Controversies in the treatment of ANCA-associated vasculitis · 2019-11-18 · The effect of...

Controversiesin the treatment of

ANCA-associated vasculitis

Vladimir TesarDepartment of Nephrology,

Charles University, Prague

Disclosure of Interests

Amgen, Baxter, Calliditas, Fresenius Medical Care, Novartis, Retrophin

(consultancy, advisory board)

KDIGO Controversies Conference on Glomerular DiseasesNovember 16-19, 2017 | Singapore

Outline of the lecture

Treatment with cyclophosphamide andcorticosteroids – effective and toxic

Replacement of cyclophosphamide withrituximab – success or failure?

Corticosteroid sparing and replacementOther biologics on the horizon?

Plasma exchange – still valuable after PEXIVAS?

Should the patients with anti-PR3 andanti-MPO disease be treated differently

Wegener´s granulomatosis – outcome of untreated pts

1958 – Walton – outcome of untreated ptsWalton,E.W.: Giant-cell granuloma of the respiratory tract (Wegeners

granulomatosis). British Medical Journal, 2: 265 – 269, 1958.

median survival: 5 months, majority of pts died ofrespiratory or renal failure

1983 – Fauci, NIH, Bethesda, survival of untreated ptsFauci,A.S., et al.: Wegeners granulomatosis: prospective clinical and therapeutic

experience with 85 patients for 21 years. Annals of Internal Medicine, 98: 76 –85, 1983.

median survival – 5 months, 1-yr mortalita 82%, 2-yr mortalita 90%

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91% marked improvement, 75% complete remission,13% mortality, 50% remissions with at least one relapse,

15-yr risk of bladder cancer 16%

mean FU 8 yrs

Cyclophosphamide – dramatic change of the outcome of pts

84% „standard treatment“ with corticosteroids and CPH 2 mg/kg at least 1 yr after complete remission

Cumulative CPH dose 50 g

Most pts had limited (localized, early systemic) disease

High risk of late occurring (6.9 – 18.5 yrs after CPH ) malignancies in pts with cumulative dose of CPH > 36 g


EUVAS studies to minimize CPH exposure

Early switch from CPH to AZAin generalized vasculitisdoes not increase the risk of relapses (within relatively short follow-up -CYCAZAREM)

CPH pulses (lower cumulative dose of CPH) are as effective as oral CPHas induction treatment in generalized vasculitis (CYCLOPS)


In CYCAZAREM after median FU of 8.5 yrsthere was a trend to relapse rate in pts switched early to AZA

In CYCLOPS there was risk of relapse in pulse CPH limb

Undertreatment shown to be one of the risk factors for relapses

First use of RTX in AAV - rapid response of BVAS, ANCA and CRPand stabilisation of renal function

75% completeremission23% partialremission2% no response

65 consecutive ptswith refractory AAV, 4 British centres

Lungs50% Kidney

5%

MMF

CYC

65 consecutive ptswith refractory AAV, 4 British centres

RAVE study194 pts with generalized AAV(2/3 with renal involvement - mean GFR 61 ml/min)randomized to either:

1) conventional treatment (CPH and CS, followed by AZA)

2) rituximab (plus CS, initially) for remission induction

64% of RTX pts vs. 53% of CPH pts reachedthe primary endpoint (non-inferiority)

RTX more effective than CPH in inducingremission in relapsing disease: 67% vs. 42% reached the primary endpoint

Rate of adverse events not differentin both limbs

RAVE study

Renal involvement in 2/3 of pts, but mean eGFR 60 m/min

Subanalysis of 102 pts from RAVE study with renal involvement,no difference in remaining in remission and improvement of eGFR

mean eGRF 41 vs. 50 ml/min

RAVE study

RITUXVAS study

RTX vs. CPH in 44 pts with new AAV and renal involvement

RITUXVAS study

CPH 6 – 10 pulsesfollowed by AZA

RTX 4x 375 mg/m2

CPH 2 pulses

Cumulative incidenceof remission

Sustained remission:RTX 76%CPH 82%Increase of GFR at 12 months:RTX 19 ml/minCPH 15 ml/min

RITUXVAS study

In RITUXVAS survival (and relapse-free and ESRD-free survival) not different between RTX and CPH limb

Analysis of 14 pts with severe renal AAV - good efficacy of RTX: all pts developed remission, eGFR improved,

treatment well tolerated

Retrospective analysis of 37 pts with AAV andeGFR < 20 ml/min demonstrated similar

efficacy of RTX with or without CPH

Efficacy of RTX compared in 59 pts with refractory AAVwith either granulomatous vs vasculitic lesions,

RTX better in vasculitic vs. (some) granulomatous manifestations

Response rate 63%, relapse rate 40%

Outcome much better in pts treated with RTX preemptively

115 pts with AAV in remission randomized to RTX or AZA maintenance

MAINRITSAN study

MAINRITSAN study - renal involvement in 70% of pts

Significantly higher rate of (major) relapses in AZA limb

5% vs. 29% major relapses

MAINRITSAN study

Rituximab better in both remaining free of major relapse (HR = 2.51, p = 0.003),or major and minor relapse (HR = 2.11, p=0.012)

60 mo FU

Rituximab better in terms of mortality (p = 0.045),no difference in remaining severe adverse event free (HR = 1.62, p=0.951)

60 mo FU

Rituximab Vasculitis Maintenance Study (RITAZAREM)

NCT01697267

Main investigator: D Jayne

190 pts with relapsing AAV treated with RTXand CS and after 4 mo randomizedfor maintenance to either RTX (a single dose every 4 mo for 2 yrs) or AZA (FU 4 yrs)

Primary outcome:time to relapse (either minor or major relapse) from randomisation

69 pts treated with 2-yr RTX maintenance compared with 28 ptswith RTX induction onlyRelapses in pts with early B cell return and reappearance of ANCARelapse rate ↓ after RTX maintenance vs. after RTX induction only

Adverse events in 172 pts treated with RTX maintenance for a median 2.1 year(up to 7 years)

AEs mainly infections, hypogammaglobulinemia and LON

One-centre analysis of 323 pts with AAV33 pts developed 45 malignancies

CPH associated with increased risk of cancer, in RTX-treated pts similar risk of cancer as in general population

What is known and what is not known

RTX is not inferior to CPH in newly diagnosedgeneralized AAV and superior to CPH in pts withmajor relapse of AAV

Can it be used also in pts with severe renal AAV and/oralveolar haemorrhage?

Should it be used as a first-line treatment in all pts withgeneralized AAV?


RTX is the best maintenance treatment in (relapsing) AAV

Can it used in all pts with AAV?

Or only pts with a history of major relapse on AZA, or only in pts treated with RTX induction, or preferably in pts with anti-PR3 disease?

How long should the pts be treated? Should they be treated preemptively, or on demand?

Analysis of data from 535 pts from EUVAS studies, FU 7 years, median time of using CS – 40.4 moFrequency of the most common VDI items and damage related to treatment at LTFU

Adjusted associations between baseline factors, number of relapses and CS use and accrual of damage

Cumulative incidence of severe adverse events

RTX 42%CYC 36%

RITUXVAS study

The effect of reduced dose of oral glucocorticoids during inductionof remission in patients with severe ANCA-associated vasculitis

M Walsh, PA Merkel, C A Peh, WM Szpirt, X Puéchal, S Fujimoto, C Hawley, N Khalidi, O Floßmann , R Wald, LP Girard, A Levin, G Gregorini, L Harper, WF Clark, C Pagnoux, U Specks, L Smyth, V Tesar, T Ito-Ihara, J Rashme de Zoysa, W Szczeklik , LF Flores-Suárez, L Guillevin, A Casian,

B Brezina, A Mazzetti, CA. McAlear, E Broadhurst, N Ives, S Mehta , and D Jayne for the PEXIVAS Investigators*

Pts randomized to standard or reduced dose of CS,Cumulative dose reduced by more than 40% within 6 mo

Week Standard Reduced-dose

<50 kg 50-75 kg >75 kg <50 kg 50-75 kg >75 kg

pulse pulse pulse pulse pulse pulse

1 50 60 75 50 60 75

2 50 60 75 25 30 40

3-4 40 50 60 20 25 30

5-6 30 40 50 15 20 25

7-8 25 30 40 12.5 15 20

9-10 20 25 30 10 12.5 15

11-12 15 20 25 7.5 10 12.5

13-14 12.5 15 20 6 7.5 10

15-16 10 10 15 5 5 7.5

17-18 10 10 15 5 5 7.5

19-20 7.5 7.5 10 5 5 5

21-22 7.5 7.5 7.5 5 5 5

23-52 5 5 5 5 5 5

>52 Investigators’ Local Practice Investigators’ Local Practice

. i

Reduced dose of CS in the PEXIVAS trial

Pts treated with reduced dose of CS had similar outcome, but significantly lower risk of serious infections

(27% vs. 33%, RR = 0.69, p = 0.02)

Activation of alternative complement pathway in AAV

Anti-C5 moAb prevented necroses and crescent formation

67 pts with AAV randomized to:

1) Standard of care (SOC) control: Placebo + CYC or RTX + full starting dose of prednisone (60 mg),

2) CCX168 30 mg b.i.d. + CYC or RTX + reduced starting dose of prednisone (20 mg), or

3) CCX168 30 mg b.i.d. + CYC or RTX + no prednisone.

Primary endpoint met: BVAS response (decrease of BVAS for at least 50%) at week 12 numerically superior and statistically non-inferior to SOC control (p = 0.005 and p = 0.02) for each of the CCX168 groups vs. control

Decrease pf BVAS fasterin avacopan treated pts

67 pts with AAV randomized to RTX or CPH and either high dose CS, avacopan + reduced CS and avacopan without CS

** P < 0.01 for superiority of CCX168 vs. Control

Urinary Albumin: Creatinine Ratio Percent Change from Baseline

(Geometric Means)

Decrease of albuminuria more expressedin pts treated with CCX168

53

Rapid improvement of the quality of lifein pts treated with CCX168

* P < 0.05 for CCX168 change or percent change from baseline vs. Control 54

Improvement of vitality (less fatigue) in pts on CCX168

** P < 0.01, * P < 0.05 for CCX168 vs. steroid control group

Adverse events possibly related to CS treatment

Adverse Effect High Dose Steroids

SOC (N=23)

CCX168 + Low Dose Steroids

(N=22)

CCX168 + No Steroids(N=22)

CCX168 Combined

(N=44)Patients with Any Event 15 (65.2%) 4 (18.2%) 11 (50.0%) 15 (34.1%) *

Psychiatric disorders 6 (26.1%) 2 1 3 (6.8%)Serious infections 1 (4.3%) 1 1 2 (4.5%)New onset/worsening diabetes/hyperglycemia

4 (17.4%) 0 1 1 (2.3%)

New onset/worsening hypertension

5 (21.7%) 2 8 10 (22.7%)

Weight gain >10 kg 2 (8.7%) 1 0 1 (2.3%)Bone fractures 1 (4.3%) 0 0 0 (0%)Cataracts 1 (4.3%) 0 0 0 (0%)* P = 0.02 for CCX168 vs. SOC Control

Conclusions:

CCX168 successful as steroid sparing drugduring the induction phase of AAV

ADVOCATE (NCT02994927)– ongoing phase 3 trial is to assess the safety and efficacy of avacopancompared to high-dose CS in inducing and sustaining remission in ptswith active AAV

The study should recruit around 300 pts with new or relapsing AAV(both GPA and MPA and anti-PR3 and anti-MPO positive)with at least one major, or at least three non-major, or at least 2 renal(proteinuria and hematuria) BVAS itemsand eGFR ≥ 15 ml/min/1.73 m2 indicated to the treatmet with RTX or CP

Primary outcomes are:remission based on BVAS at week 26 and sustained remission at week52

Secondary outcomes include adverse events, glucocorticoid toxicity, rapidity of response of health-related quality of life


CS should be reduced as much as possible using thetapering used in PEXIVAS trial

Can CS be completely replaced by avacopan?

What is the role (if any) of methylprednisolone pulses?

Is it meaningful to prolong the treatment with low doseCS beyond 18 months?

Ofatumumab effective in 8 pts with AAV

Belimumab compared with placebo in pts with AAV in remission treated with AZA

(BREVAS)

Cumulative probability of relapsesnot different

Treatment of pts with non-severe (mostly non-renal) AAVwith abatacept resulted in improvement in 90% of pts,

remission in 80%phase 3 trial ongoing

IL-5 and IgE involved in the pathogenesis of EGPA

134 pts with EGPA on treatment for at least 4 weeks and on stable dose of CS randomizedto mepolizumab or placebo for 52 weeks

Mepolizumab more effective in terms of remissionand prevention of relapse

Mepolizumab was very well tolerated


Mepolizumab should be used in pts with EGPA, especially dose with steroid-dependent asthma andrelapsing on CS

Should mepolizumab be used also in (uncommon) ptswith EGPA and severe renal involvement?

In MEPEX trial 137 pts with AAV presenting with Scr > 500 µmol/lrandomized either to PE or MP as an add-on treatmentAt 3 months 69% treated with PE compared to 49% treated with MPwere alive and with independent renal function

MEPEX

Long-term FU of MEPEX: after a median FU of 3.95 yrs there was no difference

in proportion of pts free of ESRD or death

Reduction of the risk of ESRD(0.64, confidence interval 0.40 – 1.05)did not reach statistical significance

Much lower mortality in pts treated with ivCPHcompared to MEPEX pts

PEXIVAS recruited 700 pts with AAV a Scr > 200 µmol/lto be randomized to PE or no PE as an add-on treatmentwith a 2 yr FU, 12% at least absolute risk reductionof the primary endpoint – ESRD or death – is expected

PEXIVAS


PE should not be used in all pts with generalized AAV

Should we completely stop the use of PE in pts withsevere renal vasculitis and /or alveolarhaemorrhage?

Revised CHCC nomenclature, 2012

Prednisolone dose BVAS

Anti-MPO ANCA associated with HLA-DQ,not HLA-DP, as it is in anti-PR3 ANCA

Anti-PR3 and anti-MPO disease have different presentationand outcome

Anti-PR3 and anti-MPO associatedwith different phenotypes (502 pts with AAV)

The strongest determinant of relapse risk was anti-PR3 positivity

RAVE study – 18-mo FU

anti-PR3

anti-MPO

MAIRINTSAN - 60 mo FU

Pts with anti-PR3 relapsing disease achieved remission more oftenfollowing RTX compared to CPH after 6, 12 and 18 mo

Pts with anti-PR3 disease achieved complete remissionafter 6 mo following RTX more often compared to CPH

Different treatment of anti-PR3 and anti-MPO disease?

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110 pts with AAV 18 – 24 mo after diagnosis in stable remission randomizedto continuation (up to 48 mo) or withdrawal (at 24 mo) of CS and AZA

Primary endpoint (relapse rate within 48 mo) reachedin 62.7% of pts in continuation vs. in 22% withdrawal limb

relapse rate62.7% vs. 22%,OR 5.96

major relapse rate35.3% vs. 13.5%

ESRD 7.8% vs. 0%, p = 0.012

REMAIN

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Relapse rate higher in patients ANCA positive at randomisation

REMAIN

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No significant difference in adverse event rate

REMAIN


45 pts with c-ANCA positive AAV (75% with renal involvement) in remission after oral CPH randomized to 1-yr vs 4 yr maintenance with AZA

No significant difference in relapse-free survival in both c-ANCA pos and neg pts


Study may have been underpowered to identify the difference,a trend to higher number of relapses in standard vs extended AZA

(46% vs. 25%)

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„…at least some of the pts who reached remissionof AAV require long-term immunosuppressivetherapy to prevent recurrence of the disease


Anti-PR3+ pts have higher relapse rate compared to anti-MPO pts and may respond better to RTX

Should all (newly diagnosed and relapsing) pts withgeneralised anti-PR3 AAV be treated with RTX?

Should the maintenance treatment be shorter (< 18 mo) in anti-MPO pts (or even not necessary in anti-MPOpts treated with RTX)?

Conclusions

Replacement of CPH with RTX and minimizingor replacing CS (with avacopan?) should beassociated with lower short-term and long-term toxicity and at least comparable efficacy

Role of plasma exchange in pts with severe renalAAV and AAV with alveolar haemorrhageremains uncertain

Pts with anti-PR3 and anti-MPO pts should beprobably treated differently

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