Rheumatology 2015;54:1876–1881
doi:10.1093/rheumatology/kev036
Advance Access publication 3 June 2015
RHEUMATOLOGY
Original article
Longer duration of B cell depletion is associated
with better outcome
Sofia Sapeta Dias1, Veronica Rodriguez-Garcia2, Hanh Nguyen3,
Charis Pericleous3 and David Isenberg3
Abstract
Objective. To report on the long-term follow-up, clinically and serologically, of 98 patients with SLE
treated with B cell depletion (BCD) over a 12 year period, focusing on the duration of the depletion.
Methods. A retrospective review of clinical and serological features of all SLE patients treated with BCD
from January 2000 until December 2012 in the Centre for Rheumatology, University College London
Hospital. Clinical activity was assessed by the classic BILAG score at baseline and 6 and 12 months
after the treatment.
Results. The period of depletion is extremely variable between patients and within the same patient on
different occasions. The patients were divided into two groups according to the duration of depletion and
a defined threshold of 12 months was utilized. The group with longer duration of depletion was associated
with a better outcome, with a decrease in BILAG score at 6 and 12 months. This group was also
associated with lymphopenia present at any time during the course of the patient’s disease. No other
clinical or serological feature was associated with longer duration of BCD.
Conclusion. Cycles of BCD that induce longer duration of BCD are associated with better outcome.
Lymphopenia may help to predict longer duration of the depletion and better outcome, although the
mechanism is unclear.
CLINICAL
SCIENCE
Key words: B cells, SLE, remission, dsDNA antibodies, outcome.
Rheumatology key messages
.
.
.
We report the largest single-centre experience of treating SLE patients with B cell depletion.
The longer the duration of the B cell depletion, the better the outcome overall in SLE.
Considerable variation in the response of individual SLE patients to B cell depletion is evident.
Introduction
SLE is an autoimmune rheumatic disease with a highly
heterogeneous course and response to therapy. The outcome for SLE patients has improved in the past 50 years,
mostly due to optimization of the use of immunosuppressive drugs, the introduction of dialysis and transplantation
and better control of co-morbidities. However, premature
1
Internal Medicine Department 1, Hospital de Santa Maria, Lisbon,
Portugal, 2Rheumatology Department, Hospital Regional Universitario
Carlos Haya, Malaga, Spain and 3Centre for Rheumatology,
Department of Medicine, University College London, London, UK
Submitted 15 September 2014; revised version accepted
18 February 2015
Correspondence to: David Isenberg, Division of Medicine, Room 424,
Rayne Building, 5 University Street, London WC1E 6JF, UK.
E-mail: [email protected]
death and progression to end-stage renal disease still
occur [1]. The toxicity of many standard therapies remains
of great concern.
Advances in the understanding of the pathogenesis of
SLE have allowed the use of better targeted therapies. B
cell targeted therapy is clearly rational since the immunological hallmark in SLE is autoantibody formation with
pathogenic potential; furthermore, B cells have important
antibody-independent functions, namely antigen presentation and T cell activation through pro-inflammatory cytokines. B cell depletion (BCD) therapies eliminate
pathogenic peripheral B cells and promote the expansion
of naive B cells [2].
Rituximab (RTX) is a chimeric murine/human monoclonal immunoglobulin directed against CD20 on the B cell
surface. CD20 is present from the pre-B cell stage in the
bone marrow until peripheral mature B cells. It can trigger
! The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Longer duration of BCD is associated with better outcome
apoptosis through a variety of complement- and antibodydependent mechanisms. It does not deplete bone marrow
B cell precursors or plasma cells because they do not
express CD20.
Several open-label trials have reported good results of
RTX in patients with SLE [3, 4], though randomized controlled trials have failed to meet their end points [5, 6],
probably due to the design of these trials, notably the
tendency to use large doses of steroids and immunosuppressive drugs in the standard of care arm. More encouragingly, Cordon et al. [7] recently reported the use of RTX
as initial therapy for patients with biopsy-proven LN. They
demonstrated that only 2 of 50 patients given RTX and
low-dose MMF needed oral steroids in a 2 year followup study. We have demonstrated a similar benefit in
non-renal lupus at the time of diagnosis [8].
However, the response to BCD is extremely variable
between patients in degree and duration [9, 10]. Some
of the proposed explanations or mechanisms for the heterogeneity are differences in serum RTX levels (which may
be lower in patients with SLE compared with those with
RA, although Reddy et al. [11] could not find a connection
between serum levels of RTX and the level of BCD); the
presence of intrinsically resistant B cells (thus Anolik et al.
[12] reported that SLE patients with circulating CD38high B
cells were more likely to have incomplete BCD, suggesting that these cells may be less susceptible to RTX);
human anti-chimeric antibody formation [10]; FcgRIIIa
polymorphisms (though opposite results have been published) [9, 10]; and the level of B cell activating factor
(BAFF), which is associated with disease relapse (after
RTX) [13] and is very heterogeneous in SLE patients [14].
Importantly, the connection between the degree and
duration of BCD and clinical response has been established and complete BCD has been associated with
better outcome [10, 15]. At the same time, attempts
have been made to predict the response to BCD using
serological features, and variable results have been published [13, 15, 16]. We report here a detailed analysis of
the long-term follow-up of 98 patients with SLE under our
care who have been treated in the past 12 years with
BCD, focusing in particular on whether the duration of
the depletion is associated with better outcome.
Patients and methods
Patients
Clinical notes and laboratory results of all SLE patients
treated with BCD therapy from January 2000 until
December 2012 in the Centre for Rheumatology,
University College London Hospital, were reviewed retrospectively. We collected data noting clinical and serological features, the repopulation date and classic BILAG
scores [17] at baseline and 6 and 12 months after the
treatment. As this study is an audit, it did not require hospital ethics committee approval.
The follow-up period was between the administration of
BCD and December 2013. The patients were >18 years
old and fulfilled four or more of the ACR 1997 revised
www.rheumatology.oxfordjournals.org
classification criteria [18]. In total, 195 cycles of BCD
were administered to 103 different patients from June
2000 to December 2012. Five cycles were excluded because of incomplete availability of clinical and serological
data and 10 cycles were excluded because of incomplete
depletion; the remaining 180 cycles in 98 different patients
were analysed.
Unit of analysis
The unit of analysis used in this study is the cycle of BCD.
Therapy
The protocol used after 2004 was two infusions of 1 g of
RTX 2 weeks apart, along with CYC 750 mg during the first
infusion and methylprednisolone 250 mg on both occasions. Prior to this date, most patients were given a
second dose of CYC following the second infusion of
RTX. Some infusions corresponded to other BCD therapy
different from RTX. Background immunosuppressive therapy was reduced (usually stopped) after BCD, and was
restarted only if the B cells returned and there were signs
of a clinical flare.
Clinical features
Clinical features were collected from the BILAG system
and divided into those assessed as A/B/C/D (present) or
E (never present) at any time during the course of the patient’s disease.
Outcome
The classic BILAG score was calculated at every visit. In
this study, BILAG scores at baseline, 6 and 12 months
were collected. An A score implies active severe disease
generally requiring 520 mg/day prednisolone and/or an
immunosuppressive drug; a B score implies active moderate disease often requiring steroids at a dose of
<20 mg/day; a C score implies mild activity; a D score
indicates no current activity in an organ/system that was
once active; and an E score is used when an organ/
system was never involved. The numerical BILAG score
was calculated as followed: A = 12, B = 5, C = 1, D = 0,
E = 0. Improvement was defined by a decrease in BILAG
numerical score.
Laboratory tests
B cells were counted as CD19+ cells measured by routine
laboratory tests. BCD was considered when CD19 counts
were below the normal absolute range, i.e.
0.03–0.40 109/l until 2010 and 0.69–0.11 109/l after
2010. Repopulation was defined as CD19+ counts persistently above the normal range (some patients had a period
of fluctuation of CD19 count around the normal range
before the actual repopulation; this was not considered
repopulation). Data concerning serological features of
the patients were also collected, such as ANA (by immunofluorescence), anti-dsDNA (by routine ELISA), antiSm, anti-RNP, anti-Ro, anti-La (all by ELISA) and low C3
(by routine laser nephelometry).
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Sofia Sapeta Dias et al.
Data were analysed using SPSS Statistics Data Editor
Software version 20 (IBM, Armonk, NY, USA). After the
creation of two groups based on the time to repopulate
(as further developed below), the clinical features of these
groups were compared using the chi-squared test and
logistic regression. Numerical BILAG scores for the two
study groups were compared using Student t and
Mann–Whitney tests. The significance level was set at
P < 0.05.
Results
Patients
A total of 180 courses of BCD in 98 patients between June
2000 and December 2012 were analysed. Forty-five patients had just one treatment. Fifty-three patients had
more than one treatment, up to a maximum of six (Fig. 1).
Assessing each cycle as a unit, 168 cycles (93.3%)
were administered to women, 66 (36.7%) were administered to Caucasians, 53 (29.4%) to African Caribbeans, 45
(25%) to South Asians (those from India, Pakistan or
Bangladesh), 10 (5.6%) to Chinese and 6 (3.3%) to other
ethnicities. The patients were followed until December
2013, giving at least 1 year for every cycle. The mean
follow-up of these patients after BCD was 5.05 years
(S.D. 3.12).
Adverse events
Nine patients died during long-term follow-up and three
had serious infections necessitating hospital admission.
Allergic reactions occurred in nine of the cycles.
Repopulation
For 83 of 180 BCD infusions analysed there was an accurate repopulation date. The average number of days to
repopulation was 436.84 (S.D. 422). The time to repopulate
was extremely variable, varying from a minimum of 62
days to a maximum of 2294 days, and 11 patients were
depleted for >2 years. Considering only the patients with
a repopulation date, 30.1% repopulated between 6 and 9
months and 33.7% repopulated after 12 months (Fig. 2).
Based on the results shown in Fig. 2, two groups of
cycles of BCD were distinguished based on the time to
repopulate at a defined threshold of 12 months. Group 1
consisted of patients who repopulated in <12 months and
group 2 included those who repopulated after 12 months.
Among the infusions for which there was no accurate
repopulation date (97 infusions), in 64 the patients were
depleted for >1 year, allowing the inclusion of these infusions also in group 2. These 64 infusions did not have a
repopulation date for the following reasons: for 21, the
patients had a new infusion of BCD while they were still
depleted, although >12 months after the previous infusion; for 43, the patients were still depleted at the last
count during regular follow-up. In our cohort there was a
patient who remained depleted >12 years after being
given RTX.
The remaining 33 infusions, for which we do not have an
accurate repopulation date, could not be included because the time of surveillance of CD19 counts after the
BCD was <12 months for the following reasons: for 16,
the patients received the next BCD treatment while they
were still depleted and <12 months after the initial infusion; 2 patients were lost to follow-up in <12 months; and
4 patients died within 12 months of their first infusion.
Fig. 3 shows the distribution of cycles by the two
groups: 37.4% (group 1; n = 55) repopulated in <12
months and 62.6% (group 2; n = 92) were depleted for at
least 12 months.
Approximately half of the patients (29 of 54 who had
more than one cycle of BCD with reasonable follow-up)
had a similar pattern of repopulation in different cycles.
For example, in our cohort there is a patient who received
four cycles of RTX and repopulated in all of them in <230
days. In 25 patients the pattern of repopulation was different in each cycle. For example, one patient received
FIG. 2 Patients by time to repopulation
30
28
25
Patients
Statistical analyses
20
18
10
10
2
0
< 3 months
3 − 6 months
6 − 9 months
9 − 12 months
> 12 months
Time to repopulation after BCD
FIG. 3 Groups of infusions based on time to repopulation
FIG. 1 Number of patients per number of cycles
50
45
Patients
40
Repopulated in
less than 1 year
37%
35
30
20
8
10
7
0
1
2
3
4
1
1
5
6
Depleted for
at least 1 year
63%
Cycles
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Longer duration of BCD is associated with better outcome
two infusions of RTX, following the first of which she repopulated in 250 days, but after the second she has not
repopulated after >6 years. Table 1 shows the proportion
of patients who repopulated and the time to repopulation
according to the cycle number. There is no significant difference between the cycles.
lymphopenia (P = 0.0001) and a longer time to repopulate
was also present. A weak inverse association with leucopenia was found (P = 0.046), and the association
with thrombocytopenia was not confirmed in logistic
regression.
Serological features
Clinical features
Bivariate (chi-squared test) and multivariate analysis (logistic regression) were performed to compare clinical features between the two study groups at any time in the
course of their disease. The chi-squared test was performed for each clinical feature and the positive results
are shown in Table 2.
Logistic regression was then performed to look for the
weight of each of these related variables controlling for the
presence of the others. We performed separate logistic
regressions, each corresponding to one of the following
groups of clinical features: ethnicity, skin manifestations
and haematological manifestations. We also performed
one regression with all clinical features [joint, serosis,
kidney, CNS, Sjögren, skin and haematological (with the
last two variables aggregating multiple clinical features)].
The results of the regression (Table 3) reinforce the association between alopecia and a shorter time to repopulate (P = 0.019), suggesting that patients with alopecia
may have shorter periods of depletion after BCD. No
other association with other skin manifestations was
found. Furthermore, a strong association between
TABLE 1 Numbers of patients and variability of time taken
(in days) to repopulate after each cycle of B cell
depletion
Cycle
number
Number of patients
repopulated (total)
1
2
3
4
5
6
44 (93)
24 (54)
8 (19)
6 (10)
1 (3)
0 (1)
Days to repopulation,
median (interquartile
range)
316.00
253.50
216.00
357.50
240.00
(491.00–218.50)
(386.00–194.25)
(397.75–164.00)
(724.75–262.75)
TABLE 2 Positive results of the chi-squared test comparing clinical features of the two study groups
Clinical feature
Chi-squared
P-value
n
Alopecia
Lymphopenia
Thrombocytopenia
Any haematological
manifestation
aPL
7.233
11.199
4.825
3.856
0.007
0.001
0.028
0.05
147
147
147
147
4.077
0.043
146
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No further association was found between serological
features such as the presence of anti-dsDNA or anti-Sm
antibodies or low complement (Table 4) by either the chisquared test or by logistic regression.
Outcome
The BILAG score was available at baseline for 145 infusions, at 6 months for 144 infusions and at 12 months for
121 infusions. The cohort’s mean classic BILAG numerical
score at baseline was 16.57 (S.D. 8.07). At 6 and 12
months the mean classic BILAG numerical scores were
6.71 (S.D. 5.26) and 5.99 (S.D. 5.26), respectively. The majority of patients had a decrease in the BILAG score at 6
months (80.3%) and 12 months (73.5%).
Groups 1 and 2 had similar BILAG scores at baseline
(15.65 in group 1 vs 16.22 in group 2; Student’s t-test
t = 0.443, P = 0.658), but at 6 and 12 months group 2
was associated with a lower numerical BILAG score [at
6 months: 8.78 group 1 vs 5.89 group 2 (Student’s t-test
t = 2.892, P = 0.004); at 12 months: 7.64 group 1 vs 5.29
group 2 (Student’s t-test t = 2.411, P = 0.017)]. As the numerical BILAG score is not a normal variable, the
Mann–Whitney test was also performed and showed
similar results (P = 0.013 at 6 months and P = 0.029 at
TABLE 3 Logistic regressions with clinical features
comparing groups 1 and 2
Clinical feature
bb (S.E.)
P-value
General clinical features
Skin manifestations
Haematological
manifestations
Joint
Serositis
Kidney
CNS
SS
Constant
0.134 (0.420)
0.063 (0.228)
0.750
0.783
0.425
0.318
0.295
0.220
0.837
0.380
(0.565)
(0.403)
(0.364)
(0.520)
(1.069)
(0.716)
0.452
0.429
0.418
0.673
0.433
0.596
Skin manifestations
Rash
Photosensitivity
Alopecia
Oral ulcers
Constant
0.603
0.038
0.866
0.459
0.618
(0.440)
(0.490)
(0.369)
(0.409)
(0.305)
0.171
0.938
0.019
0.262
0.043
Haematological manifestations
Haemolytic anaemia
Leucopenia
Lymphopenia
Thrombocytopenia
Constant
1.760
0.957
1.773
0.792
0.283
(0.955)
(0.479)
(0.465)
(0.665)
(0.364)
0.065
0.046
0.000
0.234
0.437
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Sofia Sapeta Dias et al.
TABLE 4 Logistic regressions with serological features
comparing groups 1 and 2
Serological feature
ANA
Sm
RNP
Ro
La
DNA
C3
Constant
b (S.E.)
0 (0)
0.383
0.133
0.094
0.180
0.425
0.024
0.169
(0.489)
(0.391)
(0.390)
(0.565)
(0.440)
(0.442)
(0.411)
P-value
0.419
0.433
0.735
0.811
0.750
0.334
0.956
0.681
12 months). Likewise, bivariate analysis showed that there
is an association with group 2 and a decrease in BILAG
score at 6 months (chi-squared test one-sided P = 0.034).
Discussion
Two aspects of the response to BCD in patients with SLE
remain to be fully explained. There is a marked variation in
the time to B cell repopulation, and once the B cells have
repopulated the time to flare is also very variable. Our unit
was the first to use RTX for SLE, and we have now analysed our data in depth to look at these two issues.
Vital et al. [15] showed that patients who have complete
BCD invariably have an initial response (partial or major)
and that incomplete BCD is associated with a lower clinical response, as measured by the BILAG score. This
study focused on the initial response but also evaluated
time for relapse in 28 patients in a follow-up >18 months.
The 39 patients treated with BCD were divided into two
groups, depending on the duration of the effect: those
who had had earlier relapses (50% relapsed in 6–18
months) and those with later relapses who maintained
clinical remission for several years without further medication. In the latter group, the B cell memory compartment remained depleted for 3–5 years and B cell
tolerance was restored, but the former group was characterized by rapid re-accumulation of memory B cells.
Albert et al. [10] also described a correlation between
the degree of BCD and clinical improvement (measured
by the SLEDAI or SLAM). Others have focused on the
pattern of repopulation was noteworthy, and memory B
cells and plasmablasts were suppressed for longer in patients with a more sustained clinical response [16, 18].
Bosma et al. [19] showed a notable return in the numbers
and function of invariant NK T cells after RTX.
In this study we present the results of a long-term
follow-up of a large and ethnically diverse cohort of
lupus patients treated with BCD. BCD was first used in
a lupus patient in our centre in 2000, and as of December
2012 >100 patients with SLE have been treated with BCD.
The median follow-up of this study is >5 years. Being a
single-centre report allows for good continuity of care
using almost the same protocol since January 2000,
with the patients followed in a similar fashion during this
1880
period of time using BILAG scores calculated at every visit
and the same key serological markers.
Comparable to previous studies, we confirm a heterogeneous response to BCD. The heterogeneity of the duration of BCD, even within the same patient on different
occasions, led us to evaluate each cycle of BCD therapy
as a unit. Nevertheless, it was interesting to note that approximately half of the patients had similar and variable
patterns of repopulation in every cycle.
For more than half of the BCD cycles given there was
no complete repopulation for a variety of reasons. A
significant percentage of these (n = 37, 38% of the nonrepopulated cycles) was followed by a new BCD cycle
when the CD19 cells were still low. This suggests that
clinical flare may precede the return to normal levels of
the B cells, although opposite results have been published; e.g. Vital et al. [15] reported in their cohort a
return of B cells for the majority of patients at 26 weeks
after RTX, preceding all relapses. For 43 patients (44% of
the non-repopulated cycles) there was no repopulation by
the close of this study. Longer follow-up will provide more
information. For the purpose of this study, they stayed
depleted for at least 1 year and were thus classified as a
longer duration of depletion.
Eighty-three of the analysed cycles led to repopulation
in a variety of time periods. We selected an arbitrary
threshold of 12 months, approximately dividing the
cohort into two similar groups: in group 1 were the
cycles that led to a shorter repopulation (<12 months)
and in group 2 were the cycles with a longer period of
depletion (>12 months). We excluded the cycles for
which follow-up was <12 months and for which the patients remained depleted.
The next logical step would be to distinguish at baseline
these two types of response to BCD treatment. Ng et al.
[16] reported that positive ENAs at baseline, in particular
the presence of anti-Sm antibodies, were predictors of
relapse at any point, and patients with low serum C3
had a shorter time to relapse. On the other hand, Vital
et al. [15] did not find an association between complement
levels, ENAs, anti-dsDNA or ESR at baseline and the level
of depletion. Likewise, Carter et al. [13] reported that
serum BAFF levels prior to BCD are not associated with
the response to treatment. In this study, however, we did
not find any serological feature associated with longer or
shorter time to repopulation.
To our knowledge, this is the first study that has looked
for an association between clinical features and duration
of BCD. Two features were found to have an association
with the duration of BCD, either in bivariate analysis or in
logistic regression, namely alopecia and lymphopenia.
Alopecia was found to have an association with shorter
time to repopulate, although there is no obvious explanation for this and external validation might be necessary.
In contrast, lymphopenia is associated with longer time to
repopulate; and it is logical that if a patient has lymphopenia due to autoimmune mechanisms, after BCD there
will be longer periods without B cells. Nevertheless, lymphopenia present at any time during the course of the
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Longer duration of BCD is associated with better outcome
patient’s disease may also be due to the BCD itself or to
the combined effects of lupus and the consequences of
the RTX therapy.
Importantly, in this study we clearly demonstrated that
longer BCD is associated with better clinical response. We
confirmed that these patients have a better outcome at 6
and 12 months (as measured by a lower median BILAG
score).
There was no evidence of a cumulative effect of RTX.
The proportion of cycles with a repopulation date did not
significantly differ if it was the first or the fourth cycle. The
time to repopulate did not differ (although the number of
patients in each cycle is different and any conclusions
may be premature).
The response to BCD treatment in SLE is very heterogeneous. In this study we demonstrated that SLE patients with
a longer duration of BCD after treatment have a better outcome at 6 and 12 months as measured by the BILAG score.
No serological feature helped to predict the response to
BCD treatment, although lymphopenia may help to predict
a longer duration of depletion and better outcome.
Acknowledgements
We acknowledge the support of the Biomedical Research
Centre award to University College London/University
College Hospital.
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
Disclosure statement: D.I. has acted as a consultant for
Roche in the past and honoraria received have been
passed onto a local arthritis charity. All other authors
have declared no conflicts of interest.
References
1 Adler M, Chambers S, Edwards C, Neild G, Isenberg D. An
assessment of renal failure in an SLE cohort with special
reference to ethnicity, over a 25-year period.
Rheumatology 2006;45:1144–7.
phase II/III systemic lupus erythematosus evaluation of
rituximab trial. Arthritis Rheum 2010;62:222–33.
6 Rovin BH, Furie R, Latinis K et al. Efficacy and safety of
rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab
study. Arthritis Rheum 2012;64:1215–26.
7 Condon MB, Ashby D, Pepper RJ et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and
mycophenolate mofetil but no oral steroids. Ann Rheum
Dis 2013;72:1280–6.
8 Ezeonyeji AN, Isenberg DA. Early treatment with rituximab
in newly diagnosed systemic lupus erythematosus patients: a steroid-sparing regimen. Rheumatology 2012;51:
476–81.
9 Looney RJ, Anolik JH, Campbell D et al. B cell depletion as
a novel treatment for systemic lupus erythematosus: a
phase I/II dose-escalation trial of rituximab. Arthritis
Rheum 2004;50:2580–9.
10 Albert D, Dunham J, Khan S et al. Variability in the biological response to anti-CD20 B cell depletion in systemic
lupus erythematosus. Ann Rheum Dis 2008;67:1724–31.
11 Reddy V, Croca S, Gerona D et al. Serum rituximab levels
and efficiency of B cell depletion: differences between
patients with rheumatoid arthritis and systemic lupus
erythematosus. Rheumatology 2013;52:951–2.
12 Anolik JH, Barnard J, Cappione A et al. Rituximab improves peripheral B cell abnormalities in human systemic
lupus erythematosus. Arthritis Rheum 2004;50:3580–90.
13 Carter LM, Isenberg DA, Ehrenstein MR. Elevated serum
BAFF levels are associated with rising anti-doublestranded DNA antibody levels and disease flare following
B cell depletion therapy in systemic lupus erythematosus.
Arthritis Rheum 2013;65:2672–9.
14 Stohl W, Metyas S, Tan S-M et al. B lymphocyte stimulator
overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum 2003;
48:3475–86.
15 Vital EM, Dass S, Buch MH et al. B cell biomarkers of
rituximab responses in systemic lupus erythematosus.
Arthritis Rheum 2011;63:3038–47.
2 Furtado J, Isenberg DA. B cell elimination in systemic
lupus erythematosus. Clin Immunol 2013;146:90–103.
16 Ng KP, Cambridge G, Leandro MJ et al. B cell depletion
therapy in systemic lupus erythematosus: long-term
follow-up and predictors of response. Ann Rheum Dis
2007;66:1259–62.
3 Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR,
Isenberg DA. An open study of B lymphocyte depletion in
systemic lupus erythematosus. Arthritis Rheum 2002;46:
2673–7.
17 Hay EM, Bacon PA, Gordon C et al. The BILAG index: a
reliable and valid instrument for measuring clinical disease
activity in systemic lupus erythematosus. Q J Med 1993;
86:447–58.
4 Pepper R, Griffith 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:
3717–23.
18 Hochberg MC. Updating the American College of
Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.
5 Merrill JT, Neuwelt CM, Wallace DJ et al. Efficacy and
safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind,
www.rheumatology.oxfordjournals.org
19 Bosma A, Abdel-Gadir A, Isenberg DA, Jury EC, Mauri C.
Lipid-antigen presentation by CD1d+ B cells is essential
for the maintenance of invariant natural killer T cells.
Immunity 2012, 36-20:477–90.
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