Ann Rheum Dis 2010;69:1158–1161. doi:10.1136/ard.2009.119222 1158
Background Rituximab inhibited structural damage at
1 year in patients with rheumatoid arthritis (RA) who had
had a previous inadequate response to tumour necrosis
factor (TNF) inhibitors.
Objective To assess structural damage progression
through 2 years.
Methods Intention-to-treat patients with one post-
baseline radiograph (rituximab n=281; placebo n=187)
received background methotrexate (MTX) and were
randomised to rituximab (2×1000 mg infusions, 2 weeks
apart) or placebo; patients were eligible for rituximab
re-treatment every 6 months. By week 104, 82% of the
placebo population had received ≥1 dose of rituximab.
Radiographic end points included the change in total
Sharp score (TSS), erosion and joint space narrowing
scores at week 104.
Results At week 104, signifi cantly lower changes in
TSS (1.14 vs 2.81; p<0.0001), erosion score (0.72 vs
1.80; p<0.0001) and joint space narrowing scores (0.42
vs 1.00; p<0.0009) were observed with rituximab plus
MTX vs placebo plus MTX. Within the rituximab group,
87% who had no progression of joint damage at 1 year
remained non-progressive at 2 years.
Conclusions Rituximab plus MTX demonstrated
signifi cant and sustained effects on joint damage
progression in patients with RA and a previously
inadequate response to TNF inhibitors.
Before the development of targeted biological
treatments, irreversible joint damage and defor-
mity leading to a progressive decline in functional
status and increased work disability were common
outcomes for patients with rheumatoid arthritis
(RA).1 2 Biological treatments that inhibit tumour
necrosis factor α (TNFα), T-cell costimulation or
interleukin 6 have demonstrated the ability to
inhibit radiographic progression in patients with
either early or longstanding disease.3–8
Rituximab, a monoclonal antibody that selectively
targets CD20-positive B cells, reduces the signs and
symptoms of RA and has been proved to inhibit joint
damage progression over 1 year in patients with RA
for whom TNF inhibitors produced an inadequate
response.9 10 Here we report the sustained effects of
rituximab on the progression of joint damage over
an extended period of 2 years.
PATIENTS AND METHODS
Patients in this post hoc analysis were participants
in the phase III REFLEX study.9 Eligibility criteria for
Continued inhibition of structural damage over
2 years in patients with rheumatoid arthritis treated
with rituximab in combination with methotrexate
Stanley B Cohen,1 Edward Keystone,2 Mark C Genovese,3 Paul Emery,4 Charles Peterfy,5
Paul Peter Tak,6 Matt Cravets,7 Tim Shaw,8 David Hagerty7
1Metroplex Clinical Research
Center, Dallas, Texas, USA
2University of Toronto, Toronto,
3Stanford University, Palo Alto,
4Leeds General Infi rmary, Leeds,
5Synarc, San Francisco,
6AMC/University of Amsterdam,
Amsterdam, The Netherlands
7Biogen Idec, Inc, San Diego,
8Roche Products Ltd, Welwyn
Garden City, UK
Dr S B Cohen, Metroplex Clinical
Research Center, Dallas, Texas,
Accepted 19 November 2009
REFLEX have been described previously.9 Briefl y,
patients were included if they had active RA despite
treatment with methotrexate (MTX) ≥10 mg/week
and had experienced an inadequate response (lack of
effi cacy or intolerance) to at least one TNF inhibitor.
The study was performed in accordance with
the Declaration of Helsinki. All participating sites
received approval from their governing institu-
tional review board (or equivalent) and all patients
provided written informed consent.
REFLEX was a randomised, double-blind, placebo-
controlled, phase III study with an option for fur-
ther treatment courses under a separate extension
study. Patients continued background MTX and
were randomly assigned to placebo or rituximab
(MabThera, Roche, Welwyn Garden City, UK;
Rituxan, Genentech, South San Francisco, California,
USA and Biogen Idec, San Diego, California, USA).
Rituximab 1000 mg was administered by intrave-
nous infusion on days 1 and 15. All patients received
corticosteroid treatment, consisting of intravenous
methylprednisolone 100 mg before each infusion
and oral prednisone during the 2-week treatment
period (60 mg on days 2−7, 30 mg on days 8−14).
From weeks 16 to 24, patients who failed to
respond to treatment could receive rescue therapy.
Patients randomised to placebo could receive ritux-
imab and patients randomised to rituximab could
receive standard care. Patients completing week
24 were eligible to receive further courses of ritux-
imab within an open-label extension study. Further
courses of rituximab were also available for placebo
patients who had responded to rescue treatment.
Radiographs of hands, wrists (posterior/anterior)
and feet (anterior/posterior) were performed at
screening (baseline) and at weeks 24, 56 and 104,
relative to randomisation. Radiographs were read
at a central reading facility by two independent
expert radiologists and scored using the Genant-
modifi ed Sharp scoring system.11 12 Radiologists
were blinded to the treatment group assignment,
chronological order of the radiographs and patients’
Radiographic outcome measures
Radiographic assessments included the mean
change in total Genant-modifi ed Sharp score
(mTSS), the erosion score, the joint space nar-
rowing score and the proportion of patients with
no further joint damage progression (defi ned as a
change in mTSS ≤0). All assessments compared
Ann Rheum Dis 2010;69:1158–1161. doi:10.1136/ard.2009.1192221159
baseline and week 104. Radiographic changes were also deter-
mined during discrete time intervals of baseline to 24 weeks,
24–56 weeks and 56–104 weeks. The annualised progression
rate (APR) was calculated to provide a measure of the rate of
change in progression standardised to a common time interval.
The APR for each patient was calculated as follows:
The primary population for the radiographic analysis was
defi ned as all patients (including those withdrawing or receiving
rescue) included in the REFLEX intention-to-treat (ITT) popula-
tion who had at least one post-baseline radiograph (either 24,
56 or 104 weeks). All missing data were imputed using linear
extrapolation of the progression observed from baseline to the
week 24/week 56 radiographs. Analyses were conducted using
a non-parametric analysis (Van Elteren test), stratifi ed by region
(USA vs non-USA) and baseline rheumatoid factor (positive vs
negative). In addition, sensitivity analyses were conducted using
observed data only.
Patient characteristics and disposition
A total of 517 patients were randomised: 308 to rituximab plus
MTX and 209 to placebo plus MTX. Of these, 468 patients (281
rituximab patients and 187 placebo patients) were included in
the REFLEX ITT population, and had a baseline fi lm at screening
and at least one post-baseline radiograph. A total of 197 ritux-
imab and 135 placebo patients had radiographs at both baseline
and week 104. The baseline characteristics and measures of dis-
ease activity were similar in both treatment groups and were
similar to those of the original ITT population (table 1).
By week 104, 165/281 patients (59%) in the rituximab group
had received two or more courses of rituximab. Of the 187
patients randomised to placebo, 154 (82%) had received at least
one dose of rituximab before their last observed radiograph,
with 94 (50%) having received two or more courses. Only 33
patients (18%) initially randomised to placebo did not receive
Radiographic effi cacy
The mean change in the mTSS from baseline to 104 weeks
was signifi cantly lower in the rituximab group than in the pla-
cebo group (1.14 vs 2.81, respectively; p<0.0001). Signifi cant
differences in the mean change in erosion and joint space nar-
rowing scores were also observed (fi gure 1).
The proportion of patients with no progression in joint dam-
age over 2 years was signifi cantly higher in the rituximab group
than in the placebo group (57% vs 39%, respectively; p<0.0001;
fi gure 2A). Similarly, a higher proportion of patients randomised
to rituximab had no change in erosion scores over the 2 years
compared with patients randomised to placebo (60% vs 44%,
respectively; p=0.0003; fi gure 2B). Sensitivity analyses using
observed data were consistent with the primary analyses.
Over discrete time intervals, the rate and extent of progression
of joint damage in patients randomised to rituximab remained
consistent. The rituximab group exhibited consistent mean
changes in the mTSS during the fi rst and second years, while
the placebo group—most of whom had by then received ritux-
imab—showed slower rates of change during their second year
(fi gure 2C). Similarly, whereas in the rituximab group the APR
remained consistent, in the placebo group it gradually declined
from 1.60 points/year during the initial 24-week period to 0.93
points/year in the second year (fi gure 2D).
The proportion of patients with no change in their mTSS
(fi gure 2A) and with no new erosions increased during each time
period in each treatment group (fi gure 2B). Of those patients
randomised to rituximab who did not progress during the fi rst
year, 87% did not progress during the second year either.
Inhibition of structural joint damage by rituximab in patients with
with RA and a previous inadequate response to TNF inhibitors
was fi rst described over a 1-year period.10 Here we have demon-
strated that the initial effects of rituximab are maintained over an
extended interval of 2 years, with all measures of joint damage
signifi cantly improved compared with placebo plus MTX.
Treatment with rituximab was associated with a signifi cantly
higher proportion of patients with no progression of joint dam-
age over the 2 years compared with placebo plus MTX. The
proportion of patients with no progression (57%) achieved with
rituximab treatment compares well with that seen with other
Table 1 Baseline demographic characteristics of the patients*
Female/male (n (%))
Disease duration (years)
Swollen joint count
Tender joint count
Anti-CCP positive (n (%))
Total Genant–modifi ed Sharp score
150 (80)/37 (20)
228 (81)/53 (19)
*Except where indicated otherwise values are the mean (SD).
CCP, cyclic citrullinated peptide; CRP, C-reactive protein; ESR, erythrocyte sedimentation
rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate.
Mean change in x-ray score
Placebo + MTX (n = 187)
Rituximab + MTX (n = 281)
Figure 1 Changes from baseline to 2 years in total Genant–modifi ed
Sharp, erosion and joint space narrowing (JSN) scores in patients
treated with rituximab (2 × 1000 mg) plus methotrexate (MTX) or
placebo plus MTX *p<0.005; **p<0.0001 versus placebo plus MTX.
Ann Rheum Dis 2010;69:1158–1161. doi:10.1136/ard.2009.1192221160
treatments with biological agents, albeit in less treatment-refrac-
tory patient populations.6 13 14 Importantly, of those rituximab
patients with no progression in the fi rst year, 87% maintained a
non-progressive status during the second year.
Although patients were initially randomised to either ritux-
imab or placebo, 82% of placebo patients had switched to
rituximab by 2 years. The impact of this switch on the progres-
sion of joint damage in this placebo–rituximab group is evident
by the reduced changes in scores between time periods and the
gradual slowing in their APR. The consequence of this switch
to active treatment is that the degree of progression observed
in the ‘placebo’ group is less than would have been observed
had those patients been maintained solely on MTX, thereby
underestimating the relative treatment effect. The extent of
this discrepancy can be estimated using the method devised by
Strand and Sharp15 for estimating APRs. By dividing the base-
line mean mTSS (32.5) by the mean disease duration (11.7),
the predicted progression for the placebo group over 2 years
was 5.55. However, the observed progression was much lower
(2.81), suggesting that the switch to rituximab had a large
infl uence on the progression of joint damage in this control
group. Consequently, the relative treatment effect size cannot
be accurately measured. Nevertheless, using the predicted and
observed progression in the placebo group a reduction in joint
damage of 59–79% for rituximab plus MTX compared with
placebo plus MTX could be estimated. Given the estimated
nature of this effect, together with the lack of available radio-
graphic data in similar patient populations, comparisons of this
effect size with other biological agents used for RA would not
In conclusion, this 2-year analysis demonstrates that ritux-
imab plus MTX has signifi cant and sustained effects on the inhi-
bition of joint damage in a population of patients with active
RA who had previously experienced an inadequate response to
Acknowledgements Writing assistance was provided by Claire Snowball (Adelphi
Communications Ltd) in consultation with the authors, Roche Products Ltd and
Funding This study was sponsored by F Hoffmann-La Roche Ltd, Genentech, Inc and
Biogen Idec, Inc. A portion of this work (Stanford University) was supported in part by
a grant from the National Institutes of Health National Center for Research Resources
(5 M01 RR000070).
Competing interests SC has received consulting and speaker fees and research
grants from Genentech and Biogen Idec. PE and PPT have received consulting and
speaker fees and research grants from Roche. EK has received consulting and speaker
fees from Roche and Genentech and research grants from Roche. MCG has received
speaker fees and research grant support from Roche and has served as a consultant
for Roche, Biogen Idec and Genentech. DH and MWC are employees of Biogen
Idec. TS is an employee and owns shares in Roche Products Ltd. CP has received
Figure 2 (A) Proportion of patients not progressing over the duration of the study. (B) Proportion of patients with no new erosions over the duration
of the study. (C) Treatment effect of placebo plus MTX and rituximab (2 × 1000 mg) plus MTX on total Genant–modifi ed Sharp score. (D) Annualised
rate of progression in total Genant–modifi ed Sharp score. BL, baseline; MTX, methotrexate *p<0.005; **p<0.0001.
Patients not progressing (%)
n=187 n=281 n=186 n=278 n=186 n=278
BL to 2
BL to 1 year1 year to 2
Placebo + MTX
Rituximab + MTX
Patients with no new erosions (%)
n=187 n=281 n=186 n=278 n=186 n=278
BL to 2
BL to 1 year 1 year to 2
Placebo + MTX
Rituximab + MTX
Mean change in x-ray score
BL to 2 yearsBL to 1 year
Placebo + MTX (n = 186)
Rituximab + MTX (n = 278)
Mean annualised change in x-ray score
Placebo + MTXRituximab
Baseline to Week 24
Week 24 to Week 56
Week 56 to Week 104
Concise report Download full-text
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date on which the committee met and granted the approval. Any modifi cations made
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