The n e w e ng l a n d j o u r na l of m e dic i n e

original article

Rituximab versus Cyclophosphamide

for ANCA-Associated Vasculitis
John H. Stone, M.D., M.P.H., Peter A. Merkel, M.D., M.P.H., Robert Spiera, M.D.,
Philip Seo, M.D., M.H.S., Carol A. Langford, M.D., M.H.S.,
Gary S. Hoffman, M.D., Cees G.M. Kallenberg, M.D., Ph.D.,
E. William St. Clair, M.D., Anthony Turkiewicz, M.D., Nadia K. Tchao, M.D.,
Lisa Webber, R.N., Linna Ding, M.D., Ph.D., Lourdes P. Sejismundo, R.N., B.S.N.,
Kathleen Mieras, C.C.R.P., David Weitzenkamp, Ph.D., David Ikle, Ph.D.,
Vicki Seyfert-Margolis, Ph.D., Mark Mueller, B.S., C.C.R.P., Paul Brunetta, M.D.,
Nancy B. Allen, M.D., Fernando C. Fervenza, M.D., Ph.D., Duvuru Geetha, M.D.,
Karina A. Keogh, M.D., Eugene Y. Kissin, M.D., Paul A. Monach, M.D., Ph.D.,
Tobias Peikert, M.D., Coen Stegeman, M.D., Ph.D., Steven R. Ytterberg, M.D.,
and Ulrich Specks, M.D., for the RAVE−ITN Research Group*

A BS T R AC T

Background
Cyclophosphamide and glucocorticoids have been the cornerstone of remission- From Massachusetts General Hospital
induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)−associated (J.H.S.) and Boston University Medical
Center (P.A. Merkel, E.Y.K., P.A. Monach)
vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and — both in Boston; Hospital for Special
may be safer than a cyclophosphamide-based regimen. Surgery, New York (R.S.); Johns Hopkins
University, Baltimore (P.S., L.P.S., D.G.);
Methods Cleveland Clinic Foundation, Cleveland
We conducted a multicenter, randomized, double-blind, double-dummy, noninferior- (C.A.L., G.S.H.); University of Groningen,
Groningen, the Netherlands (C.G.M.K.,
ity trial of rituximab (375 mg per square meter of body-surface area per week for C.S.); Duke University, Durham, NC
4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight (E.W.S.C., N.B.A.); University of Ala-
per day) for remission induction. Glucocorticoids were tapered off; the primary end bama–Birmingham, Birmingham (A.T.);
Immune Tolerance Network (N.K.T.,
point was remission of disease without the use of prednisone at 6 months. V.S.-M., M.M.) and National Institute of
Allergy and Infectious Diseases (L.W., L.D.)
Results
— both in Bethesda, MD; Food and Drug
Nine centers enrolled 197 ANCA-positive patients with either Wegener’s granuloma- Administration, Rockville, MD (V.S.-M.);
tosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and Mayo Clinic and Foundation, Rochester,
MN (K.M., F.C.F., K.A.K., T.P., S.R.Y., U.S.);
the proportion of patients with relapsing disease were similar in the two treatment Rho, Raleigh, NC (D.W., D.I.); and Ge-
groups. Sixty-three patients in the rituximab group (64%) reached the primary end nentech, South San Francisco, CA (P.B.).
point, as compared with 52 patients in the control group (53%), a result that met Address reprint requests to Dr. Specks at
the Division of Pulmonary and Critical
the criterion for noninferiority (P<0.001). The rituximab-based regimen was more Care Medicine, Mayo Clinic and Founda-
efficacious than the cyclophosphamide-based regimen for inducing remission of tion, Rochester, MN 55905, or at specks
relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with [email protected].
21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). *Members of the Rituximab in ANCA-
Rituximab was also as effective as cyclophosphamide in the treatment of patients Associated Vasculitis−Immune Tolerance
with major renal disease or alveolar hemorrhage. There were no significant differ- Network (RAVE-ITN) Research Group
are listed in the Appendix.
ences between the treatment groups with respect to rates of adverse events.
N Engl J Med 2010;363:221-32.
Conclusions
Copyright © 2010 Massachusetts Medical Society.
Rituximab therapy was not inferior to daily cyclophosphamide treatment for induc-
tion of remission in severe ANCA-associated vasculitis and may be superior in re-
lapsing disease. (Funded by the National Institutes of Allergy and Infectious Dis-
eases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

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 The n e w e ng l a n d j o u r na l of m e dic i n e

W
egener’s granulomatosis and mi- verse events with a rituximab-based regimen ap-
croscopic polyangiitis are classified as pears elsewhere in this issue of the Journal.24
antineutrophil cytoplasmic antibody
(ANCA)−associated vasculitides because most pa- Me thods
tients with generalized disease have antibodies
against proteinase 3 or myeloperoxidase.1,2 The Study Design and Patients
ANCA-associated vasculitides affect small-to-medi- The first and last authors designed the trial in
um-size blood vessels, with a predilection for the collaboration with the clinical development team
respiratory tract and kidneys.3-6 at the Immune Tolerance Network and clinical in-
Cyclophosphamide and glucocorticoids have vestigators of the RAVE research group. The site
been the standard therapy for remission induc- investigators gathered the data, and the data were
tion for nearly four decades.7,8 This regimen trans- analyzed by the RAVE data committee, which con-
formed the usual treatment outcome of severe sisted of the two coprincipal investigators and rep-
ANCA-associated vasculitis from death to a strong resentatives of the Immune Tolerance Network,
likelihood of disease control and temporary re- the National Institute of Allergy and Infectious
mission.3-5,9-11 However, not all patients have a Diseases, and the coordinating center (Rho). The
remission with this combination of drugs, and data committee did not include representatives of
those who do often have disease flares that re- either Genentech or Biogen Idec, which provided
quire repeated treatment. Moreover, side effects funding and medications for the study. The man-
of cyclophosphamide, including infertility, cytope- uscript was drafted and written by the first and
nias, infections, bladder injury, and cancer, as last authors, with input as appropriate from mem-
well as the multiple adverse effects of lengthy bers of the RAVE data committee and the clinical
courses of glucocorticoid treatment, are major investigators. The RAVE data committee made the
causes of long-term disease and death.3-5,10-14 decision to submit the manuscript for publication,
B lymphocytes play an important role in the and the first and last authors vouch for the accu-
pathogenesis of autoimmune diseases, including racy and completeness of the data and analyses.
ANCA-associated vasculitis.15 In ANCA-associated Both the full study-entry criteria, included in
vasculitis, the percentage of activated peripheral- the Supplementary Appendix, and the trial pro-
blood B lymphocytes correlates with disease ac- tocol are available with the full text of this arti-
tivity, and certain effects of cyclophosphamide cle at NEJM.org. Briefly, patients with Wegener’s
on B lymphocytes are associated with treatment granulomatosis or microscopic polyangiitis were
efficacy.16-19 Rituximab, an anti-CD20 monoclo- eligible to participate in the study if they had
nal antibody, depletes B lymphocytes through a positive serum assays for proteinase 3–ANCA or
variety of mechanisms. In uncontrolled studies, myeloperoxidase-ANCA, manifestations of severe
rituximab has shown promise as a remission- disease,11 and a Birmingham Vasculitis Activity
induction agent in ANCA-associated vasculitis.20-23 Score for Wegener’s Granulomatosis (BVAS/WG)
We conducted the Rituximab in ANCA-Associ- of 3 or more (scores range from 0 to 63, with
ated Vasculitis (RAVE) trial, a multicenter, ran- higher scores indicating more active disease).25
domized, double-blind, double-dummy, noninfe- Patients with either newly diagnosed or relapsing
riority trial to compare rituximab with standard disease were eligible for enrollment. The RAVE
cytotoxic therapy for the induction of complete trial was approved by the institutional review
remission by 6 months in patients with severe board at each participating site. All patients pro-
ANCA-associated vasculitis. We hypothesized that vided written informed consent.
treatment with rituximab plus glucocorticoids Patients were randomly assigned, in a 1:1 ratio,
would not be inferior to daily cyclophosphamide to investigational therapy (the rituximab group) or
plus glucocorticoids for remission induction and standard therapy (the control group). Randomiza-
would permit discontinuation of prednisone by tion was stratified according to clinical site and
6 months. A related article on a randomized trial ANCA type.
of rituximab versus cyclophosphamide in ANCA-
associated vasculitis (RITUXVAS; Current Con- Treatments
trolled Trials number, ISRCTN28528813) to assess The remission-induction period was 6 months. The
the treatment response and rates of severe ad- rituximab group received intravenous rituximab

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 Rituximab vs. Cyclophosphamide in Vasculitis

(Rituxan, Genentech) (at a dose of 375 mg per the other treatment group in a blinded fashion.
square meter of body-surface area once weekly Those who crossed over received the other induc-
for 4 weeks) plus daily placebo−cyclophosphamide. tion regimen in full. Limited flares were treated
The control group received placebo−rituximab in- by increasing the dose of prednisone.
fusions plus daily cyclophosphamide (2 mg per Patients were classified as having early treat-
kilogram of body weight, adjusted for renal in- ment failure if at 1 month their BVAS/WG had not
sufficiency). Patients in the control group who had decreased by at least 1 point or a new manifesta-
a remission between 3 and 6 months were eligible tion of disease had emerged. Patients with early
to switch from cyclophosphamide to azathioprine treatment failure discontinued their assigned treat-
(2 mg per kilogram per day).10 Patients in the ritux- ments, received therapies according to best medi-
imab group with a remission during the same cal judgment, and were counted as having failure
3-to-6-month period were switched from placebo− with respect to the primary end point.
cyclophos­phamide to placebo−azathioprine.
The two treatment groups received the same Adverse Events
glucocorticoid regimen: one to three pulses of All adverse events were graded according to the
methylprednisolone (1000 mg each), followed by National Cancer Institute’s Common Terminology
prednisone at a dose of 1 mg per kilogram per day. Criteria.29 During protocol development, the study
The dose was tapered so that by 5 months, all team and the Food and Drug Administration iden-
patients who had a remission without disease tified nine major adverse events, termed selected
flares had discontinued glucocorticoids (see the adverse events, for priority analysis. These events
Supplementary Appendix). included deaths (from all causes), malignant con-
ditions, grade 2 or higher leukopenia or throm-
Assessments bocytopenia, grade 3 or higher infections, drug-
Study visits occurred at baseline; at weeks 1, 2, 3, induced cystitis, venous thromboembolic events,
and 4; and at 2, 4, and 6 months. Disease activity stroke, hospitalizations, and infusion reactions that
was measured on the basis of the BVAS/WG and contraindicated further infusions.
the physician’s global assessment.25 Damage re-
lated to disease or treatment was scored accord- Statistical Analysis
ing to the Vasculitis Damage Index (scores for this In calculating the sample size, we assumed that
index range from 0 to 64, with higher scores in- 70% of the patients in both treatment groups
dicating more severe damage).26 Health-related would have disease remission after the discontin-
quality of life was scored with the use of the Med- uation of prednisone at 6 months. We specified a
ical Outcomes Study 36-Item Short-Form Health noninferiority margin of −20 percentage points
Survey (SF-36).27 Scores on this scale range from for the difference in remission rates (the rate in
0 to 100, with higher scores indicating better the rituximab group minus the rate in the con-
health. trol group) and a one-sided alpha level of 0.025.
Serial serum samples were tested for proteinase Assuming a 10% dropout rate, we calculated that
3–ANCA and myeloperoxidase-ANCA by means we would need to enroll 100 patients in each group
of a direct enzyme-linked immunosorbent assay for an 83% statistical power to demonstrate non-
(ELISA).28 inferiority.
Primary analyses were performed by the inten-
End Points tion-to-treat method. Patients who dropped out
The primary end point was a BVAS/WG of 0 and of the study before 6 months were considered to
successful completion of the prednisone taper at have a treatment failure with respect to the pri-
6 months. Secondary end points included rates of mary end point. We assessed noninferiority by
disease flares, a BVAS/WG of 0 during treatment comparing the lower limit of the 95.1% confidence
with prednisone at a dose of less than 10 mg per interval for the mean treatment difference (the
day, cumulative glucocorticoid doses, rates of ad- rate in the rituximab group minus the rate in the
verse events, and SF-36 scores. A disease flare was control group) to −20 percentage points and test-
defined as an increase in the BVAS/WG of 1 point ing the corresponding hypothesis that the differ-
or more. Patients who had severe flares during ence would be greater than −20 percentage points.
the first 6 months were eligible for crossover to Superiority was assessed by means of a one-tailed

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 The n e w e ng l a n d j o u r na l of m e dic i n e

t-test comparing the mean treatment difference the rituximab group and 8.2±3.2 in the control
with zero. To assess the consistency of the study group.
results, analyses were repeated for predefined sub- Ninety-seven percent of all patients received at
groups based on the following baseline variables: least three study-drug infusions. None were lost
type of ANCA-associated vasculitis, type of ANCA, to follow-up. Eighty-four of the patients who were
newly diagnosed disease, relapsing disease, alve- randomly assigned to the rituximab group (85%)
olar hemorrhage, and severe renal disease. With and 81 of those who were randomly assigned to
analysis of eight subgroups, chance alone would the control group (83%) completed 6 months of
result in 0.39 statistically significant results treatment without meeting criteria for early treat-
(P<0.05). We did not correct these subgroup analy- ment failure, crossing over to the other treatment
ses for multiplicity because they were prespeci- group, switching to a therapy based on best medi-
fied and had biologically plausible bases. cal judgment, or withdrawing from the protocol
For other analyses, two-sample comparisons for other reasons (Fig. 1).
were performed with the use of Student’s t-test
or a Wilcoxon rank-sum test for continuous mea- Efficacy Assessments
sures and a chi-square test or Fisher’s exact test End Points
for binary measures. Adjusted analyses were per- Sixty-three of the 99 patients in the rituximab
formed by means of analysis of covariance or lo- group (64%) reached the primary end point, as
gistic regression. Baseline covariates for these compared with 52 of 98 in the control group (53%).
analyses included type of ANCA, new versus re- The treatment difference of 11 percentage points
lapsing disease, renal function, and BVAS/WG. between the groups met the criterion for non­
Rates of adverse events were compared with the inferiority (P<0.001). The proportion of patients
use of Poisson regression. All statistical tests were who reached the primary end point was larger in
two-sided, and a P value of less than 0.05 was the rituximab group than in the control group, but
considered to indicate statistical significance (see the difference was not significant (95.1% confi-
the Supplementary Appendix for details of the dence interval [CI], −3.2 to 24.3 percentage
interim analysis). points; P = 0.09) (Fig. 2). Seventy patients treated
with rituximab (71%) reached the secondary end
R e sult s point of disease remission while receiving less
than 10 mg per day of prednisone, as compared
Patients with 61 patients in the control group (62%,
Between December 30, 2004, and June 30, 2008, P = 0.10).
a total of 197 patients with ANCA-associated vas- ANCA type, newly diagnosed disease, renal
culitis were enrolled at nine clinical sites partici- function, BVAS/WG, and age did not affect the
pating in the study (Fig. 1). The baseline charac- primary comparison when examined in logistic-
teristics of the patients are listed in Table 1. regression models (data not shown). However,
Ninety-nine patients were assigned to the ritux- among patients with relapsing disease at baseline,
imab group, and 98 patients were assigned to the rituximab was more efficacious than cyclophos-
control group. The treatment groups were bal- phamide: 34 of 51 patients in the rituximab group
anced with respect to Wegener’s granulomatosis (67%) reached the primary end point, as compared
versus microscopic polyangiitis, patients with new- with only 21 of 50 in the control group (42%,
ly diagnosed disease, disease activity, organ in- P = 0.01). Evidence of the superior efficacy of ritux-
volvement, pre-enrollment therapy, past exposure imab among patients with relapsing disease at
to cyclophosphamide, and total glucocorticoids baseline persisted even after adjustment for dif-
administered in the interval from 14 days before ferences in ANCA type and clinical site (odds ra-
informed consent was obtained to the first inves- tio, 1.40; 95% CI, 1.03 to 1.91; P = 0.03).
tigational infusion (Table 1). Forty-eight patients
(24%) had diagnoses of microscopic polyangiitis, Disease Type
and 148 (75%) had diagnoses of Wegener’s gran- Among patients with Wegener’s granulomatosis,
ulomatosis. The specific diagnosis was indetermi- 46 of 73 assigned to rituximab (63%) and 37 of
nate in 1 patient. Approximately 49% of patients 74 treated with cyclophosphamide (50%) reached
in both groups had a new diagnosis. The mean the primary end point (P = 0.11). Among the pa-
(±SD) BVAS/WG scores at entry were 8.5±3.2 in tients with microscopic polyangiitis, 16 of 24 in

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 Rituximab vs. Cyclophosphamide in Vasculitis

the rituximab group (67%) and 15 of 24 in the con-

trol group (62%) reached the primary end point
(P = 0.76). 197 Eligible patients underwent randomization

Major Renal Disease at Baseline

A subgroup of patients had at least one major re-
nal BVAS/WG item at baseline (i.e., urinary red-cell
99 Were assigned to receive rituximab 98 Were assigned to receive cyclophos-
casts, biopsy-confirmed glomerulonephritis, or plus placebo (rituximab group) phamide plus placebo (control
an increase in the baseline serum creatinine con- 24 Had microscopic polyangiitis group)
74 Had Wegener’s granulomatosis 24 Had microscopic polyangiitis
centration of more than 30%). Fifty-one of the pa- 1 Had missing diagnostic 74 Had Wegener’s granulomatosis
tients in the rituximab group (52%) had at least information
one major renal item at baseline, as compared with
51 in the control group (52%). In this subgroup,
baseline renal function in the rituximab group 99 Were evaluated for end point 98 Were evaluated for end point
was worse than in the control group (mean [±SD] 84 Completed 6 mo of treatment 81 Completed 6 mo of treatment
15 Had 22 early outcomes: 17 Had 21 early outcomes:
estimated creatinine clearance, 53.8±29.8 ml per 7 Had early treatment failure 2 Had early treatment failure
minute vs. 68.9±41.6 ml per minute; P = 0.04). How- 6 Crossed over to other group 7 Crossed over to other group
7 Switched therapy on best 6 Switched therapy on best
ever, the estimated creatinine clearances increased medical judgment medical judgment
in parallel in the two groups during the first 1 Died 2 Died
1 Withdrew (primary-outcome 4 Withdrew (primary-outcome
6 months (by 11.2 ml per minute in the rituximab failure) failure)
group and 10.5 ml per minute in the control group),
and the percentages of patients who reached the
primary end point were not significantly different
(31 of 51 patients in the rituximab group [61%] 99 Were included in analysis 98 Were included in analysis
vs. 32 of 51 patients in the control group [63%],
P = 0.92).
Figure 1. Randomization and Inclusion in the Analysis at 6 Months.
Patients were randomly assigned, in a 1:1 ratio, to the treatment and control
Alveolar Hemorrhage at Baseline groups. The study groups were balanced with respect to ANCA type. The ma-
Twenty-eight patients in the rituximab group (28%) jority of patients (84 patients in the rituximab group and 81 patients in the
had alveolar hemorrhage at baseline, as compared control group) completed 6 months of the treatment to which they were as-
with 27 in the control group (28%). Among these signed. The remainder had one or more events that led to withdrawal from
patients, 16 (57%) and 11 (41%), respectively, the study. Data related to the primary analysis were available for all patients.
Five patients who withdrew voluntarily from the trial (1 patient in the ritux-
reached the primary end point (P = 0.48). imab group and 4 patients in the control group) were regarded as having had
a treatment failure with respect to the primary end point.
Severity of Flares
Six patients in the rituximab group and 10 in the
control group had severe disease flares. The rates Peripheral-Blood B-Lymphocyte Counts
of severe flares were 0.011 and 0.018 per patient- The number of peripheral-blood CD19+ B cells
month, respectively (P = 0.30). There was no sig- decreased to less than 10 cells per cubic millime-
nificant between-group difference in the number ter after two infusions of rituximab and remained
of limited flares: there were 13 flares in 11 pa- at that level in most patients through 6 months
tients in the rituximab group and 15 flares in 14 (Fig. 3). In the rituximab group, 87 of 93 patients
patients in the control group. The rates of limited(94%) had this degree of B-cell depletion at
disease flares were 0.023 and 0.027 per patient- 1 month. Among the patients who did not have
month, respectively (P = 0.81). B-cell depletion, 4 patients reached the primary
end point and 1 patient did not. In the control
Damage and Quality of Life group, peripheral-blood CD19+ B-cell counts also
Scores on the Vasculitis Damage Index increased decreased, but the rate and magnitude of the de-
by 1.3 points from baseline to 6 months in the crease were less than in the rituximab group.
rituximab group and by 1.5 points in the control
group (P = 0.62). Quality-of-life outcomes did not ANCA Response
differ significantly between the two groups (see Among patients who remained in their original
the Supplementary Appendix). treatment groups, 47% in the rituximab group and

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Baseline Demographic and Clinical Characteristics of the Patients.*

Rituximab Group Control Group

Variable (N = 99) (N = 98) P Value
Age at onset of symptoms (yr) 54.0±16.8 51.5±14.1 0.26
Sex (%) 0.29
Male 46 54
Female 54 46
Race or ethnic group (%) 0.64
White 92 95
Black 3 3
Asian 1 0
Other 4 2
Ethnic group (%) 0.60
Not Hispanic or Latino 92 95
Hispanic or Latino 6 3
Unknown 2 2
ANCA-associated vasculitis type (%) 0.61
Wegener’s granulomatosis† 75 76
Microscopic polyangiitis 24 24
Indeterminate 1 0
Newly diagnosed at enrollment (%) 48 49 0.62
Pre-enrollment disease duration in patients with relapsed 6.5±6.7 5.3±7.4 0.31
disease (yr)
Pre-enrollment exposure to cyclophosphamide in patients 82 74 0.10
with relapsed disease (%)
Disease-assessment scores
BVAS/WG‡ 8.5±3.2 8.2±3.2 0.38
Physician’s global assessment 5.7±2.4 5.6±2.4 0.67
Vasculitis Damage Index 1.4±1.8 1.0±1.4 0.17
SF-36§
Physical component 37.2±9.8 38.6±11.9 0.38
Mental component 41.7±13.2 44.0±11.4 0.20
Organ involvement
Constitutional signs or symptoms (%)¶ 56 66 0.12
Cutaneous involvement (%) 20 16 0.48
Mucous membranes and eyes (%) 27 26 0.78
Ear, nose, and throat (%) 61 56 0.52
Pericarditis (%) 0 1 0.50
Mesenteric ischemia (%) 2 0 0.50
Pulmonary involvement (%) 52 54 0.83
Alveolar hemorrhage 27 24 0.54
Endobronchial lesions 4 9 0.15
Nodules or cavities 18 28 0.12
Other lung infiltrate 25 21 0.53
Pleurisy 8 9 0.78
Respiratory failure 2 0 0.50

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 Rituximab vs. Cyclophosphamide in Vasculitis

Table 1. (Continued.)

Rituximab Group Control Group

Variable (N = 99) (N = 98) P Value
Renal involvement (%)‖║ 66 66 0.92
Hematuria (%) 28 29 0.96
Red-cell casts (%) 37 36 0.81
Creatinine clearance (ml/min) 54±3 69±4 0.04
Neurologic involvement (%) 25 15 0.08
Cranial-nerve palsy 0 1 0.50
Meningitis 1 0 0.50
Motor mononeuritis multiplex 11 9 0.20
Sensory peripheral neuropathy 22 13 0.10
ANCA-positive at diagnosis (%)
By immunofluorescence
All 98 96
C-ANCA 66 62
P-ANCA 33 34
By ELISA
All 98 100
Proteinase 3─ANCA 67 66
Myeloperoxidase-ANCA 32 34
Mean dose of glucocorticoids from 14 days before consent
provided to first infusion of study drug
Methylprednisolone (g) 0.8±1.28 0.7±1.10
Prednisone (mg) 253.6±236.5 296.1±266.2

* Plus−minus values are means ±SD, except for the values for creatinine clearance, which are means ±SE. Race and eth-
nic group were self-reported. The chi-square test or Fisher’s exact test was used for the comparison of categorical data,
and Student’s t-test or the Wilcoxon rank-sum test was used for the analysis of continuous data. ANCA denotes anti-
neutrophil cytoplasmic antibody, C-ANCA cytoplasmic ANCA-labeling pattern, ELISA enzyme-linked immunosorbent
­assay, and P-ANCA perinuclear ANCA-labeling pattern.
† American College of Rheumatology Criteria were used for the classification of Wegener’s granulomatosis.
‡ The Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) for new or worse disease ranges
from 0 to 67, with higher scores indicating more active disease. A BVAS/WG of 0 indicates remission.
§ Scores on the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), version 2, range from 0 to 100, with
higher scores indicating better health. A score of 50 represents the mean score for the U.S. population.
¶ Constitutional signs or symptoms of disease activity included arthritis, arthralgias, and fever (temperature ≥38.0°C).
‖ On the BVAS/WG instrument, hematuria is not scored if red-cell casts are present or a renal-biopsy specimen shows
active glomerulonephritis at the same time.

24% in the control group became ANCA-negative reactivity, as measured by means of direct ELISA,
by 6 months (P = 0.004). This difference between was not significantly associated with attainment
the two treatment groups in loss of ANCA reactiv- of the primary end point.
ity was due to changes in the subgroup of pa-
tients who were initially positive for proteinase Adverse Events
3−ANCA. Fifty percent of such patients in the There were no significant differences between the
rituximab group became negative for proteinase treatment groups in the numbers of total adverse
3−ANCA, as compared with only 17% in the con- events, serious adverse events, or non−disease-
trol group (P<0.001). In contrast, equivalent per- related adverse events, or in the number of par-
centages of patients in the rituximab and control ticipants with at least one non−disease-related ad-
groups became negative for myeloperoxidase− verse event (Table 2). Fourteen patients in the
ANCA (40% vs. 41%, P = 0.95). The loss of ANCA rituximab group (14%) and 17 in the control group

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 The n e w e ng l a n d j o u r na l of m e dic i n e

of solid malignant tumors among patients who

received cyclophosphamide were prostate cancer
−3.2 10.6 24.3
Prednisone, 0 mg/day (in 1 patient) and lung cancer (in 1 patient).
Among patients with exposure to rituximab dur-
ing the trial, malignant conditions developed in
−4.7 8.5 21.7
Prednisone, <10 mg/day 6 of 124 (5%), as compared with 1 of 73 patients
without exposure to rituximab (1%, P = 0.26). With
the exception of two cases of prostate cancer, all
Noninferior Superior
patients in whom malignant conditions developed
had histories of exposure to at least two medica-
−40 −30 −20 −10 0 10 20 30 tions known to increase the risk of cancer (cy-
Differences in Complete-Remission Rate (percentage points) clophosphamide, azathioprine, or methotrexate)
(see the Supplementary Appendix).
Figure 2. Treatment Effect According to Prednisone Dose at 6 Months.
Point estimates and 95.1% confidence intervals are shown for the treatment
effect, defined as the difference in rates of complete remission between the
Discussion
treatment groups. The criterion for the noninferiority of rituximab was a differ-
ence in remission rates of 20 percentage points, and the criterion for superior- Although a randomized, controlled trial involv-
ity was a difference of 0 percentage points. For both complete remission with ing patients with severe ANCA-associated vascu-
0 mg of prednisone per day and complete remission with less than 10 mg per litis that compared cyclophosphamide head to
day, the difference in remission rates was above 20 percentage points, mean- head with another agent had long been deemed
ing that the criterion for the noninferiority of rituximab was met (P<0.001 for
both comparisons).
unethical,30 uncontrolled studies have suggested
that rituximab has efficacy for remission induc-
tion in ANCA-associated vasculitis.21-23 Those
(17%) had events leading to discontinuation of promising results led to the current study, which
treatment. suggests that rituximab plus glucocorticoids pro-
More patients in the control group than in the vides similar results to cyclophosphamide plus
rituximab group had one or more of the pre- glucocorticoids for induction of remission.
defined selected adverse events: 32 (33%) versus The observed treatment effects were consistent
22 (22%) (P = 0.01) (Table 2). More episodes of across all measures of clinical efficacy. A higher
grade 2 or higher leukopenia (white-cell count, percentage of rituximab-treated patients reached
<3000 per cubic millimeter) in the control group the primary end point (64% vs. 53%); the differ-
(10, vs. 3 in the control group) accounted for most ence exceeded the prespecified noninferiority mar-
of this difference (Table 2). Eight patients in the gin by 31%. In addition, in a prespecified sub-
rituximab group were hospitalized for adverse group analysis,31 patients who presented with
events related to either the disease or its treatment, relapsing disease and who received rituximab
as compared with 2 in the control group. No pat- fared substantially better than did those with re-
tern emerged with respect to causes of hospital- lapsing disease who received cyclophosphamide.
ization. During the first 6 months of the trial, Among patients with severe renal disease or al-
solid malignant tumors were diagnosed in 1 pa- veolar hemorrhage, the outcomes were similar
tient in each group; 2 patients in the control group with the two treatment regimens.
and 1 in the rituximab group died. The likelihood of remission at 6 months is af-
Six malignant conditions developed in 5 addi- fected by whether glucocorticoids have been ta-
tional patients after 6 months. Four of those pa- pered and discontinued entirely, as well as by the
tients had been assigned initially to rituximab and specific definition of remission.32-35 Several dif-
one had been assigned to cyclophosphamide. The ferences in trial design may explain why the re-
specific types of solid malignant tumors among mission rates in this trial were lower than those
patients who received rituximab were papillary in some other vasculitis trials.10,11,32-35 Particu-
thyroid cancer (in 1 patient), uterine cancer (in larly important is the fact that in other vasculitis
1 patient), prostate cancer (in 1 patient), colon trials, patients have generally been permitted to
cancer (in 2 patients), bladder cancer (in 1 patient), continue to receive glucocorticoids for 1 year or
and lung cancer (in 1 patient). The specific types longer. In addition, some of the patients in other

228 n engl j med 363;3 nejm.org july 15, 2010

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 Rituximab vs. Cyclophosphamide in Vasculitis

trials who were classified as being in remission

had the continuation of one or more minor BVAS A
items (i.e., a score higher than 0).
Control, MPO-ANCA
We anticipated lower rates of certain adverse 200 Control, PR3-ANCA

CD19+ B-Cell Count (cells/mm3)

events in the rituximab group, but we did not Rituximab, MPO-ANCA
observe major differences between the two groups Rituximab, PR3-ANCA
in overall adverse events. There are several possi- 150

ble reasons for this finding. First, adverse events,

by their definition, include both disease and treat- 100
ment complications, including those related to
glucocorticoid use. Second, 6 months may have
been too short a period in which to detect some of 50

the cyclophosphamide-associated adverse events

(e.g., infertility). Third, rigorous monitoring of all 0
patients in our trial may have reduced the inci- 0 15 29 60 120 180
dence of cyclophosphamide-induced leukopenia, Days after Randomization
which may occur in clinical practice if blood
B
counts are not checked every 2 weeks.
Control
Our trial had certain limitations. We enrolled 10 Rituximab
Log2 CD19+ B-Cell Count (cells/mm3)
only patients with severe ANCA-associated vas-
culitis who were ANCA-positive. Thus, it is not
clear whether the treatment effects extend to pa-
tients with limited Wegener’s granulomatosis or 5
6
those who are ANCA-negative. Patients with al-
veolar hemorrhage severe enough to require ven-
tilatory support and those with advanced renal 0
dysfunction (serum creatinine level, >4.0 mg per
deciliter [354 µmol per liter]) were excluded. Thus,
the comparative efficacy of these two regimens
is uncertain in such patients. 0 15 29 60 120 180
Our study focused exclusively on remission in- Days after Randomization
duction but did not address the question of re-
treatment with rituximab. Rituximab was not re-
Figure 3. Peripheral-Blood B-Cell Counts.
administered after the return of peripheral-blood
Panel A shows the peripheral-blood B-cell counts in the rituximab and con-
B cells (anticipated by 9 to 12 months). Longer trol groups according to antineutrophil cytoplasmic antibody (ANCA) type.
follow-up in the present trial is important to un- The counts in most patients who received rituximab decreased to less than
derstand the benefits and risks of rituximab ther- 10 CD19+ cells per cubic millimeter after two infusions and remained at
apy for ANCA-associated vasculitis. Evaluations of that level until 6 months. B-cell counts decreased more slowly in the con-
trol group than in the rituximab group and remained detectable, at low lev-
patients followed for a minimum of 18 months
els. MPO-ANCA denotes ANCA directed against myeloperoxidase, and
will explore issues such as the need for retreat- PR3-ANCA ANCA directed against proteinase 3. Panel B shows box plots of
ment, particularly in the context of peripheral log2 -transformed values for CD19+ B cells at six time points, according to
B-cell reconstitution. The finding that loss of pro- treatment group. The horizontal line within each box indicates the median
teinase 3−ANCA production occurred more fre- value; the bottom and top lines of the box depict the 25th and 75th quar­
tiles, respectively; and the whiskers show the upper and lower values at 1.5
quently with rituximab therapy than with cyclo-
times the interquartile range. The open circles represent values outside this
phosphamide therapy suggests that these two range and are considered outliers. Values equaling 0 were converted to the
treatment strategies modulate proteinase 3−pro- lowest nonzero value of 0.06 before log2 transformation.
ducing cells differently. Since the ANCA response
was not associated with the primary end point,
it is possible that the clinical efficacies of both In conclusion, our data suggest that treatment
rituximab and cyclophosphamide are due to mech- with rituximab and glucocorticoids is not inferior
anisms beyond autoantibody suppression. to the standard regimen in patients with severe

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Adverse Events at 6 Months.*

Rituximab Group Control Group Total

Variable (N = 99) (N = 98) (N = 197)
Total no. of selected adverse events† 31 33 64
>1 Selected adverse event — no. of patients (%) 22 (22) 32 (33) 54 (27)
Annual rate of selected adverse events — % 5 6 6
Specific selected adverse events — no. of events (%)†
Death 1 (1) 2 (2) 3 (2)
Cancer 1 (1) 1 (1) 2 (1)
Leukopenia (≥grade 2) 3 (3) 10 (10) 13 (7)
Thrombocytopenia (≥grade 3) 3 (3) 1 (1) 4 (2)
Infection (≥grade 3) 7 (7) 7 (7) 14 (7)
Hemorrhagic cystitis 1 (1) 1 (1) 2 (1)
Venous thrombotic event 6 (6) 9 (9) 15 (8)
Cerebrovascular accident 0 0 0
Hospitalization due to disease or treatment 8 (8) 2 (2) 10 (5)
Infusion reaction preventing further infusions of investiga- 1 (1) 0 1 (<1)
tional medication
All adverse events — no. 1035 1016 2051
All adverse events ≥grade 3 and serious adverse events — no. 79 78 157
All non−disease-related adverse events ≥grade 3 and serious 58 53 111
adverse events — no.
Patients with ≥1 non−disease-related adverse event — % 29 29 58
All adverse events ≥grade 3 and serious adverse events leading 6 8 14
to treatment discontinuation — no.
Grade 3 adverse events — no. 61 77 138
≥1 Grade 3 adverse event — no. of patients (%) 22 (22) 32 (33) 54 (27)
Grade 4 adverse events — no. 11 5 16
≥1 Grade 4 adverse event — no. of patients (%) 8 (8) 4 (4) 12 (6)
Grade 5 adverse events (death) — no. 1 (1) 2 (2) 3 (2)

* Adverse events were categorized according to the National Cancer Institute Common Terminology Criteria for Adverse
Events, version 3.
† Selected adverse events were defined as death (from any cause), cancer, grade 2 or higher leukopenia or thrombocyto­
penia, grade 3 or higher infections, drug-induced cystitis, venous thromboembolic events, stroke, hospitalization, and
infusion reactions leading to the discontinuation of further infusions.

ANCA-associated vasculitis of recent onset. More- Mayo Clinic and Foundation, the trial was supported by a Clini-
cal and Translational Science Award from the National Center
over, the regimen may be superior to the stan- for Research Resources (NCRR) (RR024150-01); at Johns Hop-
dard regimen of cyclophosphamide and glucocor- kins University, by grants from the NCRR (RR025005) and ca-
ticoids for remission induction in severe relapsing reer development awards (K24 AR049185, to Dr. Stone, and K23
AR052820, to Dr. Seo); and at Boston University, by a Clinical
ANCA-associated vasculitis. and Translational Science Award (RR 025771), grants from the
The views expressed in this article are those of the authors National Institutes of Health (M01 RR00533) and a career devel-
and do not necessarily reflect those of the Food and Drug Ad- opment award (K24 AR02224, to Dr. Merkel), and an Arthritis
ministration. Foundation Investigator Award (to Dr. Monach). Enzyme-linked
Supported by a grant from the National Institute of Allergy immunosorbent assay kits for antineutrophil cytoplasmic anti-
and Infectious Diseases to the Immune Tolerance Network body were provided by Euroimmun (Lübeck, Germany).
(N01-AI-15416; protocol no. ITN021AI). Genentech and Biogen Disclosure forms provided by the authors are available with
provided the study medications and partial funding. At the the full text of this article at NEJM.org.

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 Rituximab vs. Cyclophosphamide in Vasculitis

Appendix
Members of the RAVE-ITN Research Group are as follows: Protocol Cochairs — U. Specks (Mayo Clinic), J.H. Stone (Massachusetts Gen-
eral Hospital); Mayo Clinic ─— U. Specks, S.R. Ytterberg, F.C. Fervenza, K.A. Keogh, T. Peikert, J.M. Golbin, L. Klein, K. Mieras, C.
Beinhorn, S. Fisher, M.L. Clawson, S. Bendel, A.M. Hummel (Mayo Clinic Eisenberg Research Pharmacy); Boston University — P.A.
Merkel, E.Y. Kissin, P.A. Monach, M.R. Clark-Cotton, C.A. McAlear, J.L. Pettit, M.B. Sutton, R.L. Widom, G.A. Farina, M.J. DiMarzio,
S.P. Johnson, A. Schiller Patel; Johns Hopkins University — P. Seo, J.H. Stone, D. Hellmann, D. Geetha, A. Saleh, P. Wung, L.P. Sejismun-
do, C. Humphrey, M. Marriott, Y. Goldsborough, A. Pinachos, K. Gauss, L. King; Cleveland Clinic Foundation — C.A. Langford, G.S.
Hoffman, R.A. Hajj-Ali, J.J. Carey, E.S. Molloy, C.L. Koening, D. Bork, T.M. Clark, K.A. Tuthill, T. Markle, J. Petrich; Hospital for Special
Surgery — R. Spiera, D.R. Alpert, S.J. DiMartino, J.K. Gordon, N.K. Moskowitz, K.A. Kirou, J. Samuels, S.A. Kloiber, E. Julevic, M.
O’Donohue, A. Patel; University of Groningen — C.G.M. Kallenberg, C. Stegeman, P. Rasker, K. Mulder, P. Limburg, J. Kosterink; Duke
University — E.W. St. Clair, N.B. Allen, E. Scarlett, M. Tochacek; University of Alabama–Birmingham — A. Turkiewicz, B. Fessler, W.
Chatham, A. Turner; Coordinating Centers: Rho — D. Ikle, D. Weitzenkamp, W. Wu, T. D’Lugin, C. Jacob; National Institute of Allergy and
Infectious Diseases — L. Webber, L. Ding, S. Adah; Immune Tolerance Network — N.K. Tchao, M. Mueller, K. Bourcier, A. Asare, V. Seyfert-
Margolis, P. Tosta, N.B. Skeeter, C.L. Anderson, A.N. Archampong.

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