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NEWS & VIEWS
VASCULITIS SYNDROMES
Rituximab in AAV: when and how
to use it
Julia U. Holle and Wolfgang L. Gross
Rituximab has emerged as an alternative to cyclophosphamide for
remission induction in anti-neutrophil cytoplasmic antibody-associated
vasculitides, with recommendations now developed to direct its use in
these diseases. However, data from extended clinical trials are required
to determine whether rituximab is safer or more efficacious than
cyclophosphamide in the long term.
Holle, J. U. & Gross, W. L. Nat. Rev. Rheumatol. 7, 566–567 (2011); published online 30 August 2011;
doi:10.1038/nrrheum.2011.131
Cyclophosphamide in combination with
glucocorticoids is currently the gold standard therapy for remission induction in
anti-neutrophil cytoplasmic antibody
(ANCA)-associated vasculitides (AAV),
and is recommended by the European
League Against Rheumatism (EULAR) for
this purpose.1 However, cyclophosphamide
use has been associated with major adverse
events,2 and the vasculitis community has
searched for less toxic but equally effective
alternatives. Evidence from two randomized controlled trials (RCTs), RAVE3 and
RITUXVAS, 4 suggests that rituximab is
equally effective for remission induction as
cyclophosphamide in patients with generalized (that is, systemic, organ-threatening)
Box 1 | Level of evidence classifications
1a
Recommendation made on the basis of
data from a meta-analysis of randomized
controlled trials
1b
Evidence from at least one randomized
controlled trial used to support the
recommendation
2a
Data from at least one controlled study
without randomization support the suggestion
2b
Guideline supported by data from at least
one type of quasi-experimental study
3
Information from descriptive studies, such
as comparative studies, correlation studies
or case–control studies formed the basis for
the recommendation
4
Recommended on the basis of evidence from
expert committee reports or opinions and/or
clinical experience of respected authorities
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granulomatosis with polyangiitis (GPA, formerly Wegener’s vasculitis) or microscopic
polyangiitis (MPA), including those with
severe renal impairment. Furthermore, a
number of uncontrolled studies and case
series have described the efficacy of rituxi­
mab as a ‘rescue therapy’ in refractory
GPA and MPA, as well as in Churg-Strauss
syndrome (CSS). In light of this evidence,
a British expert committee, funded by an
unres­tricted grant from Roche (UK) and
consisting of five rheumatologists, five
nephrologists and a pediatrician, conducted
a detailed literature review and a modified
Delphi exercise to establish 15 recommendations for the use of rituximab in AAV
(Supplementary Table 1 online).5
In their new guidelines, the British panel
recom­m end rituximab as an alternative
to cyclo­phosphamide for standard remission induction in newly diagnosed patients
with AAV, and suggest that it can be used
preferen­t ially when cyclophosphamide
avoid­ance is desirable. This recommendation is made on the basis of two RCTs,3,4
corres­ponding to level of evidence 1b (See
Box 1 for description of levels of evidence).
As no patients with CSS were treated in
these trials, the recommendation of rituxi­
mab for remission induction on the basis of
this level of evidence can only be made for
GPA and MPA, not for CSS. Furthermore,
the recommenda­tions do not provide any
guidance on which therapy to use in relation to the stage of dis­ease. In the RAVE
trial, patients requiring cyclophosphamide
treatment (that is, patients with generalized disease) were recruited, whereas in
the RITUXVAS trial all patients had renal
involvement and most of them were in
the severe disease stage. Con­s equently,
rituximab should be considered as an
alternative agent for standard remission
induction in the generalized disease stage
of GPA or MPA, and con­s idered as a
‘­c yclophosphamide-sparing’ agent in the
severe disease stage. Furthermore, limited
evidence from controlled trials is available
to support the recommended use of rituxi­
mab for standard remission induction in the
localized and early systemic stages of AAV.
The authors of the recommendations
declare that no statement can be made on
the long-term outcomes for patients taking
rituximab, which certainly needs to be taken
into consideration by the treating physician.
The panel made no statement regarding the
finding that rituximab was neither su­perior in
terms of efficacy in newly diagnosed patients
nor associated with fewer adverse events
compared to cyclophosphamide. In fact, 6
of 124 patients (5%) treated with rituxi­mab
during the RAVE trial were diagnosed with
cancer versus 1 of 73 patients (1%; P = 0.26)
without exposure to this agent, a difference that might be coincidence, but which
requires attention during long-term followup. Moreover, data from cohort studies
put the toxicity of cyclophosphamide into
a different perspective: curtail­ment of the
remission induction period to 3–4 months
(if possible) and subse­quent early switching
to less toxic maintenance strate­gies, as well
as substitution of cyclophos­phamide with
methotrexate in the early systemic stage of
dis­e ase, led to consider­a ble reduction
of cumulative cyclophos­pha­mide doses and
­cyclophosphamide-induced adverse events.6
Thus it is clear that long-term results from
RCTs are needed to compare the toxici­ties of
cyclophosphamide and rituximab in patients
with AAV.
The committee recommend the use of
rituxi­mab in refractory and relapsing forms
of AAV, and when conventional therapy has
failed. This recommendation is given with
level of evidence 1b. Data from the RAVE
trial do support the recommendation of
rituxi­mab as a first choice option for remission induction in relapsing patients with
GPA or MPA. 3 How­e ver, with regard to
patients with refractory AAV, no evidence
from RCTs exists to show that rituximab is
efficacious; this use of rituximab should,
therefore, be labeled with a level of evidence
2b. The authors of the recommenda­tions
emphasize that rituxi­mab is an effective
treatment for refractory head and neck
manifestations of AAV, with the majority
of reports demonstrating res­ponse rates of
>80% in granulomatous mani­festations,
including orbital masses. How­e ver, data
from a cohort of patients with refractory
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NEWS & VIEWS
GPA treated with rituximab suggest that
this agent is more efficient in vasculi­t ic
mani­festations than in some granuloma­tous
manifestations—especial­ly orbital masses
and pachymeningitis.7
The treatment recommendations suggest
that resistance to rituximab should probably only be declared after the patient has
received at least two courses of this agent
and been followed for 6 months. However,
this advice is not in line with current assessment and treatment strategies,1,8 and evidence supporting this approach is sparse.
Moreover, waiting 6 months for a response
in a patient with a refractory disease manifestation might not always be feasible in
clinical practice.
Other guidelines presented by the British
experts suggest that use of rituximab should
be considered in children with AAV who
present with relapsing disease—in order to
avoid cyclophosphamide toxicity—or have
failed to respond to conventional induction therapy, as well as in patients with
CSS when conventional therapy has failed.
These recommenda­tions are based on case
series and uncontrolled studies (level of evidence 4). However, as the authors mention,
only 20 cases of rituximab use in CSS have
been reported. Furthermore, no guidance
is provided as to whether rituxi­mab should
be used in ANCA-positive CSS only or considered for ANCA-negative CSS as well.
As rituximab targets precursors of ANCAproducing plasma cells, it remains unclear
whether this agent would have any therapeutic effect in ANCA-negative CSS. Thus, more
evidence from controlled trials is needed
in order to support any use of rituximab
other than as a rescue treatment in pediatric
patients with AAV or patients with CSS.
The recommendations give guidance on
some practical points regarding the manage­
ment of AAV with rituximab. With respect
to dosing, the authors conclude that for
remission induction four doses of 375 mg/m2
at weekly intervals or two doses of 1 g given
2 weeks apart can be used (level of evidence 4). The 1 g fortnightly regimen has
only been assessed in patients with refractory
disease and not for standard remission induction, whereas the four doses of 375 mg/m2
weekly regimen has been used for standard remission induction in the RAVE and
RITUXVAS trials and in some uncontrolled
studies in refractory AAV. The committee
state in their report that relapse is common
after treatment with rituximab, and that
patients should be monitored accord­ingly
(level of evidence 4), which is a very important point. An urgent need exists to establish evidence for a maintenance regimen
after rituximab therapy. Further treatment
with rituxi­mab can be considered for patients
who relapse after rituximab-induced remission (level of evidence 4), or as a pre-emptive
treatment in order to reduce relapse rates
(level of evidence 4).
Uncertainty remains surrounding glucocorticoid tapering protocols and the use of
other immunosuppressive drugs, including
cyclophosphamide, in patients receiving
rituxi­mab; however, routine use of concomitant cyclophosphamide is not recom­mended
(level of evidence 4) other than in life­threatening situations or when organ damage
is possible. This statement requires validation
in controlled trials. The authors suggest that
high-dose glucocorticoids (such as methylprednisolone) can be given with the initial
course of rituximab—as in the protocol used
in the RAVE trial (level of evidence 4). Yet,
early mortality in AAV might be linked to the
administration of high-dose gluco­corticoids
and subsequent high rates of infection. 9
More­over, the termination of gluco­corticoid
treatment after 6 months in the RAVE trial3
might account for the low remission rates
reported in both treatment arms compared
with those described for other European
Vascu­litis Study Group trials.1 There­fore,
whether rituximab can safely and effectively induce remission without the need
for initial methyl­prednisolone pulses, and
whether it can achieve higher remission
rates in conjunction with a maintenance
regimen of low-dose glucocorticoids needs
to be established.
As stated previously by some experts,10 the
RAVE and RITUXVAS trials did not demonstrate the expected benefit of rituxi­mab over
cyclophosphamide in regard to their safety
profiles in patients with AAV. Although
no difference in the occurrence of serious
infections was found between the drugs in
either RAVE or in RITUXVAS, rituximabassociated serious adverse events such as
hypogammaglobulinemia, neutropenia and
progressive multifocal leuco­encephalopathy
(described in patients with SLE) are of
concern. Therefore, whether or not rituxi­
mab will become the new gold standard for
remission induction in AAV depends on its
long-term safety profile.
NATURE REVIEWS | RHEUMATOLOGY Vasculitis Center, Department of
Rheumatology, University Hospital SchleswigHolstein, Campus Lübeck and Klinikum
Bad Bramstedt, Oskar-Alexander-Straße 26,
24576 Bad Bramstedt, Germany (J. U. Holle,
W. L. Gross)
Correspondence to: J. U. Holle
j.holle@klinikumbb.de
Acknowledgments
We would like to thank Prof. Stefan Gadola, Professor
of Immunology/Consultant Rheumatologist,
Department of Infection, Inflammation and Immunity,
Faculty of Medicine and Health and Life Sciences,
School of Medicine, University of Southampton, for
his valuable contribution to this manuscript.
Competing interests
J. U. Holle and W. L. Gross declare associations with
the following company: Roche. See the article online
for full details of the relationships.
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Supplementary information
Supplementary information is linked to the online
version of the paper at www.nature.com/nrrheum
VOLUME 7 | OCTOBER 2011 | 567
© 2011 Macmillan Publishers Limited. All rights reserved