(ANCA) Vasculitis Koyal Jain,1 Pankaj Jawa,1 Vimal K. Derebail,1

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Kidney360 Publish Ahead of Print, published on February 5, 2021 as doi:10.34067/KID.0007142020

Treatment updates in Antineutrophil Cytoplasmic Autoantibodies (ANCA) vasculitis

Koyal Jain,1 Pankaj Jawa,1 Vimal K. Derebail,1 and Ronald J. Falk1,2

1UNC Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

2Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Corresponding author:

Koyal Jain MD MPH 7024 Burnett Womack Bldg, CB 7155 Chapel Hill, NC 27599 Phone: 919-966-2561 Fax: 919-966-4251 Email: [email protected]

Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis is a small vessel vasculitis (SVV) resulting in inflammation of small- and medium-sized blood vessels. Since the initial description of SVV, there have been tremendous advances in our understanding of the pathogenesis. Over the last decade, we have made significant progress in understanding the pathogenesis and improving the treatment and prognosis of patients with ANCA vasculitis. Patient and renal survival has improved, and treatment is moving towards individualizing care, minimizing severe adverse events, and preventing relapse. This review focuses on treatment updates in ANCA vasculitis, duration of therapy, and management of relapses. We also describe the existing treatment protocols utilized at our institution.

Introduction

ANCA vasculitides are a group of rare disorders occurring predominantly in the sixth and seventh decades of life. ANCA vasculitides can present phenotypically as Granulomatosis with Polyangiitis

(GPA), Microscopic Polyangiitis (MPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), and renal-limited vasculitis (RLV) with pauci-immune necrotizing and crescentic glomerulonephritis on renal biopsy. Serologically, patients may exhibit autoantibodies to myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA), with a small proportion remaining ANCA-negative.

The estimated annual incidence of ANCA vasculitis is 10-20 per million.1 In United States, the

incidence and prevalence rate of GPA is 13 and 218 per million,2 compared to 8.6 and 95 per million in

Australia,3 and 9.7 and 62.9 per million in the UK,4 respectively. Overall, the prevalence in people of

European ancestry is twice as high as those of non-European ancestry (104.7 versus 52.5 per million).5

Geographically, GPA and PR3-ANCA are more prevalent in Northern Europe compared to Southern

Europe and Asia where MPA is more common.6 ANCA vasculitis is more common in Caucasians.

Patients of African descent are more likely to have MPO-ANCA and are younger at presentation. One

study found no difference in treatment response, development of end-stage kidney disease (ESKD), renal relapse and death rates between African Americans and Caucasians.7

Numerous factors have been implicated in the pathogenesis of ANCA vasculitis. Recent studies suggest

ANCAs themselves are pathogenic, especially MPO-ANCA autoantibodies.8-10 Genetic susceptibility,

environmental triggers such as silica, drug exposure and infections have been associated with the

development of ANCA vasculitis.11-13 Drugs commonly implicated are levamisole-adulterated cocaine,

hydralazine and propylthiouracil.14 There is potential association of minocycline, allopurinol, methimazole, penicillamine and sulfasalazine with drug-induced vasculitis.14

Management of ANCA vasculitis consists of remission induction, maintenance and relapse therapy.

Here we focus on these components and discuss recent treatment updates.

Induction of Remission

Corticosteroids

Optimal glucocorticoid dosing and duration in ANCA vasculitis remains controversial. Traditionally for

life- or organ-threatening ANCA vasculitis, intravenous (IV) methylprednisolone 1-3 g has been used,

followed by oral prednisone 1mg/kg/day. The Rituximab versus Cyclophosphamide for ANCA-

Associated Vasculitis (RAVE) trial successfully tapered prednisone by 5 months15 with other trials

maintaining 5mg/day dose beyond six months.15,16

Recent studies have focused on reducing cumulative glucocorticoid dose and other steroid-sparing

therapies. The Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis

(PEXIVAS) trial compared standard-dose or reduced-dose oral glucocorticoid regimens in severe

ANCA vasculitis.17 At 6 months the reduced-dose group had 60% less glucocorticoid exposure.

Although both groups remained on 5 mg through week 52, reduced-dosing was non-inferior to standard-

dosing with regards to all-cause mortality and ESKD.17 Among 49 patients who received combination

cyclophosphamide-rituximab infusion, rapid glucocorticoid withdrawal (between 1-2 weeks) reduced

severe adverse events (SAEs) with effective remission induction compared to matched previous

European Vasculitis Society (EUVAS) trials.18 Additionally, retrospective analysis of 114 patients showed no benefit of adding IV methylprednisolone, and higher incidence of diabetes and infection was noted.19 Currently, a low-dose prednisolone (0.5 mg/kg/day) versus high-dose prednisolone

(1mg/kg/day) plus rituximab trial is underway to assess relapse and safety profile.20

Corticosteroid Sparing Strategies

Corticosteroid reduction may be further achieved with complement-based therapy, although these have

not yet been approved. Avacopan (CCX168), oral C5a receptor (C5aR) antagonist, in addition to

cyclophosphamide or rituximab successfully replaced corticosteroids in a phase 2 RCT (CLEAR).21

Preliminary results from the ADVOCATE study show similar remission achievement in 166 avacopan- treated patients compared to 164 glucocorticoid-treated at 26 weeks (72.3% versus 70.1%).22,23

Avacopan was superior to prednisone at 52 weeks in sustaining remission.23 IFX-1 (anti-C5a antibody)

is currently being studied in phase 2 trials, although the steroid dose is not reduced (NCT03712345,

NCT03895801).

We recommend a reduced-dose corticosteroid regimen with tapering and discontinuation for most

patients by 16 weeks.

Cyclophosphamide

Cyclophosphamide is an alkylating agent that inhibits nuclear DNA replication, potently affecting

rapidly dividing cell populations.24 Cyclophosphamide has been used for induction therapy since the

first published case series in 1971 in GPA.25

Risks of cyclophosphamide include infertility, urotoxicity including cystitis and transitional-cell

carcinoma of the bladder, hematologic toxicity, and infections.26,27 The pulse versus continuous

cyclophosphamide for induction of remission (CYCLOPS) trial compared IV cyclophosphamide to daily

oral cyclophosphamide with no difference in time to remission (HR 1.098, 95% CI:0.78-1.55). Pulse

cyclophosphamide therapy led to lower cumulative dose (8.2 g versus 15.9 g) and lower rate of

leukopenia (HR 0.41, 95% CI:0.23-0.71) as compared to oral cyclophosphamide.28 In long-term follow-

up of patients from CYCLOPS, Harper et. al. found a higher relapse risk with pulse cyclophosphamide,

but no difference in survival and renal function.29 Both groups received azathioprine for maintenance

which is associated with higher relapse rates than rituximab.30 The French Vasculitis Study Group

demonstrated fewer SAEs in patients ≥65 years with fixed low-dose intravenous cyclophosphamide

compared with conventional cyclophosphamide dosing (500mg/m2 every 2-3 weeks). The overall

mortality was approximately 20% with no significant difference between the two groups.31 Older age has been associated with increased mortality.32

We recommend utilizing monthly IV cyclophosphamide (0.35gm-0.75gm/m2) with lower dosing for

patients who are older (≥65years) or have markedly reduced kidney function

(eGFR<30ml/min/1.73m2).

Rituximab

Rituximab is an anti-CD20 chimeric monoclonal antibody. A decade ago, two groundbreaking RCTs

revolutionized the treatment of ANCA vasculitis.15,16 RAVE trial found rituximab non-inferior to oral

cyclophosphamide for remission induction in 197 patients with newly-diagnosed or flaring GPA or

MPA. Rituximab was more efficacious in relapsing disease (OR 1.40, 95% CI:1.03-1.91).15 Post-hoc

analysis showed a higher complete remission rate for PR3-ANCA patients with rituximab compared to

cyclophosphamide at 6-, 12- and 18-months.33 Although patients with serum creatinine >4 mg/dL were excluded from this study, remission rates between two groups based on the estimated glomerular filtration rates (eGFR) were not different.34

Rituximab versus Cyclophosphamide in the ANCA-Associated Renal Vasculitis (RITUXVAS) trial

compared a combination of rituximab with two IV cyclophosphamide doses against IV

cyclophosphamide for 3-6 months, followed by azathioprine. As opposed to RAVE, the RITUXVAS

trial did include patients with severe renal disease (median eGFR 18 mL/min/1.73 m2). The two groups had similar high remission induction rates at 12 months (76% rituximab versus 82% cyclophosphamide)

and SAEs.16 At 2-years, the composite outcome of death, ESKD, and relapse was similar between the

two groups.35 A retrospective study of 225 patients with severe renal involvement (eGFR<30

ml/min/1.73m2) noted no significant difference between cyclophosphamide and rituximab for

induction.36

We advise use of rituximab over cyclophosphamide in patients ≥65years who have high hematologic

toxicity risk and younger patients who desire to preserve fertility. We also recommend rituximab in

patients with significant past exposure to cyclophosphamide, relapsing disease, and PR3-ANCA

vasculitis.

Combination of Cyclophosphamide and Rituximab

RITUXVAS paved the way for other studies showing success with combination cyclophosphamide and

rituximab,18,37,38 allowing rapid tapering of corticosteroids.

Combined induction with corticosteroids, rituximab, and low-dose intravenous cyclophosphamide was

studied in a cohort of 66 patients with biopsy-proven renal ANCA vasculitis.37 Compared to propensity- matched patients in EUVAS trials, 94% of patients achieved remission in 6 months. Additionally, the

combination treatment had lower death rates (HR 0.29, 95% CI:0.125-0.675), progression to ESKD (HR

0.20, 95% CI:0.06-0.65), and relapse rates (HR 0.49, 95% CI:0.25-0.97).37

To reduce cyclophosphamide exposure, we recommend using intravenous cyclophosphamide and

rituximab for induction in ANCA vasculitis, especially with severe renal involvement

(eGFR<30ml/min/1.73m2 or diffuse crescentic glomerulonephritis) or severe pulmonary hemorrhage

(requiring supplemental oxygen or mechanical ventilation). We suggest using cyclophosphamide and

combination cyclophosphamide-rituximab based regimens to help achieve earlier withdrawal of

steroids.

Plasma Exchange (PLEX)

Role of PLEX remains uncertain in the treatment of ANCA vasculitis. The Plasma Exchange or High-

Dosage Methylprednisolone (MEPEX) trial compared the addition of PLEX in 137 patients with newly-

diagnosed ANCA-vasculitis on renal biopsy and serum creatinine >5.8 mg/dL.39 Both groups received

oral corticosteroids and cyclophosphamide; one group received intravenous methylprednisolone and the

other PLEX. Renal biopsy characteristics were similar in both groups. No difference in adverse events

and survival at one year was observed. However, PLEX was associated with lower progression to ESKD

over 12 months (HR 0.47, 95% CI:0.24-0.91).39 A meta-analysis also showed potential reduction in the

composite endpoint of ESKD and death in patients with ANCA vasculitis treated with PLEX.40

Long-term follow-up of MEPEX patients showed no difference in all-cause mortality. The risk of

progression to ESKD was not statistically significant, with a potential trend towards benefit (HR 0.64;

95% CI:0.40-1.05).41 In PEXIVAS, PLEX did not reduce the primary composite outcome of all-cause mortality and ESKD (HR 0.86, 95% CI:0.65-1.13) in patients with severe ANCA vasculitis, defined as eGFR<50 mL/min/1.73m2 or pulmonary hemorrhage.17 One limitation of PEXIVAS was the wide range

of renal injury without a kidney biopsy to assess interstitial fibrosis and tubular atrophy. Furthermore, in

subgroup analyses of patients with pulmonary hemorrhage, PLEX showed a trend for benefitting the

primary composite outcome, although not statistically significant.17 PLEX may have a potential role in

severe acute renal damage without chronic changes. Although another retrospective study of 251

patients showed no benefit with PLEX,36 the updated American Society of Apheresis guidelines still

supports use of PLEX in a subset of patients with severe acute kidney failure and pulmonary

hemorrhage.42

We recommend limiting PLEX use for ANCA vasculitis to patients with severe acute kidney injury

(eGFR<30ml/min/1.73m2 without significant interstitial fibrosis) and lung hemorrhage (requiring

supplemental oxygen or mechanical ventilation). We also recommend kidney biopsy when indicated

and safe to assess underlying chronicity and rule out concomitant disease (e.g. anti-glomerular

basement membrane disease).

Mycophenolate

Various reports exist regarding the success of mycophenolate induction in patients with ANCA

vasculitis.43-45 In a retrospective study, 29 of 67 patients treated with mycophenolate mofetil (MMF)

received MMF for remission induction. MMF was comparable to cyclophosphamide for induction.45

Jones et. al. randomized 140 newly diagnosed active ANCA vasculitis patients (132 adult and 8

pediatric) to receive either MMF or pulse cyclophosphamide, followed by azathioprine for remission

maintenance. Patients with life-threatening vasculitis, eGFR<15 mL/min/m2 or rapidly declining kidney

function were excluded. While MMF was non-inferior to cyclophosphamide in inducing remission (67%

vs. 61%), more relapses were seen in the MMF group (33% vs. 19%) with similar serious infectious

risk.43 In another RCT with 84 patients, fewer participants attained sustained remission with MMF as

compared to cyclophosphamide (66% vs. 81%).44 Thus, MMF may have a role in nonlife-threatening

vasculitis.

Remission Maintenance

Over the past two decades, considerable progress has been made in maintaining remission in patients

with ANCA-vasculitis with a variety of medications including rituximab, azathioprine, mycophenolate,

methotrexate, and glucocorticoids.

The cyclophosphamide or azathioprine as a remission therapy for vasculitis (CYCAZEREM) trial

demonstrated that azathioprine could safely replace oral cyclophosphamide for maintenance without

increasing the relapse rate.46 The International Mycophenolate Mofetil Protocol to Reduce Outbreaks of

Vasculitides (IMPROVE) trial compared MMF to azathioprine in maintaining remission after cyclophosphamide induction. While both treatment arms had similar adverse events, MMF had a higher relapse rate (HR 1.69, 95% CI:1.06-2.70).47 The Wegener's Granulomatosis–Entretien (WEGENT) trial

was designed to compare the safety of azathioprine to methotrexate. Among 126 patients in remission,

there was no difference in the safety or relapse between the two groups.48 Other trials have found

methotrexate to be a safe alternate to cyclophosphamide in maintaining remission.49 Methotrexate can be used in patients without significant kidney dysfunction who are unable to receive azathioprine or rituximab.

Use of rituximab for remission was evaluated by the Maintenance of Remission using Rituximab in

Systemic ANCA-associated Vasculitis trial (MAINRITSAN) which compared low-dose rituximab

(500mg on days 0 and 14, then months 6, 12 and 18) with azathioprine (until 22 months) after induction with cyclophosphamide. Rituximab was superior to azathioprine in maintaining remission at 28 months, but azathioprine was tapered earlier than typical.30 Long-term follow-up showed higher relapse-free

survival for the rituximab group at 60 months.50

Optimal maintenance therapy after rituximab has been evaluated in the rituximab versus azathioprine in

remission maintenance (RITAZAREM) trial which enrolled patients who achieved remission with

rituximab after experiencing a relapse. Patients received 1000mg rituximab every 4 months for 5 doses

or 2mg/kg/day of azathioprine for 24 months.51 While the final analyses of the maintenance phase has

yet to be published, 170 patients were randomized and 18% of patients in the rituximab arm versus 38%

in the azathioprine arm experienced a relapse. Fewer SAEs occurred in the rituximab group.52

Dosing, Relapses and Duration of Treatment

MAINRITSAN2 examined dosing of rituximab for remission. Participants in remission either received

fixed 500mg rituximab infusion on days 0 and 14, then 6, 12 and 18 months or tailored therapy. The

tailored group received 500mg rituximab at randomization and re-dosed based on CD19+ B-

lymphocytes or ANCA titer.53 Relapses were similar in both groups at 28 months (17.3% versus 9.9%),

but the tailored group received fewer infusions (median 3 versus 5).53

Optimal duration of maintenance therapy is unknown. Patients with PR3-ANCA (compared to MPO-

ANCA), upper respiratory or lung involvement are more likely to relapse.54,55 While they may require

longer treatment, it is controversial when and if immunosuppression can be discontinued.

The prolonged remission-maintenance therapy in systemic vasculitis (REMAIN) trial compared

azathioprine/prednisolone maintenance for 24- versus 48-months after cyclophosphamide induction.56

While the 48-month therapy had fewer relapses (22% versus 63%), although higher than other rituximab

trials,51 and lower ESKD rate (0 versus 4 cases), more frequent SAEs were noted in this group (9 versus

3 events).56

In the Glomerular Disease Collaborative Network (GDCN) registry, we analyzed 427 patients, of whom

277 (65%) stopped therapy at a median of 20 months post-induction. These patients remained off

immunosuppression for a median of 36 months (IQR 13-88).57 Sixty-three patients were off therapy for

five or more years, with 13 (20.6%) patients relapsing after five years. Patients were more likely to come off treatment if they were women, had MPO-ANCA and renal-limited disease.57

Recently, MAINRITSAN3 studied the effect of extended maintenance rituximab therapy on relapse and death.58 MAINRITSAN3 included patients from MAINRITSAN2 who were in remission at month 28.

Ninety-seven participants either received placebo or rituximab (500mg biannually) for an additional 18

months.58 At 28 months, 96% receiving rituximab versus 74% receiving placebo were relapse-free (HR

7.5, 95% CI:1.67-33.7). The number of SAEs were similar between the two groups, although the mean

gamma globulin was lower in the rituximab group.58 While extended rituximab therapy may be safe and benefit some patients , especially those with frequent relapses, MAINRITSAN3 did select patients who previously tolerated rituximab successfully. Furthermore, none of the patients with ANCA and undetectable CD19+ B-cells relapsed.58

For remission maintenance with Rituximab we suggest a 500mg dose tailored to CD19+B-lymphocyte

count. Additionally, as long-term remission (≥2years off therapy) is possible,57,59 risk of

hypogammaglobulinemia with long-term rituximab exists,60-62 and re-induction for relapse is quite

successful,57 we highly recommend discontinuing maintenance therapy in those with long-term

remission.

Alternative Therapies

Mepolizimab, an interleukin-5 monoclonal antibody, is approved by the Food and Drug Administration for treating EGPA following studies showing efficacy and acceptable safety.63,64 Intravenous immunoglobulin (IVIG) has been utilized successfully as adjunctive therapy in both MPO- and PR3-

ANCA vasculitis for refractory or relapsing disease.65-68 IVIG is usually considered in patients with hypogammaglobulinemia, especially with recurrent infections, either as immunoglobulin replacement therapy or in addition to ongoing immunosuppression.68,69 In patients unable to receive blood products or cyclophosphamide, eculizumab along with rituximab and steroids has been used successfully in case reports.70

Belimumab, an anti-B-lymphocyte stimulator monoclonal antibody, did not reduce relapses when used as adjunctive therapy to azathioprine and glucocorticoids in remission maintenance.71 Similarly,

Alemtuzumab, an anti-CD52 monoclonal antibody, and anti-thymocyte globulin have been investigated, but concerns exist regarding toxicity.72,73

Management in the Dialysis Population

Management of ANCA vasculitis in patients with severe kidney dysfunction is challenging due to poor renal and patient prognosis.32 A study of 100 patients who underwent diagnostic kidney biopsy at study entry found fibrous crescents predicted dialysis requirement at presentation.74 Age, tubular atrophy, and intraepithelial infiltrates were all predictors of dialysis at 12 months.74

A time-limited trial of immunosuppression may be worthwhile in patients initially presenting with dialysis needs. We retrospectively examined 155 patients in the GDCN registry with a median eGFR of

7.1mL/min/1.73m2; 87% requiring hemodialysis. Cyclophosphamide therapy and treatment response within 4 months of kidney biopsy were associated with improved renal and patient survival.75 Fifty-one percent responded to treatment within 4 months, and 50% remained dialysis-free at 12 months. As

expected, treatment response was lower in patients with severe renal scarring.75 Another retrospective

study noted patients were more likely to come off dialysis within 3 months of immunosuppression.

However, 12 out of 156 patients became dialysis independent after 3 months.76

Renal Transplant and ANCA Vasculitis

Per United States Renal Data System data, kidney transplants decrease all-cause mortality by 70% in

patients with ESKD from GPA.77 In the European Renal Association-European Dialysis and Transplant

Association registry, the 10-year patient and transplant survival after first kidney transplant was 74.8%

and 63.7%, respectively, for patients with ANCA vasculitis.78Numerous studies have highlighted

benefits of kidney transplantation in ANCA vasculitides.79-83 One study noted a higher risk of graft

failure in MPA compared to GPA patients.84

Appropriate timing of kidney transplants in ANCA vasculitis patients is unclear. A 2009 study showed

higher risk of graft loss due to death if transplanted within 12 months of remission.85 Therefore, the

Kidney Disease Improving Global Outcomes recommends waiting at least one year after clinical

remission before transplantation.86

Presence of positive ANCA titers should not preclude transplantation. However, presence of PR3-

ANCA does carry a higher risk of relapse post-transplant,87 and these patients require closer follow-up.

Relapse rate post-transplantation can vary from 4.7% to 17.3% over 44-66 months post-transplant.79,85

Treatment of ANCA-vasculitis flares post-transplant is similar to pre-transplant, taking patient characteristics and severity of flare into consideration.

Conclusion

In the last decade, we have made significant advancements in the field of ANCA vasculitis. We have

been successful in improving patient prognosis with earlier remissions and lower relapse rates.

However, many questions remain unanswered including optimal timing of treatments, and more

importantly, when to withdraw therapy. Rituximab has gained popularity as a single agent and in

combination, and there are new trials underway that may again change the landscape in the next decade.

Our understanding of the pathogenesis continues to expand and reveals the complexity of the disease.

We need targeted therapies to tailor treatment based on patient preference, comorbidities, relapse risk,

and ANCA type.

Disclosures: VK Derebail has served on Advisory Boards for Bayer, Novartis and Retrophin and

received honoraria from UpToDate, Inc and RTI International. Ronald J. Falk and Vimal K. Derebail

receive funding from NIH/NIDDK (5P01DK058335-20) outside this work. Remaining authors have

nothing to disclosure.

Funding: None

Author Contributions:

K Jain: substantial contributions to conception and design, and acquisition of data; drafting the article or

revising it critically for important intellectual content, final approval of the version to be published.

P Jawa: substantial contributions to conception and design, and acquisition of data; drafting the article or

revising it critically for important intellectual content, final approval of the version to be published.

V. K. Derebail: revising the article critically for important intellectual content, final approval of the

version to be published.

R. J. Falk: substantial contributions to conception and design; revising the article critically for important

intellectual content; final approval of the version to be published.

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