NDT Advance Access published July 3, 2012

Nephrol Dial Transplant (2012) 0: 16

doi: 10.1093/ndt/gfs285

Original Article

Beyond the LUNAR trial. Efcacy of rituximab in refractory lupus

nephritis
Marc Weidenbusch, Christoph Rmmele, Angelika Schrttle and Hans-Joachim Anders
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universitt Mnchen, Munich, Germany
Correspondence and offprint requests to: Hans-Joachim Anders; E-mail: hjanders@med.uni-muenchen.de

Equal contribution.

Keywords: systemic lupus erythematosus; glomerulonephritis; B-cell

ablation; proteinuria; anti-CD20; B-cells; lupus nephritis; MabThera;
remission; response; therapy

Introduction
Lupus nephritis (LN) often complicates systemic lupus erythematosus (SLE) determining morbidity and mortality
of SLE patients [1, 2]. The management of LN is 4-fold:
(i) identifying patients at risk of disease progression; (ii)

treating patients at risk with intensive immunosuppressive

therapy to control systemic as well as tissue inammation;
(iii) monitoring patients for remittent, persistent or aring
disease activity to tailor treatments to individual needs
and also (iv) avoiding treatment-associated side effects.
Patients at risk show urinary abnormalities and will
undergo a renal biopsy to allow for further investigation.
A sophisticated work-up by a renal pathologist of the
renal cells collected is required to categorize renal lesions
according to the current classication of LN [2]. When
left untreated, proliferative (class III/IV) and membranous
forms of LN (class V) often progress to renal failure and
thus treatment with intensive immunosuppression immediately upon diagnosis is administered. Very few treatments
have proven to be efcient in randomized controlled trials
(RCT). One of the rst RCT on LN documented that highdose steroids alone were not as effective as steroids plus
cyclophosphamide (CYC) to maintain long-term renal
function and are-free intervals [4]. Recently, mycophenolate mofetil (MMF) was proven to be as efcient as highdose CYC in controlling class III/IV/V LN in Caucasian
patients [5]. However, the use of both drugs is associated
with severe side effects including fatal infections. Therefore, it remains an unmet medical need in the eld of LN
to develop novel drugs that are efcient but less toxic than
current therapies. As the toxicities of CYC and MMF
largely relate to their unspecic immunosuppressive
activity, it is tempting to speculate that novel drugs that
more specically block any central disease pathomechanism of LN will meet this unmet medical need.
The underlying pathomechanism that links SLE to LN
is the same for all classes, i.e. immune complex disease
[6, 7]. In fact, in SLE, systemic inammation alone is
unable to elicit LN in the absence of mature B-cells,
lupus autoantibodies and renal immune complex deposition [8], even though mature B-cells appear to be more
important than the autoantibodies themselves [9, 10]. For
this reason, B-cell-directed therapies have raised great
hope to more specically target the immunopathology in
SLE when compared with steroids, CYC or MMF. The
lead compound in this area is rituximab (RTX), a

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Abstract
Background. The treatment of lupus nephritis (LN)
remains problematic because the current treatment regimen
based on unspecic immunosuppressants such as steroids,
cyclophosphamide and mycophenolate has signicant side
effects and is often inefcient. B-cell ablation with the
chimeric anti-CD20 antibody rituximab (RTX) has been
considered as an alternative treatment option but the randomized controlled LUNAR trial failed to show any
additive effect of RTX beyond a steroidmycophenolate
mofetil (MMF) combination for LN type III/IV/V in incident patients. At present, no such trial is available for the
use of RTX in refractory LN.
Methods. We analysed existing evidence on this topic by
performing a systematic analysis of reports that document
outcomes of RTX treatment for refractory LN.
Results. Out of 233 reports, we selected 26 for analysis,
which described 300 patients with a mean follow-up of 60
weeks. The complete or partial response criteria were met
by 87% of patients with LN class III, 76% with class IV
and 67% with class V, respectively. Mixed classes responded in 76% of patients. RTX induced complete
responses in 60% (type III), 45% (type IV), 40% (type V)
and 24% (mixed types), respectively.
Conclusions. Our systematic review of existing evidence
suggests that RTX effectively induces remission of LN in
patients who have not achieved remission with standard
therapies. Another randomized controlled trial should be
conducted to test the efcacy of RTX in refractory LN.

Materials and methods

We searched the PubMed database for studies and case reports including
adult patients (>18 years old) with LN who were treated with anti-CD20/
RTX (MabThera). Our search for the terms lupus and rituximab
(using a lter to select only studies in humans) in the MEDLINE
indexed international journals between August 2001 and July 2011 resulted in 412 articles (Figure 1). We also searched the ISI Web of
Knowledge database for non-indexed publications (using the same
search terms) and thoroughly checked citations of included articles for
additional data. In total, title/abstract information suggested clinical data
on the use of RTX in SLE patients in 233 articles which, with minor

Fig. 1. Selection of identied studies for analysis in this systematic review.

limitations due to language and access barriers, we then studied in more

detail. Clinical data were found in 70 articles. After evaluation of the full
text, 44 articles were excluded because they either described paediatric
patients, included non-relevant data or included information about
patients who were already described in other publications (Figure 1). In
the case of multiple published data, we chose the most recent paper.
Finally, the remaining 26 articles were selected for systematic analysis as
listed in Table 1 [1239]. Reported data were screened for the following
criteria: (i) established diagnosis of SLE in accordance with the American College of Rheumatologys revised criteria (ACR), (ii) the presence
of active LN documented by renal biopsy and persistent clinical ndings
such as elevated serum creatinine or proteinuria and active urine sediment, despite (iii) previous therapy with one or more immunosuppressive
agents. Unless otherwise indicated, responses were dened following the
consensus of the American College of Rheumatology and the European
League against Rheumatism [40, 41]. In brief, a complete patient
response is dened as (i) the absence of all initial disease-related symptoms, (ii) the absence of an active sediment, (iii) proteinuria <0.5 g/g
creatinine and (iv) return to normal or baseline serum creatinine. A
partial patient response includes the absence of an active sediment,
stable kidney function and a reduction of proteinuria by 75% or <1 g/g
creatinine.

Results
Type of reports on RTX in refractory LN
Among the 26 studies retrieved, 9 were prospective
clinical trials, albeit non-randomized or blinded (Table 1).
Another 9 were retrospective analyses studies, 4 case
series and 4 single case reports. Together, at present treatment efcacy of RTX in LN is only reported by observational cohort studies and case reports. RCT on this topic
are not currently available.
Patient characteristics
A total of 300 patients with a mean age of 35.1 years
were reported in the 26 studies (Table 2). Eighty-seven
percent of the patients were female. Ethnicity data were
reported for 138 of the patients of which 59 (43%) were
Caucasians, 31 (22%) were Afro-Caribbeans, 28 (20%)

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chimeric anti-CD20 antibody that efciently and reliably

depletes CD20-positive B-cells [11]. RTX was approved
in 1997 for the treatment of various forms of B-cell lymphoma and later also for the treatment of rheumatoid arthritis [12]. In addition, its excellent toxicity prole
renders RTX an attractive candidate drug for improving
the treatment of LN.
During the last decade, an increasing number of case
reports and small case series have reported RTX treatment
outcomes in LN patients which have led to a, so far,
single RCT that compared high-dose steroids plus MMF
with high-dose steroids plus MMF plus RTX [13]. Addon RTX treatment did not signicantly increase the
response rates which were selected as the primary end
point, even though RTX doubled partial responses in
black patients. There is an ongoing debate about the
interpretation of these results which relates to dosing of
the drugs, to the selection of end point parameters, and to
patient selection. Furthermore, the intense background immunosuppressive regimen with repetitive infusion of 1 g
methylprednisolone and high-dose oral MMF left little
chance for RTX to prove additional benets. In addition,
it is a fact that the LUNAR trial included only incident
LN patients, whereas most previous uncontrolled studies
describe different patient cohorts. Here, we systematically
reviewed reports about RTX treatment outcomes from
patients with refractory LN only.

M. Weidenbusch et al.

Rituximab in lupus nephritis

Table 1. Reports on RTX use in refractory LN selected for analysis

Type of
study

Prospective
Prospective
Prospective
Prospective
Prospective
Prospective
Prospective

11
10
16
13
18
10
22

39
26
38
38
37
29
29

11
8
11
11
7
6
6

1:10
0:10
0:16
1:12
3:15
1:9
3:19

Prospective

13

36

2:11

RTX treatment regimen

Prospective

29

2:5

Retrospective 31
Retrospective 43
Retrospective 20
Retrospective 113
Retrospective
3

40
31
24
39
28

8
5
3
9
10

3:28
3:40
1:19
25:111
2:1

Retrospective 31
Retrospective 10
Retrospective
5
Retrospective 107

33
28
40
36

10
6
10
n.a.

1:30
4:6
0:5
13:94

The use of RTX differs among the different reports and

various dosing regimen have been also applied for the
treatment of LN. In the reports selected for this systematic
review, a dose of 4 375 mg/m2 was commonly used
(49%) followed by 2 1000 mg per 2 weeks in 37% of
patients (Table 5). RTX was not uniformly given as an
alternative or add-on therapy. Thirty percent of cases received cyclophosphamide along with RTX, 25% received
mycophenolate mofetil, 7% received azathioprine and 4%
received methotrexate.

Case series
Case series

3
3

20
41

9
13

0:3
2:1

Case series
Case series
Case report
Case report

3
3
1
1

31
28
20
43

10
11
4
n.a.

0:3
1:2
0:1
0:1

Case report

31

10

0:1

Case report

42

0:1

Complete and partial responses of refractory LN to RTX

therapy
After a mean follow-up of 60 weeks (range 12120
weeks), RTX had induced a complete response in 40% of
cases (Figure 2A) and a partial response in 34%. Twentysix percent of cases showed no response at all. In total,
RTX induced some response ( partial or complete) in 74%
of patients with refractory LN.
Table 3. Previous immunosuppressive therapies
Absolute No.

Percentage

289
175
139
138
87
57
23
1

96%
60%
47%
47%
30%
19%
8%
0,3%

Table 2. Classes of LN according to the ISN/RPA classication [3]

Class I or II
Class III
Class IV
Class V
Mixed type
Not classied

Absolute No.

Percentage

3
40
118
25
25
91

1%
13%
39%
8%
8%
30%

were Asians and 18 (13%) were Hispanics. While LN

was present in all patients by denition, extrarenal lupus
manifestations were reported only in 110 patients as listed
in Table 2. The most frequent extrarenal manifestations
affected the skin (88%), musculoskeletal (82%) and haematological system (81%). Neuropsychiatric lupus was
present in 13% of patients. The histopathological classes
of LN included 1% of the International Society of
nephrology/Renal Pathology Association (ISN/RPA) classes
I/II, 13% class III, 39% class IV, 8% class V and 8% with
mixed classes III/V or IV/V. In 30% of cases, the class of
the LN was not classied. Data on previous treatments were

Data availablea
Cyclophosphamide
MMF
Azathioprine
Hydroxychloroquine
Methotrexate
Cyclosporine A
Tacrolimus
a
Remaining patients had
immunosuppressive drugs.

on

average

two

other

previous

Table 4. Denition of refractory disease

Active disease under steroids +

1 Immunosuppressant
1, On average two immunosuppressants
2 Immunosuppressants
3 Immunosuppressants
Data not available

Absolute No.

Percentage

300
96
51
52
11
90

32%
17%
17%
4%
30%

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Albert et al. [14]

Boletis et al. [17]
Jnsdttir et al. [24]
Li et al. [26]
Pepper et al. [31]
Skakis et al. [35]
Vigna-perez et al.
[39]
Garcia-Carrasco
et al. [22]
Arce-Salinas et al.
[15]
Catapano et al. [19]
Galarza et al. [21]
Melander et al. [29]
Terrier et al. [37]
Gottenberg et al.
[23]
Lu et al. [27]
Lateef et al. [25]
Reynolds et al. [33]
Ramos-Casals et al.
[32]
Camous et al. [18]
Roccatello et al.
[34]
Moroni et al. [30]
Chehab et al. [20]
Tahir et al. [36]
van den Bergh et al.
[38]
Mardjuadi et al.
[28]
Bacconnier et al.
[16]

No. of Mean Mean

m:f
patients age
duration ratio
of
disease
(months)

available for 289 patients (Table 3). Sixty percent had been
pretreated with cyclophosphamide, and 47% with MMF.
Another 47% were treated with azathioprine, and 30% with
hydroxychloroquine prior to RTX treatment. Methotrexate
was used in 19% of the patients, and cyclosporine A and
tacrolimus in 8% and 0.3%, respectively. The denition of
refractory disease varied among the reports and included
the use of 1 to 3 immunosuppressant drugs in addition to
corticosteroids before RTX was considered (Table 4). Thus,
the reports represent a global patient cohort typical of
severe SLE with mostly proliferative forms of LN that had
been pretreated with multiple immunosuppressive drugs.

M. Weidenbusch et al.

Table 5. RTX dosing

Dose/interval
4 375 mg/m2 per week
2 750 mg/m2 per 2 weeks
2 500 mg per 2 weeks
3 500 mg per 2 weeks
4 500 mg per 2 weeks
2 1000 mg per 2 weeks
Other regimen

Classes of LN and RTX efcacy

Absolute No.

Percentage

297
150
5
3
1
1
113
24

100%
49%
2%
1%
0%
0%
37%
8%

The histopathological class of LN is a predictor of renal

survival; hence, we examined the treatment efcacy of
RTX in the different ISN/RPA classes of LN in those
reports containing relevant data (Figure 2B). Complete
responses were most frequent in type III (60%) and less
frequent in type IV (45%) or type V (40%). Mixed types
showed a complete response in only 24% of the reports.
Any response (complete or partial) was also most frequent
in type III (87%) and 76% (type IV), 67% (type V) and

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Fig. 2. Response rates upon RTX treatment. (A) The diagram illustrates the percentages of complete, partial or non-responders upon treatment with
RTX in a mean follow-up period of 60 weeks. (B) The same type of graph illustrates the respective percentages for each of the types of LN as
indicated.

Rituximab in lupus nephritis

74% (mixed type), respectively. As such, patients with

type V membranous LN had the lowest responder rates
with 1 out of 3 patients who did not respond at all to
RTX within the mean follow-up period of 60 weeks.

Discussion

not all reports adhere to the current denitions of partial

and complete responses or report outcomes after different
treatment periods. The rates of remission of LN, although
commonly conned to a 6-month period after starting a
cytotoxic agent, continue to increase over the rst 1 to 2
years. Therefore, patients who improve with RTX after
not having achieved a partial or complete response at 6
months may actually simply reect the delay in achieving
responses from the initial therapy and not really represent
an RTX effect. These drawbacks on data quality must be
taken into account. Other RCTs are clearly necessary to
prospectively test the efcacy of RTX in refractory LN or
even in incident LN as an alternative rather than an addon drug. RTX may be likely to show similar outcomes
with less side effects. This strategic approach led to US
Food and Drug Administration and European Medicines
Agency approval of RTX for the treatment of rheumatoid
arthritis at times where tumor necrosis factor blockers
were already available. But until proven otherwise,
current evidence currently supports the off-label use of
RTX to induce remission of refractory LN.
Acknowledgements. M.W., C.R. and H.J.A. were supported by the
Deutsche Forschungsgemeinschaft Graduate College 1202.

References
1. Manger K, Manger B, Repp R et al. Denition of risk factors for
death, end stage renal disease, and thromboembolic events in a
monocentric cohort of 338 patients with systemic lupus erythematosus. Ann Rheum Dis 2002; 61: 10651070.
2. Croca SC, Rodrigues T, Isenberg DA. Assessment of a lupus nephritis cohort over a 30-year period. Rheumatology (Oxford) 2011; 50:
14241430.
3. Weening JJ, Dagati VD, Schwartz MM et al. The classication of
glomerulonephritis in systemic lupus erythematosus revisited. J Am
Soc Nephrol 2004; 15: 241250.
4. Austin HA, 3rd, Klippel JH, Balow JE et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J
Med 1986; 314: 614619.
5. Appel GB, Contreras G, Dooley MA et al. Mycophenolate mofetil
versus cyclophosphamide for induction treatment of lupus nephritis.
J Am Soc Nephrol 2009; 20: 11031112.
6. Couser WG. Basic and translational concepts of immune-mediated
glomerular diseases. J Am Soc Nephrol 2012; 23: 381399.
7. Migliorini A, Anders HJ. A novel pathogenetic concept-antiviral immunity in lupus nephritis. Nat Rev Nephrol 2012; 8: 183189.
8. Lech M, Weidenbusch M, Kulkarni OP et al. IRF4 deciency abrogates lupus nephritis despite enhancing systemic cytokine production. J Am Soc Nephrol 2011; 22: 14431452.
9. Jacob N, Stohl W. Autoantibody-dependent and autoantibody-independent roles for B cells in systemic lupus erythematosus: past,
present, and future. Autoimmunity 2010; 43: 8497.
10. Chan OT, Hannum LG, Haberman AM et al. A novel mouse with B
cells but lacking serum antibody reveals an antibody-independent
role for B cells in murine lupus. J Exp Med 1999; 189: 16391648.
11. Leandro MJ, Edwards JC, Cambridge G et al. An open study of B
lymphocyte depletion in systemic lupus erythematosus. Arthritis
Rheum 2002; 46: 26732677.
12. Edwards JC, Szczepanski L, Szechinski J et al. Efcacy of B-celltargeted therapy with rituximab in patients with rheumatoid arthritis.
N Engl J Med 2004; 350: 25722581.
13. Rovin BH, Furie R, Latinis K et al. Efcacy and safety of rituximab
in patients with active proliferative lupus nephritis: the lupus

Downloaded from http://ndt.oxfordjournals.org/ by guest on January 21, 2015

The LUNAR trial failed to demonstrate any signicant

therapeutic effect of RTX as an add-on therapy on top of
steroids and MMF in incident LN patients [13]. As such,
the add-on-RTX-on-top-of-standard care concept which
had been proven effective in B-cell lymphoma is no
longer considered for incident LN. However, the intense
background immunosuppressive regimen with repetitive
infusion of 1 g methylprednisolone and high-dose oral
MMF left little chance for RTX to prove additional
benets. Furthermore, the subgroup analysis of the
LUNAR trial revealed that black patients with particularly
poor prognosis had higher partial response rates with addon RTX [13]. These data indicate that RTX may be effective in patients who are not sufciently controlled by standard treatments, an aspect that was not addressed by the
study protocol of the LUNAR trial or by any other RCT.
In fact, the LN community had instead considered RTX
as an alternative than as an add-on drug on top-of-standard care which is documented by the fact that most
reports on off-label RTX use in LN describe patients who
had not achieved remission with standard treatments. This
could represent an explanation for the apparent discrepancy of the data from LUNAR and other reports. So the
question remains as to whether RTX is still a valuable
therapeutic option for patients who cannot be controlled
by either high-dose steroids and CYC or high-dose
steroids and MMF. Our systematic review on this particular question revealed that RTX is effective in inducing
partial and, to a lesser extent, also complete remission of
LN in these patients. The response rates of 87% in refractory LN type III, 76% in type IV and at least 67% in type
V are comparable with what can be achieved with highdose cyclophosphamide in incident patients [4].
Of course, this kind of meta-analysis is sensitive to a
publication bias which favours reports on positive outcomes of RTX-treated patients. Thus, the real-life efcacy
of RTX in refractory LN may be lower than our ndings
would suggest. There is also a considerable heterogeneity
in co-medication, steroid use and the history of immunosuppressive drugs used in the patients reported here and
the data quality does not allow to dissect this carefully.
This, however, seems to represent the real life of lupus
care, i.e. it may not really be a drawback to the interpretation of our ndings. Also, RTX dosing and treatment intervals were heterogenous even though to date there have
been no reports that provide clear evidence that one
regime is more effective than others for B-cell depletion
and response rates in LN. There is a general concern that
nephrotic syndrome could affect the pharmacokinetics of
RTX as the antibody may be more rapidly excreted along
with albuminuria and other immunoglobulins. This could
account for the lower response rates in class V LN and
may argue for the use of more frequent dosing. Finally,

14.

15.

16.

17.

18.

19.

20.

22.

23.

24.

25.

26.

27.

28.

nephritis assessment with rituximab (LUNAR) study. Arthritis

Rheum 2012; 64: 12151226.
Albert D, Dunham J, Khan S et al. Variability in the biological
response to anti-CD20 B cell depletion in systemic lupus erythaematosus. Ann Rheum Dis 2008; 67: 17241731.
Arce-Salinas CA, Rodriguez-Garcia F, Gomez-Vargas JI. Long-term
efcacy of anti-CD20 antibodies in refractory lupus nephritis. Rheumatol Int 2011; 32: 12451249.
Bacconnier L, Combe B, Canaud B et al. Efcacy of rituximab in a
patient with lupus nephritis despite low levels of CD19. Rheumatology (Oxford) 2010; 49: 24522453.
Boletis JN, Marinaki S, Skalioti C et al. Rituximab and mycophenolate mofetil for relapsing proliferative lupus nephritis: a long-term
prospective study. Nephrol Dial Transplant 2009; 24: 21572160.
Camous L, Melander C, Vallet M et al. Complete remission of
lupus nephritis with rituximab and steroids for induction and rituximab alone for maintenance therapy. Am J Kidney Dis 2008;
52: 346352.
Catapano F, Chaudhry AN, Jones RB et al. Long-term efcacy and
safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol Dial Transplant 2010; 25: 35863592.
Chehab G, Sander O, Fischer-Betz R et al. Anti-CD20 therapy for
inducing and maintaining remission in refractory systemic lupus
erythematosus. Z Rheumatol 2007; 66: 330336.
Galarza C, Valencia D, Tobon GJ et al. Should rituximab be
considered as the rst-choice treatment for severe autoimmune rheumatic diseases? Clin Rev Allergy Immunol 2008; 34: 124128.
Garcia-Carrasco M, Mendoza-Pinto C, Sandoval-Cruz M et al. AntiCD20 therapy in patients with refractory systemic lupus erythematosus: a
longitudinal analysis of 52 Hispanic patients. Lupus 2010; 19: 213219.
Gottenberg JE, Guillevin L, Lambotte O et al. Tolerance and short
term efcacy of rituximab in 43 patients with systemic autoimmune
diseases. Ann Rheum Dis 2005; 64: 913920.
Jonsdottir T, Gunnarsson I, Risselada A et al. Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects,
serological changes, and predictors of response. Ann Rheum Dis
2008; 67: 330334.
Lateef A, Lahiri M, Teng GG et al. Use of rituximab in the treatment of refractory systemic lupus erythematosus: Singapore experience. Lupus 2010; 19: 765770.
Li EK, Tam LS, Zhu TY et al. Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus
nephritis? Rheumatology (Oxford) 2009; 48: 892898.
Lu TY, Ng KP, Cambridge G et al. A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at university college London hospital: the rst fty patients.
Arthritis Rheum 2009; 61: 482487.
Mardjuadi A, Soedirman M, Utoyo B et al. Prompt remission of
severe SLE with only three doses of rituximab infusion and low
dose steroid: the rst case report from Indonesia. Clin Rheumatol
2009; 28(Suppl 1): S27S30.

29. Melander C, Sallee M, Trolliet P et al. Rituximab in severe lupus

nephritis: early B-cell depletion affects long-term renal outcome.
Clin J Am Soc Nephrol 2009; 4: 579587.
30. Moroni G, Gallelli B, Ban G et al. Rituximab monotherapy for
remission induction of proliferative lupus nephritis ares: description of 3 cases. J Nephrol 2010; 23: 357361.
31. Pepper R, Grifth M, Kirwan C et al. Rituximab is an effective
treatment for lupus nephritis and allows a reduction in maintenance
steroids. Nephrol Dial Transplant 2009; 24: 37173723.
32. Ramos-Casals M, Garcia-Hernandez FJ, De Ramon E et al.
Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases. Clin Exp Rheumatol 2010; 28: 468476.
33. Reynolds JA, Toescu V, Yee CS et al. Effects of rituximab on resistant SLE disease including lung involvement. Lupus 2009; 18:
6773.
34. Roccatello D, Sciascia S, Rossi D et al. Intensive short-term treatment with rituximab, cyclophosphamide and methylprednisolone
pulses induces remission in severe cases of SLE with nephritis and
avoids further immunosuppressive maintenance therapy. Nephrol
Dial Transplant 2011; 26: 39873992.
35. Skakis PP, Boletis JN, Lionaki S et al. Remission of proliferative
lupus nephritis following B cell depletion therapy is preceded by
down-regulation of the T cell costimulatory molecule CD40 ligand:
an open-label trial. Arthritis Rheum 2005; 52: 501513.
36. Tahir H, Rohrer J, Bhatia A et al. Humanized anti-CD20 monoclonal antibody in the treatment of severe resistant systemic lupus
erythematosus in a patient with antibodies against rituximab. Rheumatology (Oxford) 2005; 44: 561562.
37. Terrier B, Amoura Z, Ravaud P et al. Safety and efcacy of rituximab in systemic lupus erythematosus: results from 136 patients from
the French Autoimmunity and rituximab registry. Arthritis Rheum
2010; 62: 24582466.
38. Van Den Bergh B, Selleslag D, Boelaert JR et al. Management of
therapy-resistant systemic lupus erythematosus with rituximab:
report of a case and review of the literature. Acta Clin Belg 2005;
60: 102105.
39. Vigna-Perez M, Hernandez-Castro B, Paredes-Saharopulos O et al.
Clinical and immunological effects of Rituximab in patients with
lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther 2006; 8: R83.
40. Renal Disease Subcommittee of the American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus
Response Criteria. The American College of Rheumatology
response criteria for proliferative and membranous renal disease in
systemic lupus erythematosus clinical trials. Arthritis Rheum 2006;
54: 421432.
41. Gordon C, Jayne D, Pusey C et al. European consensus statement
on the terminology used in the management of lupus glomerulonephritis. Lupus 2009; 18: 257263.
Received for publication: 29.2.12; Accepted in revised form: 19.4.12

Downloaded from http://ndt.oxfordjournals.org/ by guest on January 21, 2015

21.

M. Weidenbusch et al.