New insights into the vole of the complement altema- tive pathway in pathogenesis lad to the development of the oral ant-C5a receptor avacopan, which was superior ‘over 1 year to a standard glucocorticoid tapering zeei- ‘men, when given in combination with ntuximab or cy. 300 pmol/L (3.38 mg/d) (18). AAV patients ‘wit lung haemorrhage and hypoxia at presentation in toe PEX- INAS cial showed tend to reduced mortality with plasina ex: change [19] An increased risk of infection with plasma exchange was observed in the meta-analysis and this isk needs to be bal anced against potential benefits Dosing and duration of glucocorticoids had been partslly stan- ardized in the design of eay clinical trials in AAW, but di comparison of different glucocorticoid regimens has now been reported from the PEXIVAS and Etfect of Reduced.Dose ws High- Dose Glucocorticoids Added co Rituximab on Remission Induction lm ANCA-Associated Vasculitis (LOVAS) tials [15,20] The PEXIVAS tuial demonstrated similar efficacy for a reduced-dose oval gluco corticoid regimen (Table 2) compared with a standard glucocort- oid regimen {cumulative exposure difference between groups of +407) for the psimary endpoint (ESKD or death) but fewer serious infections occurred with the redveed dase vegimen. The major ity of PEXIVAS patients received cyciophosphamide induction and itis not clear whether the reduced-dose glucocorticoid regimen should be vecammended with steximab as dosing was lower than ‘hat used in the RAVE weil. nthe Avacoyan for the Tleatment of ANCA-Associated Vasculitis (ADVOCATE) Tia, when compared ‘with s glucocorticoid regimen similar to the reduced dose PEX- IAS regimen but with withdrawal at 21 weeks, avacopan lee ta move patients having sustained remission at +2 months and showed superiority for improvement in quality of life, recovery of GER and fewer glucocortcoid-related complications (10). tis ‘therefore an altemative to glucocorticoids, attractive fer those patents at high risk of glucocorticoid toxicity, Notably, in AD- VOCATE among the patients with renal involvement (81%), the vacopan-teated group experienced a more rapid improvement i dhe urine aloumin-creatinine ratia by the Sst month (sbeo lute difference 20% (52% to-22%) and higher GFR recovery wnt 52 weeks {fnean ditfevence 5.2 mi/min/1.73 m’), The differences in GFR recovery were more proncumcedin patients with lower GFR (enean difference 5.5 m/min in GFR <20 ml/min, 84 ml/min In GER <20 mL/min), which was sustained during the 8-week follow-up period after discontinuation [21]. However, there is no clinical trial data to support the use of avacopan for patients with GER <15 mb/min/1.73 mor fo longer term therapy beyond 41 year Intravenous methylprednisolone at cumulative doses be- tween 1000 mg and 3000 mg is widely used for patients presenting ‘with organ-threatening disease but has not bean ested in a ran. domized clinical tra, (Table 2). the fallue of a patient to respond to induction therapy ot to achieve 2 complete remission defines refractory disease [22] Alternative diagnoses, or the presence of a vasculitis secondaty to anather disease process (maligrancy, infection, drugs, eg caine) need co be considered, instability in contiol of disease ac: ‘ivy early in the treatment course is not infrequent anc is man. aged by an increase in oral, or use of incravenous, glucocorticoids Other options are to combine cyclophosphamide and rituximsh, te inuoduee avacopan or consider PLEX High-dose intavenous immunoglobulins has also been used especially in the context of concurrens infection yuendenpunuoo'dno-awepede)r sch Woy peneouNoG 02 soquieceq 20 Uo js0n6 Ka LezeBeL/LEZPAIBNPLIEEO! OL/OPIAOA.ChalkiaandD Jayne | 3 | Classification criteria ACR/EULAR 2022 ‘GPA/MPA | Induction of Remission Treatment MMF or mmx Alkernative + Hot organsife threatening Consult centre of expertise Consider: + Combination ATK + Mic * Rvacopan | GC+RTK or CYC ‘Avacopan PLEX. ‘consider: Consider: * Steroid sparing + tfereatinine> + Infower GFR 300 mol/L. (3.39 me/a) Alternatives ‘Total duration shoul be considered based on individual isk factors relapse an infection isk) Figure 1: Proposed therapeu gorithm forthe management of GPA and MPA. GC hucocotioid RIX rituximab; CYC. cyclophosphamide, Mal mycophenolate mofetil MIX, methotrexate; VIG inttenous immurogisbulin, AZA. azathioprine, TMP-SMX, tlmetkopiin/Sulfamethoxazae “The Gtst choice for maintenance of remission veatment after induction with ritucmnad or cyclophosphamide has changed to rituximab from azathioprine or methotrexate following the Ritu Jmab versus Azathioprine for Maintenance in ANCA-Associated vasculitis (MAINRITSAN) and RITAZAREM results [11, 23}. “These tals studied diffevent patient populations and different rituximae doses, but a dose of $00 mg every § months for 2a years ig now recommended, although some patients may require 2 higher/more frequent dose (Table 1). Extending the remission (eatmenl pevied fiom 2 to 4 years has bean sup. ported by data with azathioprine and prednisolone from the Randomised controlled trial of prolonged treatment in the re ‘mission phase of ANCA-associated vasculitis (REMAIN) Trial [24] and from prolonged rituximab use in the Long-Term Ritux: mab Use to Maincain Remission of Antineutrophil Cytapias mic Antbody-Associated Vasculitis (MAINRITSAN Ii} Teal [25 Frequent complications of rituximab ate infections and hy: pogammaglobulinemia, which can be severe, equiring prolonged 02 sequies9q 29 Uo js0n6 fa LeZzBEL/LEZPEIBAPLICEO! OL/OPIAPIe-soUEARERPUYOS dno swOpEDe/'sdH Woy PEDEOIUNE4 |. Nephrol Dial Transplant, 2073, Vol 0, No.0 ae | Classification criteria ACR/EULAR 2022 EGPA FFS>1. Induction of Remission Treatment 4 | | GC +CYC or RTX GC +/- AZA, MTX or MMF —— As tame ———— Figure 2: Proposed sherapeuic algorithm forthe management of EGPA. GC, glucocorticoid, RIX viwimala, CYG eyclophesphamide, ALA auithloprine: MIX methotrexate MME, mycophenolate motel; MEPO, mepolizumab, TMP-SMX, uimethoprimisulfamethaxazale 02 sequies9q 29 Uo js0n6 fa LeZzBEL/LEZPEIBAPLICEO! OL/OPIAPIe-soUEARERPUYOS dno swOpEDe/'sdH Woy PEDEOIUNEA.chalkia and D Jayne | 5 Infection prophylaxis and immunoglobulin replacement therapy. Immunog.obulin G levels should be monitored every 6 months and a falling level, such as below 5 yl, requires reassessment of risk/oenefic for continuing rituximab treatment. Patient factors Including the perceived relapse risk, the possible consequences Of relapse and the risks of ongoing treatment toxicicy need to be reviewed curing the course of mainzenance therapy Azathioprine, mothotiexate and mycophenalate mofetil ate alternatives (onc ‘uximab and are often combined with low~tose glucocorticoids (Cable 1). Gucocorticoid withdrawal increases relapse risk in this, sexing TREATMENT IN EGPA ‘The Five-Factor Score (FFS, impaired kidney function, protein. tris, cardiomyopathy, gastrointestinal eract and central nervous system invelvement, each 2 point if present) defined organ in- volvement that predicted mortality in EGPA, and a FFS 21 is used to define poor prognosis patients Tor these patients the recom- ‘mendation is high cose of glucocorticoids and cyclophospaamide a initial teatment. A recent prospective study of 70 patients With EGPA and cardiac involvemenc treated by glucocorticoid and cyclophosphamide, also reported favourable long-term progno- sis (26), The Rituxima versus Conventional therapeute strate gy (or vemistion induction in easinophilic granulomatosis with polyangills (REOVAS) rial randomiged 105 EG2A patients (407 FES =1) 10 rituximab or eyclophosphamice and reported that t= ‘uximab was not inferior for remission induction at S months (abe strict) (27) with a high-dose glucocorticoid tapering regimen. in lone study, Adding Azathioprine to Remission-induction Glucocor ticoids ‘or Eosinophilic Granulomatesis With Polyangitis (Churg: Strauss), Microscopic Palyangits, or Polyartertis Nodosa Without Poor Prognosis Factors (CHUSPAN) Tlil for EGPA patients with FES of 0, the addition of azathioprine to glucocorticoids did nnot reduce relapse risk [28], However, relapses in EGPA ave {quent a ghicocortccids are reduced and most patients accrue 4 high glucocorticoid exposure. As a result, other immunosuppres sives ae stl often used, to uy to limit glucocorticoid expasure ‘The antisinterleukin 5 (1L-5) monoctonal antibody mepalizumab osed at 300 mg every 4 weeks was effective in prevalent EGPA patients, wheve it reduced steroid exposure, smpioved remission rates and reduced relapse rsk in the Mepolizurnab or Placebo for Fosinophilic Gramulonsatosis with Polyangiitis (MIRRA) Teal [28 The mepolizumab dose approved for treating severe eosinophilic asthma (100 mg every 4 weeks) may also be considered for EGPA [20]. Randomized tals evaluating optimal mepolizumab dose in IEGPA have nat been performed, in the EGPA MIRA trial, much lof the improvement reflected control of asthma and naso-sinus disease, and theve are insufficient data to recommend use of ‘mepolizumab in severe vasculiti presentations with organ (all lure The benefit of antisiL5 s seen in both ANCA-negative and - positive EGPA subgroups, and is maintained beyond I year of eat- ‘ment Benefit has also been reported with rituximab in obeerva- tional studies of prevalent GPA patients with relapsing/refractory disease [21], however, the inference across studies is that rtux- smab is not as beneficial in EGPA compared with GFA/MPA, MANAGING INFECTION, TREATMENT-RELATED COMPLICATIONS AND COMORBIDITIES Infective prophylaxis for pneumocystis with ttimethoprimy sulfamethoxazole is recommended when cyclophosphanide or rituximab and/or high doses of glucocorticoids are used, and ap eats to have amore general effect on reducing bacterial infection frequency [32] Response to immunization is markedly ‘mpa'rec following vtuximat and theve is rarely the opportunity to ime nize prior to induction cherapy [23], However, vaccination timing can be optimized during ritoximnab maintenance therapy, ideally administering vaccines at least 4 weeks before the next rituximab dose. Fundamental principles in the management of AAV patients also involve the periodically screening for and management of cardiovascular factors, such as diabetes, lipids, blood pressure and other treatment-related complications, including osteoporo- sis, guided by general EULAR recommendations (34,35) Addeese ing the distinctive characteristics of AAV patients, including vu nezable demographics like the eldely, who are more susceptible to higher infection rates and treatment-associated toxicities, and ‘younger patisnss of reproductive age, the notion of tailoring eat ‘ments considering the teatinent toxicity profile (Table 1) could be incorporate tegles for personalizing weatmentin AAV. Personalizing treatment based on patients characteristics + Pationts with severe kidney disease Consider addition of plasma exchange (f serum eveati nine >300 woV/L} ‘Consider adition of avacopan for lower GER Elderly/tral patients (vulnerable to myelotoxicty and infections) Consider rituximab over cyclophosphamide Consider steroid-sparing strategy with avacopan + Precmenopausal women and men conceming thei fer shy ‘Consider rituximab over cyclophosphamide + atients with relapsing disease Consider rituximab (MPA/GPA) Consider mepolizamab (EPA) Personalized treatment based on choice of treatment + Combination cyclophosphamide and rituximab Severe kidney cisanse Slow disease vesponse Refractory disease igh risk of glucocorticoid toxicity (steroidsparing strat. eo) High sk of cyclophospleamide toxicity (eyclophos phamide-sparing strategy) + Addition of avacopan ‘luecoeortcoids contraindicated/igh tsk of toxicity Lower GER Refractory disease After starting avacopan, consider rapid glucacorticcid taper and withdrawal by end of Week 4 Duration 12 months NEW DEVELOPMENTS Pathophysiology Genetic factors contribute to the pathogenesis of AAV. Genetic ‘variants, toth within the majo hstocompatibilty complex (ME) yuendenpunuoo'dno-awepede)r sch Woy peneouNoG 02 soquieceq 20 Uo js0n6 Ka LezeBeL/LEZPAIBNPLIEEO! OL/OPIAO6 |. 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Both seiotypes are associated With variants of SERPINAI (encodes for alpha 1 anti-trypsin), a kcey inhibitor of the serine protease PR3, PTPNZ2 (protein ¢yro- sine phosphatase non-receptor type 22} and CTLM (cytotoxic T lymphocyte antigen 4) which play soles in T cell activation [27].A genome-wide association study has indicated associations Dbetween FILA-DQ and MPO-ANCA-positive EGPA, winle ANCA. negative EGPA is related to variants associated with mucosal re- sponses and eosinophil biclogy [24 ‘The success of B-cell depletion therapy has been attributed to the recognition of the central role of 8 cells in the pathogenesis (of AAV, given their key roles of ANCA-preducing plasma cells and ‘heir function as andgen-presenting cells that support T-cell a vation and possisly other cell types, especialy ir granulomatous lesions. Specifc Bacell cytokines, especially cell-activacing face ‘or/lymphecyte stimulator (BAFF/BLyS], have emerged asa crucial {actor inthe development and function of calls. BAFF cevels core relate with AAV disease activity and BAFE/BLyS receptor antago- axe potenti} creatment targets [29] ‘The complemen: alternative pathway in AAV has been shown Sn experimental models tobe a etic] pathway for ANCA vasculie tis and in vive complement activation through increased serum levels of complement component C5a, C3a, factor B and mem brane attack complex (MAC) ate seen in patients with active dis- tease, and remission associates with Une veduction /40) CSa ie a potent chemotactic factor for leukocytes and promotes activation annd degranulation of neutrophils through its interaction with the (5a receptor, C5aR1, which ie the target for the ora) complement inhibiter avacopan Fig. 3) Diagnosis Prior to diagnosis of AAW suspicion of a vasculiti ilness is key ad these disorders should be considered in patients with une explained systemic or organ specific inflammation and/or dys- fonction. Diagnostic delay remains an important contibuto: to poor outeomes especialy fr those wth Kicney involvemen® The chagnosis of AY invoives « compreheasive approach that ine dudes ciioal manifestations, serologic testing fimmuncassays for PRE-ANCAs and M2O-ANCAS, eosinophils, exclusion of anc= sglomeralsr basement membrane disease and systemic hupesenj- thematosus (SLE) and when feasible tise biopsy. Prompt eat rents ofter intate in highesuspicion case, while biopsy may ssl be performed later to confinn the diagnosis, exclude AAV rmimics and guide further management, particulary fom the kid- ney [41] The Intemational Chapel Mill Consensus Conference on the Nomenclature of Systemic Vascultides and the subsequent ACR and EULAR have established classification criteria for AY te aid in research and clinical stadies, but ate not designed co be Aiagnoscic criteria [42-44 Outcome prediction Disease-state definitions differentiate active disease ftom remis- sion [22] and delays in achieving remission associate with higher rortality and ESKD rs (2) Thus, monitoring for disease accigy and response to treatment is key tothe management AAV Bemis sion is defined by the absence of features of active disease while the patientis ona law prednisolone dose fusualiy «10 me/day) fl lowing 2-6 months of immumosuppressive induction treatment, Renal remission is ypically assessed by monitoring GFR, and rine abnormalities, particularly presence of haematuria, Persis- tent aematuria conbrbates toa higher nsk of elapse while per sistence of proceinunia (protein/creatinine ratio 20.05 mmol st 6 months) associates with worse long-term GFR [45 4). 1tis un cortan to what extent these urinary findings vepvesent ongoing. disease activity or persistent damage from the intial inflamma- tion in the absence of repeat biopay studies New urine bionsatke fs such as soluble CD163 and MCP-1 have been investigated to gain insights inco renal remission and treatment response [47 ‘An ongoing project by the ACR and EULAR is developing consen: sus composite response cr:teria for clinical tals 48) ‘Three clinicopathologieal sk scores, incorporating baseline parameters (clinica? and pathological), have been developed to identify patients with renal involvement at risk of developing. ESKD [19) The Berden ciassifiction includes glomerslar lesions {acuta/ehronic) and defines four classes; focsl, mixed, eescentic and sclerotic and Une Maye Cline Chnomiety scote (MCCS) come bines only the chronic features ‘tom all the renal compartments (glomerl, ners! vessels) and presents four proups of sever iy, The ANCA Renal Risk Score (ARRS) incorporates both base- line Kidney faction, and histopathologieal characteristics (nae ral glomeruli and tubular atropiayfintrstitial fibrosis) to predict the risk of ESKD categorized into three severity groups (recentiy Updated to four groups) 50], Although even in eases withthe most tluronie esions or dhe highest risk of #SKD, there is stl a chance of renal recovery. these scores camot detenmine management de- cisions. However, further refinement has the potential for more precise medica! interventions for example histology findings to predict how patients will respond to specific drugs and/or PLEX. ‘Testing PRS/MPO-ANCA andor CDI84 B cells for relapse pre- diction oF guiding maintenance treatment duration can be helpe fal, but should net replace elnical assessment. The have been attempts to use these biomarkers to divect rituximab desing ‘which may allow a low total cumulative rituximab dose; how: ever, freavency of monitoring, and sensitivity and specifcity of assays limits ability to reliably prevent relapse (51. Evidence sug gests that ANCA levels and 8.02] rerum mayoe most helpful to predict relapse after tuximnab withdrawal [52] ‘Management Rituxlmab is an ant-CD20 B-cell depleting manocional antibody that has proved effective in AAV’ as bot induction and main. tenance treatment; however, a small proportion of patients fil to achieve remission, especially in granulomatous disease, with the possiility of early relapses and rituximab resistance asso- cated with an anti-globulin response. Obinutazwnab, a Type It yuendenpunuoo'dno-awepede)r sch Woy peneouNoG 02 soquieceq 20 Uo js0n6 Ka LezeBeL/LEZPAIBNPLIEEO! OL/OPIAOA.chalkia and D Jayne | 9 I am Sa esegraim irre ey coke we i chemotaxis priming Rituximab ual targeted therapies INE tumor necrosis factor alpha; 1, ntrleukin-t ISR intviekin 5 receptor: Th2 ‘Pheer ? eels svacopan tanget Coad, bela, tages css, belmamat, tgs: BAP F/biys, ntuxmae arpa C520, cbinuturumal tages 2029. abatacep,Tgand-binding domain of CLAS, mepaizurab, target Ls; benralizumab,rget 3 AantCD20 monoclonal antibody has superior direct call death and antibody-dependent cell-mediated cytotoxicity compared with rituximab ane was efficacious in a phase II lupus nepiaiis tal, where more complete ang sustained B-cell depletion occurred ‘than bas been observed in vituxlmab-eated SLE cohorts. Tae potential of obinutuaumab in AAV is being explored in Obinu- ‘uaumab compared wich rituximab for treating ANCA-associated vasculitis (ObiVas) Tal (ISRCTN12069620), Failure to demon- strate & reduction of relapse risk with belirmumab a 21yS n+ Iibitor in the Hfficacy and Safety of Belimumab and Azathio- prine for Maintenance of Remission i Antineutrophil Cy:oplas. ‘mic Antibody-Associated Vasculitis (@REVAS) This! was linked to issues of tial design and a low event rate in the placebo group [53], but the potential for a synergistic B-cel) depleting effect when belimumab is combined with niuximab {fom remis= sion induction is being studied inthe Randomised stacy of rtuxe JImab and bellmumab sequential therapy in PR3 ANCA-associated vasculitis (COMBIVAS) [54] ‘Targeting cells or T-cell help is also rational approach inthe ‘yextment of AY due to the crucial rele of T celle the pathogen= esis of the disease. Abatacept is comprised of the ligand-rinding domain of CTLAA plus human immunoglobulin ane cartes the potential to modulate ce costimulatory signal required for T cell activation, The promising results from sn open-label tril of batacept in non-severe GPA in terms of high rate of remission and its steroid-spaving effect has paved the way for the angoing Abatacept (CTLAtIg) for the Treatment of Relapsing, Non Severe, GGranulomatosis with Polyangitis (Wegener's) (ABROGATE) TMial (evcToai0se60) ‘The pivotal role of complement component CSa has addressed new carget of Weatment with avacopan and a newer ant-CSa monoclonal antibody (vlobelima) which has brought promis- ing results from phase 2 tral (abstract [55], Ongoing clinical ti als with anteiLS agents (cenralizumad (Eficacy and Safety of Benralizurnab in EGA Compared (o Mepolizumab (MANDARA) ‘Dial NCTO4157348) and depemokima (Cffcacy and Safety of De. pemokirnab Compared With Mepolizurmab in Adults With Relaps. ing or Refractory EGPA (OCEAN) Teal; NCTOS762934)] will x5 their effectiveness compared with mepolizumab in EGA, Benral igumab and resizamab have shown initial efficacy in small-open Intel plo EGPA studies [5s] ig 3). SUMMARY ‘The updated FULAR recommendations for the management of AY indicate significant progress in the field of AAV trestin ‘Tae direction towards 4 more effective qeatment strategy with faster and higher races of remission s of great importance in AAV management Achieving remission promptly is vial ‘or prevent ing disease progression, reducing organ damage ana improving ‘kidvey outcomes, Advancements in understanding the unde lying pathophysiology have led to the development of targeted yuendenpunuoo'dno-awepede)r sch Woy peneouNoG 02 soquieceq 20 Uo js0n6 Ka LezeBeL/LEZPAIBNPLIEEO! OL/OPIAO10 | Nephro Dial Transplant, 2022, Vol. 0, No.9 ‘therapies, such as B-cell depletion, complement inhibition, ell inhibition and antIL-s inhibition, offering new opportunities for ‘allored treatments and improved disease rvanagement. Tae goal of eliminating relapses is 2.20 crucial sn providing lasting disease contol and preventing recurtent disease fates."he ultimate goal Js to provide patients with AAV the best chance for sustained re. ‘mission, kidney outcome, improved quality of life and reduced tak of relapses, while minimizing eatment-related side effects, ACKNOWLEDGEMENTS AG has been awarded a research fellowship athe University of ‘Cambridge by Stavros Niatches Foundation in collaboration with Hellenic Society of Nephrology and European Renal Association 1D) ds supported by the National Institute for Health and Care Re- search Cambridge Biomedical Recearch Centre Figure 8 was gen= erated with BloRendercom under publication license FUNDING No specific funding was received for the preparation of this smanusctpl AUTHORS’ CONTRIBUTIONS AG and Dj were mutually involved in the planning, outline ‘and writing A.C. wiote the original mamuseript and designed the graphics. Dj edited all the revisions ofthe manuscript DATA AVAILABILITY STATEMENT No new data were generated or analysed in support of this research, CONFLICT OF INTEREST STATEMENT Dj bas received consulting fees from Astrazeneca, Aurinia, BMS, hoehringerIngelheim, Chemocentryx, GSK, NICE, Novartis, Ot suka, Roche/Genentech, Takeda, UCB and Vitor, lecture fees from (GSK sid CSL Vifor, and reaesreh grants from GSK, Rache and CSL. Vifor. A.C. declares no conflicts of interest ylated to this work, REFERENCES 1, Walton EW. Giant-cell granloms of the respiratory tact (We= gene's granulomatosis) Br Med) 1956;2.265-70, hups (di org/ 10:1136/0e 25091.265 2. Faue AS, Katz P. Haynes BP eal. Cyclophorphamide apy of severe systemic necrotizing vasculitis. 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