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Management of nonresponse to rituximab in rheumatoid arthritisPredictors and outcome of re-treatment.

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Vol. 62, No. 5, May 2010, pp 1273–1279
DOI 10.1002/art.27359
© 2010, American College of Rheumatology
Management of Nonresponse to Rituximab in
Rheumatoid Arthritis
Predictors and Outcome of Re-treatment
E. M. Vital,1 S. Dass,1 A. C. Rawstron,2 M. H. Buch,1 V. Goëb,1 K. Henshaw,1
F. Ponchel,1 and P. Emery1
compared. First-cycle nonresponders (n ⴝ 25) were
treated with a second cycle of rituximab at least 6
months after the first cycle. HSFC was performed at
baseline, immediately prior to the second infusion (week
2), 1 month after the second infusion (week 6), and then
every 3 months for each cycle of rituximab. Complete B
cell depletion was defined as being <0.0001 ⴛ 109
Results. At baseline, the number of preplasma
cells was significantly higher in first-cycle nonresponders than in first-cycle responders (P ⴝ 0.003).
Following the first infusion of the first cycle of rituximab, only 9% of first-cycle nonresponders (3 of 34)
exhibited complete depletion of B-lineage cells, compared with 37% of first-cycle responders (22 of 59) (P ⴝ
0.007). Following the first infusion of the second cycle of
rituximab, 38% of first-cycle nonresponders exhibited
complete depletion. Twenty-six weeks after the second
cycle, there was a significant improvement in the Disease Activity Score in 28 joints, with 72% of patients
exhibiting a EULAR response.
Conclusion. RA patients whose disease did not
respond to an initial cycle of rituximab have higher
circulating preplasma cell numbers at baseline and
incomplete depletion. Our findings indicate that an
additional cycle of rituximab administered prior to total
B cell repopulation enhances B cell depletion and
clinical responses.
Objective. A proportion of patients with rheumatoid arthritis (RA) have disease that fails to respond to
an initial cycle of rituximab. Using highly sensitive flow
cytometry (HSFC), it has been shown that most patients
who do not exhibit a response, as measured using the
European League Against Rheumatism (EULAR) criteria, have persistent circulating B cell levels at week 2
after initial treatment with rituximab. This study was
undertaken to examine whether an additional cycle of
rituximab would improve B cell depletion and clinical
response in patients whose disease did not respond to
the initial cycle.
Methods. Patients with RA (n ⴝ 158) were treated
with a first cycle of rituximab (2 infusions of 1 gm each).
Clinical responses were assessed using EULAR criteria,
and patients were categorized as either first-cycle responders or first-cycle nonresponders. Baseline characteristics of first-cycle nonresponders (n ⴝ 38) and
first-cycle responders (n ⴝ 65) with complete data were
Dr. Vital is recipient of a Research Training Fellowship from
the National Institute of Health Research. Dr. Goëb is recipient of a
travel grant from the French Society of Rheumatology. Dr. Emery is
an Arthritis Research Campaign Professor of Rheumatology.
E. M. Vital, MBChB, MRCP, S. Dass, MBBChir, MA,
MRCP, M. H. Buch, MBChB, MRCP, PhD, V. Goëb, MD, PhD, K.
Henshaw, FIBMS, F. Ponchel, PhD, P. Emery, MA, MD, FRCP:
University of Leeds, Chapel Allerton Hospital and Leeds Teaching
Hospitals National Health Service Trust, Leeds, UK; 2A. C. Rawstron,
PhD: St. James’s Institute of Oncology, Leeds, UK.
Drs. Vital, Dass, and Buch have received honoraria from
Roche (less than $10,000 each). Dr. Emery has received consulting
fees, speaking fees, and/or honoraria from UCB and Centocor (less
than $10,000 each) and has served as a study investigator for Centocor.
Address correspondence and reprint requests to P. Emery,
MA, MD, FRCP, Section of Musculoskeletal Disease, Leeds Institute
of Molecular Medicine, Chapel Allerton Hospital, Chapeltown Road,
Leeds LS7 4SA, UK. E-mail:
Submitted for publication July 6, 2009; accepted in revised
form January 11, 2010.
Rituximab is an effective therapy for resistant
rheumatoid arthritis (RA); good responses may be
achieved in patients whose disease has failed to respond
to conventional disease-modifying antirheumatic drugs
(DMARDs) and to anti–tumor necrosis factor (antiTNF) agents (1). Consequently, patients who do not
exhibit an adequate response to rituximab have frequently exhausted all other available therapy options,
and treatment of these patients is challenging. Anti-TNF
or newer biologic agents may be considered in this
context, although there are limited data on the safety of
these agents in patients in whom the number of B cells
remains below normal.
The findings of initial studies into the use of
rituximab appeared to indicate complete depletion of
circulating B cells in all patients (2), suggesting that the
failure to exhibit a clinical response was due to B
cell–independent pathways of inflammation or to the
persistence of pathologic plasma cells. Recently, the use
of more sensitive methods to measure circulating B cell
depletion has offered an alternative explanation. According to highly sensitive flow cytometry (HSFC), 95%
of patients who failed to exhibit a response, as measured
using the European League Against Rheumatism
(EULAR) criteria (3), also had incomplete B cell depletion (4). In addition, studies of synovial biopsies have
indicated that, although B cell numbers are reduced
after treatment, synovial B cell depletion is seldom complete and that the persistence of synovial B-lineage cells is
associated with poorer responses (5–7). These observations
suggest that the enhancement of the initial depth of B cell
depletion could increase the rate of clinical response by
reducing synovial B cell presence. However, it has been
unclear what determines the initial depth of B cell depletion and therefore how depletion might be enhanced.
Accordingly, we investigated the determinants of
the depth of B cell depletion and of clinical response,
including levels of peripheral blood B cell subsets, as
measured using HSFC. We hypothesized that a second
cycle of rituximab, administered before B cells were fully
repopulated in patients who did not exhibit a EULAR
response after the first cycle, would increase both B cell
depletion and the clinical response rate. Herein, we
report the findings of our study of clinical responses and
the depth of B cell depletion in 25 patients with RA
whose disease had not responded to the first cycle of
rituximab and who were given a second cycle.
Patients and study design. All patients were diagnosed
according to the American College of Rheumatology (formerly, the American Rheumatism Association) criteria for RA
(8) and were positive for either rheumatoid factor or anti–
cyclic citrullinated peptide antibodies or both. All patients had
exhibited an inadequate response or a toxic reaction to ⱖ2
nonbiologic DMARDs, including methotrexate. In addition,
62% of patients exhibited an inadequate response or a toxic
reaction to ⱖ1 anti-TNF agent.
There were 103 patients who received rituximab and
had complete data. We have previously reported data regarding B cell depletion and response to the first cycle of rituximab
for 60 of these patients (5). All patients received 2 infusions (1
gm each) of rituximab, each preceded by methylprednisolone
(100 mg). Patients were maintained on concomitant methotrexate (n ⫽ 73) unless it was not tolerated or contraindicated,
in which case leflunomide (n ⫽ 15), azathioprine (n ⫽ 2), or no
DMARD (n ⫽ 13) was used.
Disease activity was assessed by the Disease Activity
Score in 28 joints using the C-reactive protein level (DAS28CRP) (9). Six months after treatment, EULAR response
criteria were used to categorize patients into first-cycle responders and first-cycle nonresponders. HSFC was used to
enumerate B cell subsets at baseline, immediately prior to the
second infusion (week 2), 1 month after the second infusion
(week 6), and then every 3 months after each cycle of
From the first-cycle nonresponders, 25 patients were
re-treated with a second cycle, using the same rituximab dose,
at a time when circulating B cell levels had not yet returned to
baseline levels. DAS28-CRP scores were assessed 6 months
after the second cycle and were compared with baseline scores
to calculate the EULAR response.
B cell HSFC. Peripheral blood B cell subset levels were
measured using 6-color flow cytometry, counting 500,000
events to reliably enumerate B cells, as described previously
(5). Briefly, B cell levels and subsets were enumerated following standard cell surface staining techniques using a sequential
gating strategy. First, B cells were identified using phycoerythrin (PE)–Cy5.5–conjugated CD19 (Invitrogen) and PECy7–conjugated CD38 (BD Biosciences) expression and lightscatter characteristics. Fluorescein isothiocyanate–conjugated
CD3 and PE-conjugated CD14 (BD Biosciences) were used to
exclude contaminating events, and B cells were classified,
according to expression of PE-Cy7–conjugated CD38 and
allophycocyanin (APC)–conjugated CD27 (BD Biosciences),
as naive (CD19⫹⫹CD27⫺), memory (CD19⫹⫹CD27⫹), and
preplasma (CD19⫹/⫺CD27⫹⫹CD38⫹⫹). APC-Cy7–
conjugated CD45 (BD Biosciences) was used to identify total
leukocytes for calculation of absolute levels of B cell subsets.
Statistical analysis. Baseline clinical variables and B
cell subsets, as predictors of response, in first-cycle responders
were compared with those in first-cycle nonresponders, using
univariate logistic regression. In first-cycle nonresponders receiving re-treatment, changes in DAS28 scores and B cell
counts over time were compared using paired t-test and
Wilcoxon’s matched pairs signed rank test, respectively. P
values less than 0.05 were considered significant.
Prediction of first-cycle nonresponse. Among
first-cycle nonresponders, there was a trend toward
lower DAS28 scores, and response rates were lower in
patients who were not treated with a concomitant
DMARD. Consistent with the findings of our previous
study (4), complete depletion of B cells (measured using
HSFC and defined as a total B cell count that is
⬍0.0001 ⫻ 109 cells/liter after both the first and the
Figure 1. Baseline levels of B cell subsets in first-cycle nonresponders (NR) and in first-cycle responders (R). Data are shown
as box plots. Each box represents the 25th to 75th percentiles. Lines inside the boxes represent the median. Bars outside the boxes
represent the 10th and 90th percentiles. Circles and asterisks indicate outliers and extreme outliers, respectively. Note the different scales for each subset.
second infusion of rituximab) was a predictor of
EULAR response at 6 months. Among first-cycle nonresponders, 9% (3 of 34) had complete depletion, com-
pared with 37% of first-cycle responders (22 of 59).
Total B cell levels and levels of all circulating B cell
subsets was higher at baseline in first-cycle nonre-
Table 1. Baseline clinical variables and B cell subsets among responders and nonresponders, as determined using univariate logistic regression*
DMARD use (n ⫽ 103), no. (%)
Mono (n ⫽ 13)
Combination (n ⫽ 90)
Prior anti-TNF use (n ⫽ 103), no. (%)
Yes (n ⫽ 63)
No (n ⫽ 40)
ESR, mm/hour†
RF, IU/liter§
B cell subset
Naive cells¶
Memory cells¶
Preplasma cells¶
B cell depletion (n ⫽ 93), no. (%)
Incomplete (n ⫽ 68)
Complete (n ⫽ 25)
(n ⫽ 65)
(n ⫽ 38)
OR (95% CI)
59.03 (55.97–62.08)
58.08 (53.48–62.67)
1.01 (0.98–1.04)
4/13 (30.8)
61/90 (67.8)
9/13 (69.2)
29/90 (32.2)
4.73 (1.35–16.65)
36/63 (57.1)
29/40 (72.5)
7.03 (6.53–7.52)
5.92 (5.63–6.20)
4.84 (4.34–5.34)
27/63 (42.9)
11/40 (27.5)
7.35 (6.55–8.15)
5.56 (5.17–5.96)
5.33 (4.68–5.98)
1.98 (0.84–4.65)
0.93 (0.76–1.13)
1.33 (0.92–1.93)
0.88 (0.70–1.09)
6.10 (5.79–6.42)
4.86 (4.57–5.15)
2.66 (2.45–2.88)
6.58 (6.17–7.00)
5.60 (5.26–5.94)
3.25 (2.88–3.62)
0.68 (0.44–1.04)
0.67 (0.44–1.03)
0.47 (0.28–0.78)
0.44 (0.25–0.80)
37/68 (54.4)
22/25 (88.0)
31/68 (45.6)
3/25 (12.0)
* Values for continuous variables are the mean (95% confidence interval [95% CI]). OR ⫽ odds ratio; DMARD ⫽ disease-modifying antirheumatic
drug; anti-TNF ⫽ anti–tumor necrosis factor; ESR ⫽ erythrocyte sedimentation rate; DAS28-CRP ⫽ Disease Activity Score in 28 joints using the
C-reactive protein level; RF ⫽ rheumatoid factor.
† Square root value; n ⫽ 63 responders, 36 nonresponders.
‡ n ⫽ 65 responders, 38 nonresponders.
§ Natural log of (value ⫹ 1); n ⫽ 62 responders, 38 nonresponders.
¶ Natural log of ([value ⫹ 0.0001] ⫻ 10,000). For naive and memory cells, n ⫽ 51 responders, 31 nonresponders; for preplasma cells, n ⫽ 54
responders, 32 nonresponders.
Figure 2. Total B cell levels and levels of B cell subsets in 25 patients
with rheumatoid arthritis that did not respond to cycle 1 of rituximab
and who were re-treated with a second cycle. Data are shown as box
plots. Each box represents the 25th to 75th percentiles. Lines inside the
boxes represent the median. Bars outside the boxes represent the 10th
and 90th percentiles. Circles and asterisks indicate outliers and
extreme outliers, respectively. Note the different scales for each subset
and time point (represented as weeks after each cycle).
sponders than in first-cycle responders (Figure 1 and
Table 1). The majority of persistent circulating B cells
that were present for 3 months after the first cycle of
rituximab were preplasma cells, as reported previously
Baseline clinical data, log-transformed B cell
variables, and complete/incomplete B cell depletion
were evaluated as potential predictors of response, using
univariate analysis. DMARD therapy (P ⫽ 0.015), preplasma cell numbers (P ⫽ 0.003), and complete/
incomplete B cell depletion (P ⫽ 0.007) were significantly predictive of response to rituximab (Table 1).
Re-treatment of nonresponders: enhanced B cell
depletion. Total B cell counts after each cycle of rituximab are shown in Figure 2. Although only 9% of
first-cycle nonresponders had complete B cell depletion
after the first infusion of cycle 1, 38% had complete B
cell depletion after the first infusion of cycle 2. Median
B cell numbers were lower at all time points after the
second cycle of rituximab compared with median numbers after the first cycle, and the numbers of memory
and preplasma cell were significantly reduced 26 weeks
after cycle 2, compared with the numbers of cells after
cycle 1 (Figure 2).
Re-treatment of nonresponders: enhanced clinical responses. As illustrated in Figure 2, rituximab
re-treatment was administered to 25 first-cycle nonresponders prior to total peripheral B cell repopulation,
with the total number of B cells at baseline for cycle 2
significantly lower than the number at baseline for cycle
1 (P ⬍ 0.0001). Six months after cycle 2, there was a
significant improvement in DAS28 scores compared
with scores either immediately before cycle 2 (P ⬍
0.001) or at baseline (P ⬍ 0.001) (Figure 3). After
re-treatment with rituximab, 18 patients (72%) exhibited
a EULAR response, 8 patients (32%) exhibited a good
EULAR response, and 4 patients (16%) had disease
classified as being in remission, as compared with baseline. There was also significant improvement in each
component of the DAS28 (Figure 3C). Across both
cycles, a good or moderate EULAR response occurred
in 50% of cases with complete B cell depletion and in
31% of cases with incomplete B cell depletion. Response
occurred in 39% of cases receiving a concomitant
DMARD and in 25% of cases not receiving a concomitant DMARD. Of the first-cycle nonresponders who
exhibited response to the second rituximab cycle, 9
patients experienced a relapse. The median time from
the beginning of cycle 2 to relapse was 11 months, which
was the same time observed among first-cycle responders who experienced a relapse. No re-treated patient had
Figure 3. Clinical responses as assessed 6 months after the second cycle of rituximab in 25 patients with rheumatoid arthritis that did not respond
to the first cycle. A, European League Against Rheumatism response rates, which include patients who exhibited no response (Non), patients who
exhibited a moderate or good response (Mod/Good), patients who exhibited a good response, and patients whose disease was classified as being in
remission (Rem). B, Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) measured at baseline (BL), 6 months after
cycle 1 (C1), and 6 months after cycle 2 (C2). C, Components of the DAS28-CRP, including tender joint count (TJC), swollen joint count (SJC),
CRP (mg/liter), and the visual analog scale assessment of global health (GH-VAS). ⴱ ⫽ P ⬍ 0.05 versus baseline. Values in B and C are the mean
and 95% confidence interval.
immunoglobulin titers below the lower limit of normal
after cycle 1, but 1 patient developed low IgM after cycle
The results of our previous study indicated that
almost all patients who fail exhibit a clinical response to
rituximab have persistent circulating B-lineage cells after
the first infusion of rituximab and often after both
infusions (4). This suggests that these patients may have
disease that potentially would respond to B cell depletion if depletion were more effective. The present study
extends these observations with 3 key findings. First,
patients whose B cells are not adequately depleted and
who do not exhibit a clinical response have significantly
higher numbers of circulating preplasma cells at baseline. Second, in these patients, a second cycle of rituximab administered prior to total repopulation of B cells
results in greater B cell depletion. Third, clinical responses are enhanced following a second cycle of rituximab. These findings have a number of implications for
understanding of the role of B cells in RA, for using
treatment to target them effectively, and for developing
a rational approach to the management of resistant RA.
Preplasma cells do not express CD20 (and hence
cannot be directly depleted by rituximab) but are generated from CD20⫹ B cells following their participation
in germinal center reactions (10). Their circulating halflife is short, and the finding that there are some patients
with undetectable preplasma cells after treatment with
rituximab demonstrates that these cells may be indirectly
depleted. Conversely, their continuing presence in the
circulation in the absence of naive and memory B cells
suggests continuing B cell activity at other sites. This is
consistent with the findings of previous studies that have
shown increased numbers of synovial plasma cells in
nonresponders at baseline (7) and the persistence of
synovial B cells and plasma cells after treatment (5,7).
Patients who do not exhibit complete B cell depletion
and clinical response after treatment with rituximab may
have a higher burden of B cell number, tissue infiltration, and activity. This may serve as a useful predictor of
response and may identify a group of patients who
require more intensive B cell–depleting therapy.
The observation that B cell depletion could be
enhanced by additional cycles of rituximab was not
necessarily expected. A number of factors have been
suggested as potential contributors to inadequate depletion after treatment with rituximab, and not all of them
could necessarily be overcome by a higher dose. Fc␥
receptor polymorphisms affect the degree of B cell
depletion in the treatment of lymphoma and systemic
lupus erythematosus (11,12) but have not yet been
investigated in RA. The B cell survival factor B lymphocyte stimulator and the complement inhibitory factor
CD55 are expressed in lymphoid tissues and in the
rheumatoid synovium and may inhibit B cell killing by
rituximab (13,14). Some patients develop human antichimeric antibodies following initial exposure to rituximab (1), which may be expected to lead to even less
effective depletion after subsequent treatments.
The key finding from the current study is the
demonstration that many patients who initially fail to
exhibit a response to rituximab may exhibit a response to
a second cycle. There was previously a paucity of data on
how best to manage the disease in this challenging group
of patients. One approach is to switch to a different
biologic agent, such as an anti-TNF␣ agent, abatacept,
or tocilizumab. However, data on the safety of using
these agents in patients with reduced B cell numbers are
limited (15). Previous experience suggests that blocking
multiple immune or inflammatory pathways may have
unpredictable consequences. In contrast, there are substantial data to indicate the safety of repeat cycles of
rituximab (16). While re-treatment was administered
early in the present study, incomplete initial B cell
depletion, early repopulation, and the longer retreatment interval of subsequent cycles may offset concerns regarding safety. The EULAR consensus statement on rituximab suggests that re-treatment should be
considered for residual disease activity, although this
was not based on trial data (17). The present study
provides the first evidence to support this strategy.
Our results require confirmation in larger studies. However, as a result of these observations, retreatment of nonresponders to rituximab is now standard practice in our unit. HSFC is a convenient tool for
assessing different therapeutic strategies in B cell–
depleting therapies, and future research will use HSFC
in order to assess different dosing regimens and patient
populations. More rapid suppression of disease would
be preferable, and future investigations will address this
issue. Since baseline B cell levels and early B cell
depletion have now been identified as convenient early
biomarkers of response, in the future, re-treatment may
be instituted more quickly after the first cycle, thereby
reducing the time needed to achieve control of disease.
Re-treating nonresponders prior to full B cell repopulation is one strategy to enhance depletion in nonresponders, but alternative strategies may include using a
different B cell–depleting agent or a different initial
dose of rituximab.
In conclusion, these data suggest that RA patients whose disease did not respond to rituximab have
higher circulating B cell levels at baseline, which can
lead to inadequate depletion. However, this can be
overcome in a majority of patients, using an additional
cycle of rituximab. The hypothesis that patients exhibiting initial nonresponse to rituximab have B cell–
independent disease is not supported by our current
results. Rather, our findings indicate that the full potential of B cell–depleting therapies has not been realized
by current approaches and that more patients than
previously thought may benefit from this therapy if its
use is refined.
We thank Dr. Elizabeth Hensor (University of Leeds,
Chapel Allerton Hospital and Leeds Teaching Hospitals National Health Service Trust, Leeds, UK) for assistance with
statistical analysis.
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Emery had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Vital, Dass, Ponchel, Emery.
Acquisition of data. Vital, Dass, Rawstron, Buch, Goëb, Henshaw,
Ponchel, Emery.
Analysis and interpretation of data. Vital, Dass, Buch, Goëb, Ponchel,
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outcomes, treatment, nonresponse, arthritispredictors, rituximab, rheumatoid, management
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