This document summarizes a randomized controlled trial comparing rituximab to cyclophosphamide for inducing remission in patients with severe ANCA-associated vasculitis. The trial found rituximab to be non-inferior to cyclophosphamide at inducing remission at 6 months when both were combined with glucocorticoids. Rituximab achieved similar rates of remission and disease control as cyclophosphamide with comparable safety profiles. Based on these results, rituximab was subsequently approved by the FDA for treatment of granulomatosis with polyangiitis and microscopic polyangiitis.

1. MODERATOR – DR NEERU P AGGARWAL
PRESENTER – PREM MOHAN JHA
CYCLOPS / RAVE /
RITUXVAS / MEPEX

4. Among patients with newly-diagnosed ANCA-
associated vasculitis with renal involvement, is pulse
cyclophosphamide superior to daily oral
cyclophosphamide for the induction of remission?

5.  Among patients with newly-diagnosed ANCA-
associated vasculitis with renal involvement, there
was no difference in rates of, or time to remission
when comparing pulse cyclophosphamide to daily
oral cyclophosphamide.
 Those receiving pulse cyclophosphamide required
a lower cumulative dose and had a lower risk of
leukopenia.

6.  ANCA-associated vasculitis was almost uniformly fatal until
the introduction cyclophosphamide and glucocorticoid
therapy was first demonstrated by Fauci and colleagues in the
1970s.
 The optimal dosing of these medications was unclear.
 While several small studies suggested that pulse
cyclophosphamide was likely equivalent to daily oral
cyclophosphamide for the induction of remission in patients
with ANCA-associated vasculitis, no large trial had been
performed.

7.  Published in 2009, CYCLOPS randomized 149
patients with newly-diagnosed ANCA vasculitis to
pulse cyclophosphamide or daily oral
cyclophosphamide.
 Both groups received corticosteroids and
azathioprine.
 Despite its lower cumulative cyclophosphamide
dose, pulse cyclophosphamide resulted in similar
rates of remission as daily oral cyclophosphamide.

8.  Pulse cyclophosphamide was associated with a
significantly lower risk of leukopenia but a non-
significant trend towards higher risk of relapse.
 In 2012 the authors published follow-up results
(median 4.3 years), showing a higher relapse in the
pulse cyclophosphamide group than the daily oral
group (39.5% vs. 20.8%; P=0.029) with mean
follow-up of 4.3 years.

9.  KDIGO Glomerulonephritis (2012)
◦ Recommended treatments for ANCA vasculitis with
glomerulonephritis:
 Cyclophosphamide 0.75 g/m2 IV q3-4 weeks,
decrease dose to 0.5 g/m2 if age >60 or GFR <20
mL/min/1.73 m2, adjust following doses to achieve
2-week WBC nadir >3,000 cells/mm3
 Alternative dose of 15 mg/kg q2 weeks for 3 ulses
then 15 mg/kg every 3 weeks for 3 months
beyond remission, with dose reductions for age
and GFR as above.

10.  Plus pulse and oral steroids
◦ Cyclophosphamide 1.5-2 mg/kg/day PO, with
reduced dose if age >60 or GFR <20
mL/min/1.73 m2, adjust following doses to
achieve WBC nadir >3,000 cells/mm3
◦ Methylprednisolone 500 mg IV daily x3 days as a
pulse.

11. ◦ Prednisone 1 mg/kg/day PO for 4 weeks to a maximum
dose of 60 mg/day, tapering down over 3-4 months
◦ Rituximab 375 mg/m2 IV weekly x4 weeks
 Plus pulse and oral steroids
◦ Plasmapheresis, 60 mL/kg volume replacement:
 Vasculitis without anti-GBM Ab:
 No pulmonary hemorrhage: 7 treatments over 14 days
 Diffuse pulmonary hemorrhage: Daily treatment until
the bleeding stops then q48 hours for a total of 7-10
treatments
 Vasculitis with anti-GBM Ab: Daily for 14 days or until
anti-GBM Abs are no longer detectable.

12.  Multicenter, open-label, parallel-group,
randomized, controlled trial
 N=149 (160 screened)
◦ Pulse cyclophosphamide (n=76)
◦ Daily oral cyclophosphamide (n=73)
 Setting: 42 centers in Europe and Mexico
 Median follow-up: 18 months
 Analysis: Intention-to-treat
 Primary outcome: Time to remission.

13.  Age 18-80 years
 Newly diagnosed ANCA-associated vasculitis,
including any of the following:
 Granulomatosis with polyangiitis (previously
referred to as "Wegener's granulomatosis")
 Microscopic polyangiitis
 Renal-limited vasculitis

14.  Renal involvement of the disease, defined by ≥1 of
the following:
 Creatinine >150 umol/L (1.69 mg/dL) but <500
umol/L (5.6 mg/dL)
 Biopsy showing necrotizing glomerulonephritis
 RBC casts
 Urine showing >30 RBC/high-powered field and
proteinuria (>1 gram/day)
 Confirmatory histology or ANCA positive serology.

15.  >2 weeks of prior cyclophosphamide or other
cytotoxic drug therapy in the prior year or
corticosteroids for >4 weeks
 Other multisystem autoimmune disease
 Hepatitis Be Ag+, HCV Ab+, or known HIV
 Creatinine >500 umol/L (5.6 mg/dL)
 Life-threatening organ dysfunction
 Prior malignancy
 Pregnancy or lack of appropriate contraception in
women
 Anti-GBM Ab+

16.  From the pulse cyclophosphamide group.
◦ Demographics: Age 57 years, male 54%
◦ Diagnosis:
 Granulomatosis with polyangiitis: 33%
 Microscopic polyangiitis: 50%
 Renal limited vasculitis: 17%

17.  Diagnostics:
◦ +biopsy, +ANCA: 79%
◦ +biopsy, -ANCA: 0%
◦ -biopsy, +ANCA: 21%
 BVAS score 20
 Labs: Creatinine - 2.52 mg/dL, PR3+ 39%, MPO+
50%, PR3+ and MPO+ 5%, PR3- and MPO- 5%, CRP
524 nmol/L

18.  Randomized to a group:
 Pulse cyclophosphamide: 15 mg/kg IV pulses
every 2 weeks for 6 weeks, then 15 mg/kg IV
pulses very 3 weeks until remission and then
for 3 months following remission, adjusted for
WBC level, age, and renal function
 Weeks 7-25 could be be administered orally
as 5 mg/kg/day for 3 days per week

19. ◦ Daily oral cyclophosphamide: 2 mg/kg/day until
remission (generally about 3 months), then 1.5
mg/kg/day for 3 months following remission,
adjusted for WBC count, age, and renal function

20.  Additional immunosuppression (administered to
both groups):
◦ Prednisolone 1 mg/kg/day oral, tapered to 0.4
mg/kg/day by month 3 and 5 mg/kg/day by
month 15
◦ Azathioprine 2 mg/kg/day starting 3 months
after remission, continued until the end of the
study

21.  Primary Outcomes
 Median time to remission3 months (range 0.5-
8) vs. 3 months (range 1-7.5)Hazard ratio 1.098
(95% CI 0.78-1.55; P=0.59)

22.  Secondary Outcomes
 Proportion in remission at 9 months
 88.1% vs. 87.7%
 Relapses
 Of the 78.9% of patients who achieved remission by 9
months
 Any: 13 vs. 6 patients (HR 2.01; 95% CI 0.77-5.30)
 Major: 7 vs. 3 patients
 Minor: 6 vs. 3 patients
 Any adverse events
 77% vs. 77%
 Severe or life-threatening: 19 vs. 31 patientsAll-
cause mortality6.5% vs. 12.3% (P=0.79)

23.  Changes in renal function (improvement in
eGFR)
 5 ml/min/1.73 m2 vs. 8 ml/min/1.73
m2 (P=0.36)
 Leukopenia
 26% vs. 45% (P=0.016)
 Multiple bouts: 4 vs. 15 patients
 Time to first event: 219 vs. 68 days (HR
0.41; 95% CI 0.23-0.71)

24.  Infection
 20 vs. 21 patients
 Time to first event: 147 days vs. 68 days (HR
0.88; 95% CI 0.42 to 1.83)
 Life threatening: 7 vs. 10 eventsCumulative
dose of cyclophosphamide8.2 grams vs.
15.9 grams (P<0.001)Cumulative dose of
prednisolone7587 mg vs. 7586 mg

25.  BVAS score
◦ Similar at all points

26.  Unclear how patients would do with this protocol in
areas with endemic TB; pulse cyclophosphamide
may be lead to worse outcomes in patients with
latent TB
 Daily oral therapy may have been more effective
than pulse therapy for renal function recovery
 Contrary to the author's comments, pulse therapy
is not likely more convenient
 No report of proteinuria

29.  In patients with severe ANCA-associated vasculitis,
how does rituximab compare to cyclophosphamide
for induction of remission when combined with
glucocorticoids?

30.  Rituximab is non-inferior to cyclophosphamide in
inducing remission of severe ANCA-associated
vasculitis when combined with glucocorticoids.

31.  The ANCA-associated vasculitides (eg,
granulomatosis with polyangiitis or GPA, and
microscopic polyangiitis or MPA) affect small- and
medium-caliber vessels and are associated with
pulmonary and renal injury.

32.  The efficacy of cyclophosphamide in combination
with glucocorticoids was first demonstrated by
Fauci and colleagues in the late 1970s and early
1980s and has been the mainstay of therapy since.
 The role of the newer anti-CD20 monoclonal
antibody rituximab was unclear.

33.  The Rituximab in ANCA-Associated Vasculitis
(RAVE) trial randomized 197 patients with severe
ANCA-associated vasculitis to either
cyclophosphamide or rituximab in addition to
glucocorticoids tapered to symptoms.
 At 6 months, rituximab was non-inferior to
cyclophosphamide in induction of remission and
ability of patients to remain off of glucocorticoids.

34.  The FDA has subsequently approved rituximab with
glucocorticoids for treatment of GPA and MPA.
 No large organizations have released
recommendations regarding rituximab in GPA and
MPA, although an independent research group has
recommended its use in newly diagnosed patients
(grade 1b).

35.  Multicenter, randomized, double-blind, double-
dummy, noninferiority trial
 N=197 patients with severe ANCA-associated
vasculitis
◦ Rituximab (n=99)
◦ Cyclophosphamide (n=98)

36.  Setting: Nine centers
 Enrollment: 2004-2208
 Follow-up: 6 months
 Analysis: Non-inferiority
 Primary outcome: Remission of disease without the
use of prednisone at six months

37.  GPA or MPA
 Positive serum assay for PR3-ANCA or MPO-ANCA
 New diagnosis at time of screening or presenting
with a severe disease flare

38.  Birmingham Vasculitis Activity Score for WG
(BVAS/WG) of ≥3
 Severe disease requiring treatment with
cyclophosphamide
 Patient to be otherwise considered for treatment
with cyclophosphamide and glucocorticoids

39.  Churg-Strauss syndrome or anti-GBM disease
 Limited disease which would not otherwise be
treated by cyclophosphamide
 Alveolar hemorrhage requiring intubation
 Creatinine ≥4.0 mg/dL from current episode's
renal disease activity

40.  WBC <4,000/mm3 or platelets <120,000/mm3
 Liver function tests >2.5x ULN
 Allergy to monoclonal antibodies or murine
proteins
 Infection
◦ Previous deep space infections

41.  HBV, HCV, or HIV infection
 Liver disease
 Malignancy in <5 year other than SCC, BCC, or CIS
after curative treatment
 Live vaccine in prior 4 weeks
 Cyclophosphamide in previous 4 months
 Glucocorticoids for >14 days previously
 Previous adverse effects from standard therapy
 Previous treatment with rituximab or alemtuzumab
 Treatment with plasma exchange in prior 3 months

42.  From the rituximab group.
 Demographics:
 Age: 54 years
 Female: 46%
 Race/ethnicity:
◦ White: 92%
◦ Back: 3%
◦ Asian: 1%
◦ Other: 4%
◦ Hispanic or Latino: 6%

43.  Disease-specific:
 Vasculitis type:
◦ GPA: 75%
◦ MPA: 24%
◦ Indeterminate: 1%
 New diagnosis: 48%
 Disease duration with relapse: 6.5 years
 Previous cyclophosphamide in relapsed
disease: 82%

44.  Patients were randomized in 1:1 fashion to
either
◦ Rituximab 375 mg/m2 IV weekly for four weeks
plus placebo
◦ Cyclophosphamide 2 mg/kg with adjustments for
renal function plus placebo with the option to
switch to azathioprine if remission attained
between 3-6 months
 Both groups received methylprednisolone 1g
once, followed by prednisone 1 mg/kg/day
with a taper according to symptoms

45.  Comparisons are rituximab vs. cyclophosphamide.
 Primary Outcome
 Remission of disease and off prednisone at 6 months64% vs.
53% (P<0.001 for non-inferiority; NS for superiority)GPA: 63%
vs. 50% (P=NS)MPA: 67% vs. 62% (P=NS)

46.  Secondary Outcomes
 Remission of disease and prednisone <10mg
daily at 6 months71% vs. 62% (P=0.10)Disease
flaresLimited: 0.023 vs. 0.027 per patient-month
(P=0.81)Severe: 0.011 vs. 0.018 per patient-
month (P=0.30)Change in Vasculitis Damage
Index at 6 months+1.3 vs. +1.5 (P=0.62)Quality
of lifeNo differenceANCA negativity at 6
months47% vs. 24% (P=0.004)PR3: 50% vs. 17%
(P<0.001)MPO: 40% vs. 41% (P=0.95)Treatment
discontinuation14% vs. 17% (P=NS)

47.  Subgroup Analysis
 The primary outcome was not affected for ANCA
type, new diagnosis of disease, renal function,
alveolar hemorrhage, major renal disease, loss of
ANCA at 6 months, BVAS/WG, and age.
 Relapsing disease at baseline62% vs. 42% (OR
1.40; 95% CI 1.03-1.91; P=0.01)Adverse Events
 Any adverse eventTotal number: 31 vs.
33Patients with >1: 22% vs. 33%Death1% vs. 2%

48.  The authors identify that the included patient population
(severe disease and ANCA positivity, excluding alveolar
hemorrhage requiring intubation and renal failure) limits the
generalizability of the results as well as whether retreatment
of long-standing ANCA vasculitis with rituximab would be
safe or beneficial
 Selection bias favoring rituximab, in that many participants
had recurrent ANCA-associated vasculitis with many having
already failed cyclophosphamide therapy; this may represent
increased cyclophosphamide metabolism, for example.
 Short follow-up period of 6 months is insufficient to draw
long-term conclusions.
 Use of glucocorticoids confounds the analysis of efficacy
between treatment groups.

49. THANK YOU

50. Randomized Trial of Plasma
Exchange or High-Dosage
Methylprednisolone as
Adjunctive Therapy for
Severe Renal Vasculitis