Transcript ASCO 2007 Breast Cancer Research

ACR/ARHP 2008
Update:
Rheumatoid Arthritis
ACR/ARHP 2008: Update on Rheumatoid Arthritis

Efficacy and safety of repeat treatment courses of rituximab in rheumatoid arthritis patients
with inadequate response to tumour necrosis factor inhibitors: long-term experience from
the REFLEX study

Long-term safety of rituximab: a six-year follow-up of the rheumatoid arthritis clinical trials
and re-treatment population

Efficacy and safety of various dosing regimens of rituximab in patients with active
rheumatoid arthritis: results of a phase III randomized study (MIRROR)

Safety of other biologic therapies following rituximab treatment in RA patients

Improved quality of life with rituximab as first-line biologic therapy in patients with active
rheumatoid arthritis: results from a phase III, randomized, controlled study (SERENE)

Prospective follow-up of rituximab treatment in 965 patients with refractory rheumatoid
arthritis: tolerance and efficacy data from the French Registry AIR (Autoimmunity and
Rituximab)

ACR and DAS 28 response over 24 weeks in rheumatoid arthritis patients treated with
rituximab after an inadequate response to one tumour necrosis factor inhibitor

Efficacy, safety, and dose frequency of re-treatment with rituximab in rheumatoid arthritis:
results from a randomized, controlled trial (SUNRISE)
ACR = American College of Rheumatology
ARHP = Association of Rheumatology Health Professionals
Efficacy and safety of repeat treatment courses
of rituximab (RTX) in RA patients (pts) with
inadequate response (IR) to tumour necrosis
factor (TNF) inhibitors: long-term experience
from the REFLEX study
Keystone EC, et al. ACR/ARHP 2008; Abstract 367.
Background

Clinical trials using rituximab as selective B-cell–targeted therapy have
demonstrated significant efficacy and safety in modifying the signs and
symptoms of rheumatoid arthritis (RA).1,2,3

In the phase III REFLEX study, Cohen and colleagues demonstrated the
efficacy and safety of rituximab in RA patients who had an inadequate
response to at least one tumour necrosis factor (TNF) inhibitor.1

ACR/ARHP 2008: Keystone and colleagues presented updated interim
data from an open-label extension of the REFLEX study designed to
evaluate long-term safety and efficacy of rituximab in this patient
population.4
1. Cohen SB, et al. Arthritis Rheum 2006;54(9):2793–2806.
2. Edwards JC, et al. N Engl J Med 2004;350(25):2572–2581.
3. Emery P, et al. Arthritis Rheum 2006;54(5):1390–1400.
4. Keystone EC, et al. ACR/ARHP 2008; Abstract 367.
ACR = American College of Rheumatology
ARHP = Association of Rheumatology Health Professionals
Study design: REFLEX extension study

Criteria for re-treatment with rituximab included:
•
reduction of ≥20% in both swollen joint count (SJC) and tender
joint count (TJC) during any follow-up visit from week 16,
following initial treatment in REFLEX;
•
active RA with SJC ≥8 (66 joint count) and TJC ≥8 (68 joint
count);
•
need for repeated course as determined at the discretion of the
physican.

Patients who received placebo in the initial treatment arm received
open-label rituximab (2 x 1000 mg).

All treatment courses with rituximab consisted of two 1000 mg IV
infusions separated by 2 weeks.
Keystone EC, et al. ACR/ARHP 2008; Abstract 367.
Study design: REFLEX extension study (cont’d)
Study design: REFLEX extension study (cont’d)

Rituximab infusions were all premedicated with IV glucocorticoids
(100 mg methylprednisolone).

A 14-day course of oral prednisone was also administered.

All patients continued to receive MTX (10–25 mg per week), with
allowance for a dose reduction due to intolerance.

Primary and secondary efficacy measures included the ACR 20%,
50%, and 70% improvement criteria (ACR20/50/70), the EULAR
responses (moderate/good), DAS28, low disease activity, and DAS
remission.

Efficacy was calculated relative to the original baseline assessed
prior to the administration of the first course of rituximab.
Keystone EC, et al. ACR/ARHP 2008; Abstract 367.
ACR = American College of Rheumatology
DAS = Disease Activity Score
EULAR = European League Against Rheumatism
Key findings
Baseline characteristics and disposition

Of the 502 patients randomized to REFLEX, a total of 480 patients were
treated with rituximab, either as randomized treatment or following a switch
from placebo (n = 172, 35.8%).

Of these patients, 307 received two courses (C2), 235 patients received three
courses (C3), 146 patients received four courses (C4), and 58 patients
received five courses (C5)

Over four courses, a total of 230 patients withdrew from treatment. The
primary reason for withdrawal was lack of efficacy/other reasons (192
patients, 40%), with 26 patients (5.4%) withdrawing because of adverse
events (AEs).

The majority of the withdrawals (157 patients, 33%) occurred during the first
course (C1). Of the remaining patients, 12%, 9%, and 11% withdrew following
C2, C3, and C4, respectively.

Of the 235 patients who received a third course, 179 had an efficacy analysis
at 24 weeks, following C3, and were included in the efficacy analysis.
Keystone EC, et al. ACR/ARHP 2008; Abstract 367.
Key findings (cont’d)
Efficacy

Of the 408 patients treated with rituximab, 235 patients received ≥3 courses.
Of these, 179 patients had completed 24 weeks of follow-up after each
treatment course, which permits a within-patient analysis by course.

Within-patient comparison of ACR 20, 50, and 70 scores at 24 weeks following
C1, C2, and C3 showed that repeated treatment with rituximab was effective
over multiple courses.

ACR 20 responses at week 24 following each course were maintained or
increased with subsequent courses, while ACR 50 and 70 responses
improved. ACR70 responses increased from 14% following C1 to 26%
following C3.

The proportion of patients with a EULAR response was comparable for C1 to
C3, with over 80% of patients achieving a EULAR good/moderate response
with each course.

The proportion of patients receiving a EULAR good response showed an
increase with each treatment (C1, 17%; C2, 26%; C3 34%).

Sustained improvement in DAS2 low disease activity and remission was
observed during C2 and C3, with remission rates increasing from 8.8% to
17.6% from C1 to C3.
Keystone EC, et al. ACR/ARHP 2008; Abstract 367.
ACR = American College of Rheumatology
C = course
EULAR = European League Against Rheumatism
Figure 1. ACR response at week 24 after three rituximab
treatment courses versus original baseline
Figure 2. EULAR response at week 24 after three rituximab
treatment courses versus original baseline
Figure 3. Percentage of patients achieving DAS28
low disease activity or remission at week 24 after three rituximab
treatment courses versus original baseline
Key findings (cont’d)
Safety

AE rates per 100 patient-years (95% CIs) in each treatment course remained relatively
stable between courses (377–399 events per 100 patient years).

Majority of AEs reported were mild to moderate (grade 1/2) in severity, with an observed
reduction in reported AEs over treatment courses.

AE rate leading to withdrawal decreased significantly from C1 (3.5%) to C3 (1.7%).

Incidence of commonly reported AEs remained stable with each treatment course, although
incidences of RA exacerbations declined over subsequent courses.

SAE rates per 100 patient-years did not vary significantly between courses.

Incidence of infusion-related reactions (IRRs) decreased with each repeat course, with 26%
of patients experiencing an IRR during C1, 17% during C2, and 12% during C3.

IRRs were most frequent during the initial infusion of the first course (22%).

The rate of all infections showed a general increase from C1 (96.8 events/100 patient
years) to C3 (119.9 events/100 patient years), although confidence intervals (CIs) were
wide and overlapping.

In total, 87 serious infection events (SIEs) were reported, providing an overall rate of 6.75
events/100 patient-years. The SIE rate remained stable from C1 to C3, with wide and
overlapping CIs.

No opportunistic infections or cases of tuberculosis were reported.
Keystone EC, et al. ACR/ARHP 2008; Abstract 367.
Key conclusions

In patients with active RA and an IR to TNF inhibitors, repeated
courses of rituximab showed a comparable degree of sustained
efficacy relative to the original baseline.

The safety profile observed over this extended observation period is
consistent with that previously reported for rituximab, with no
evidence of newly emerging safety concerns.
Keystone EC, et al. ACR/ARHP 2008; Abstract 367.
Long-term safety of rituximab:
6-year follow-up of the RA clinical trials
and re-treatment population
Van Vollenhoven RF, et al. ACR/ARHP 2008; Abstract 361.
Background

Rituximab has been shown to be effective and well tolerated in the
treatment of patients with active rheumatoid arthritis (RA).1–3

Rituximab acts by selectively depleting CD20-positive B cells. This novel
mode of action differs from that of other biologic agents and DMARDs.1–3

Treatment with rituximab produces peripheral B-cell depletion, which is
either maintained or re-induced with multiple courses. The safety of longterm B-cell depletion is currently being evaluated in open-label studies with
rituximab.1–3

ACR/ARHP 2008: van Vollenhoven and colleagues presented a pooled
analysis of safety data collected from RA patients treated with rituximab in
combination with methrotrexate (MTX) from several of the international
clinical trials such as the phase II DANCER and SIERRA trials, and the
phase III SERENE, SUNRISE, MIRROR, and REFLEX studies.4
1. Cohen SB, et al. Arthritis Rheum 2006;54(9):2793–2806.
2. Edwards JC, et al. N Engl J Med 2004;350(25):2572–2581.
3. Emery P, et al. Arthritis Rheum 2006;54(5):1390–1400.
4. Van Vollenhoven RF, et al. ACR/ARHP 2008; Abstract 361.
ACR = American College of Rheumatology
ARHP = Association of Rheumatology Health Professionals
DMARD = disease-modifying anti-rheumatic drug
Study design

The safety data for this analysis was collected from RA patients treated with
rituximab in combination with methrotrexate (MTX) in an international clinical
trials program

Patients initially randomized to placebo and subsequently treated with
rituximab were also included in the analysis, from the start of treatment with
rituximab.

Prior to each infusion of rituximab, patients received peri-infusional
corticosteroids (methylprednisolone 100 mg IV), and, in some cases,
additional oral corticosteroids, depending on the specific study.

Data were available from 2578 patients, accounting for 5013 patient-years of
exposure to rituximab.

A total of 2244 patients were observed for ≥1 year, 851 for ≥2 years, 720 for
≥3 years, 317 for ≥4 years, and 97 for ≥ 5 years.

All 2578 patients received at least one treatment course, and a total of 1890,
1043, 425, and 133 patients received ≥2, ≥3, ≥4, and ≥5 courses, respectively.

The maximum number of courses administered was 10 (n = 1).
Van Vollenhoven RF, et al. ACR/ARHP 2008; Abstract 361.
RA = rheumatoid arthritis
Key findings

The rate of adverse events (AEs) by rituximab course decreased after the first
course (C1), and subsequently stabilized, following multiple courses of rituximab.

The most commonly reported AEs were those associated with infusion reactions,
especially during C1.
Infusion reactions

Infusion reactions during the first infusion of each course decreased from 25% in C1
to 13%, 9%, 9%, and 3% in C2, C3, C4, and C5, respectively.

The most common events reported during infusions were headache, pruritus, throat
irritation, flushing, rash, uticaria, hypertension, and pyrexia. Most reactions were
mild or moderate in severity.

Thirteen patients (0.5%) experienced a total of 18 serious infusion reactions. These
reactions were variable in nature and included rash, headache, blood pressure
changes, anaphylactic reactions, and edema. Twelve of these 18 events occurred
following the first infusion of C1. There were no serious infusion-related reactions
(IRRs) beyond C2.

The proportion of patients who reported IRRs that required slowing, stopping, or
interruption of treatment with rituximab was the highest after C1 (9%), and
subsequently decreased to 5%, 3%, and 2% after C2, C3, and C4, respectively.

Overall, <1% of patients withdrew because of IRRs.
Van Vollenhoven RF, et al. ACR/ARHP 2008; Abstract 361.
C = course
Figure 1. Incidence of acute infusion reactions by
treatment course of rituximab
Key findings (cont’d)
Infections1

A total of 1663 patients (65%) experienced ≥1 infection (both non-serious and serious),
with an overall rate of infection of 97.7 events/100 patient-years (95% CI, 95–100.5).

The most common infections were upper respiratory tract infections (19%),
nasopharyngitis (13%), urinary tract infections (11%), bronchitis (10%), diarrhea (9%),
sinusitis (8%), and influenza (5%).

A total of 170 (7%) patients experienced a serious infection event (SIE), providing an
SIE rate of 4.31/100 patient-years (95% CI, 3.77–4.92).

The most common serious infection was pneumonia, affecting 2 (1%) patients. No
cases of tuberculosis were reported in this population.

Rates of overall and serious infections were stable between courses.

Analysis of infections during consecutive twelve-month intervals, irrespective of multiple
courses, showed no evidence of increased risk of infection over time.

The rate of overall, but not serious, infection was highest in the initial year of treatment
with rituximab.

The overall rate of infection for rituximab-treated patients was similar to that previously
reported for other therapies in patients with RA. 2,3
1. Van Vollenhoven RF, et al. ACR/ARHP 2008; Abstract 361.
2. Dixon WG, et al. Arthritis Rheum 2006;54(8):2368–2376.
3. Listing J, et al. Arthritis Rheum 2005;52:3403–3412.
CI = confidence interval
RA = rheumatoid arthritis
Figure 2. Overall rate of infections per 100 patient-years
Figure 3. Rate of serious infections per 100 patient-years
Figure 4. Incidence of serious infections per 100 patient-years
Key findings (cont’d)
Immunoglobulins

At baseline, prior to receiving rituximab, 38 (1.5%) and 41 (1.7%) patients had IgM
and IgG below the lab lower limit of normal (LLN), respectively.

Serum immunoglobulins (Ig), expecially IgM, decreased following multiple courses of
rituximab; 620 (23%) and 141 (5%) of patients developed IgM and IgG below the
LLN, respectively.

Median Ig levels were >LLN during the entire follow-up period. There were no cases
of undetectable Ig levels.

IgG decreases were often transient and sustained low IgG (<LLN for at least one
year) was observed in 32 (1.2%) of patients. Decreases in IgG were related to
corticosteroidal use and older age.

Older age was an independent predictor of sustained low IgG (HR 1.43; 95% CI,
1.24–1.63, p <0.001 for every 10 years of increased baseline age).

Serious infection rates were similar prior to and after the detection of low IgM or IgG.

Patients with low IgM did not have increased rates of serious infection. Patients with
low IgG had increased point estimates of infection rates, both prior to and after
detection of low levels.

It is unclear if rituximab-treated patients with low IgG are at increased risk of
infection.
Van Vollenhoven RF, et al. ACR/ARHP 2008; Abstract 361.
CI = confidence interval
HR = hazard ratio
Key findings (cont’d)
Malignancies1

The overall incidence of malignancies (excluding non-melanoma skin
cancer) was 1.06/100 patient-years, of which 41 were reported as serious
adverse events (SAEs) (0.82/100 patient-years).

The incidence of malignancy did not increase with multiple courses or
rituximab.

There was no difference in the overall rate of pattern of malignancy in
patients treated with rituximab, when compared with other patients with RA
described in epidemiologic studies.2–4
1. Van Vollenhoven RF, et al. ACR/ARHP 2008; Abstract 361.
2. Mellemkjaer L, et al. Eur J Cancer 1996;32(10):1753–1757.
3. Watson K, et al. Rheumatology 2006;45(Suppl 1):i10.
4. Wolfe F , et al. Arthritis Rheum 2007;56:2886–2895.
RA = rheumatoid arthritis
Key conclusions

In this update on safety in RA clinical trials, rituximab was well
tolerated over multiple courses and consistent with previous
studies. No new safety concerns were identified.

The overall rates for AEs and SAEs were stable over time and
subsequent treatment courses.

Infections, including serious infections—a potential concern for
prolonged B-cell depletion—did not increase over time, or with
multiple courses of rituximab.

Ig levels, in particular IgM, decreased with multiple courses of
rituximab, although this was not associated with increased risk of
infection.

The rate of malignancies was consistent with previous studies and
with the incidence of malignancy in patients with RA.
Van Vollenhoven RF, et al. ACR/ARHP 2008; Abstract 361.
AE = adverse event; Ig = immunoglobulin
RA = rheumatoid arthritis; SAE = serious adverse event
Efficacy and safety of various dosing regimens
of rituximab in patients with active RA:
results of a phase III
randomized study (MIRROR)
Rubbert-Roth A, et al. ACR/ARHP 2008; Abstract 363.
Background

Rituximab (2 x 1000 mg) has been shown to successfully treat
patients with an intolerance or an inadequate response (IR) to
tumour necrosis factor (TNF) inhibitor therapies.1

Significant clinical improvements in disease symptoms have also
been reported in patients with an IR to disease-modifying antirheumatic drugs (DMARDs) treated with rituximab (2 x 500 mg and
2 x 1000 mg) in combination with methotrexate (MTX).2

The effects of repeat treatment and of dose escalation were not
explored.

ACR/ARHP 2008: Rubbert-Roth and colleagues presented the
results of the phase III, randomized MIRROR study to evaluate the
efficacy and safety of three dosing regimens of rituximab in
combination with MTX in patients with active RA who respond
inadequately to MTX and who had been previously treated with no
more than one biologic agent approved for use in RA.3
1. Cohen SB, et al. Arthritis Rheum 2006;54(9):2793–2806.
2. Emery P, et al. Arthritis Rheum 2006;54(5):1390–1400.
3. Rubbert-Roth A, et al. ACR/ARHP 2008; Abstract 363.
RA = rheumatoid arthritis
Study design


Key inclusion criteria were as follows:
•
patients ≥18 years old who had been diagnosed with RA for ≥6
months;
•
Swollen joint count (SWC) ≥8 (66 joint count), and tender joint
count (TJC) ≥8
(68 joint count) at screening and baseline;
•
elevated baseline values of C-reactive protein (CRP) ≥0.6 mg/dL
(6 mg/L), or erythrocyte sedimentation rate (ESR) ≥28 mm/h;
•
Inadequate response to methotrexate (MTX) at 10–25 mg/week
for ≥12 weeks;
•
Absolute neutrophil count ≥1500/μL, hemoglobin level ≥8 g/dL,
immunoglobin (Ig)M and IgG levels ≥40 and 500 mg/dL.
A total of 30% of the study population were permitted to have received
≤1 previous biologic agent approved for use in RA.
Rubbert-Roth A, et al. ACR/ARHP 2008; Abstract 363.
RA = rheumatoid arthritis
Study design (cont’d)

Patients were randomized to three treatment groups. All patients
received a first course of two infusions of rituximab on days 1 and 15,
with a second course administered between weeks 24 and 26
according to the treatment group:
•
reduced dose group (RD) (2 x 500 mg at baseline and week 24);
•
dose escalation group (DE) (2 x 500 mg at baseline and 2 x 1000
at week 24);
•
standard dose group (SD) (2 x 1000 mg at baseline and week 24).

Primary endpoint was ACR20 response at week 48.

Secondary endpoints included ACR50/70 and EULAR moderate/good
responses.
Rubbert-Roth A, et al. ACR/ARHP 2008; Abstract 363.
ACR = American College of Rheumatology
EULAR = European League Against Rheumatism
Study design (cont’d)
Key findings

Because of errors in a medication pack list which rendered an intent-to-treat (ITT)
analysis as randomized invalid, results presented are from a modified ITT analysis
performed with patients analyzed by treatment received (mITT population).

Sensitivity analyses using the standard ITT as randomized were conducted and were
consistent with the modified ITT presented.

Demographic and baseline disease activity were well balanced across the 3 treatment
groups.

Of the 378 patients recruited, 346 patients were treated with a protocol-defined regimen,
and 334 (88%) patients completed 24 weeks of follow-up. From all three treatment
groups, 321 (85%) patients received a second treatment course, and 314 (83%) patients
completed the full 48-week period of the study.

A majority of patients (66%) across all three treatment arms achieved at least an ACR20
response at week 48.

Response rates in the SD group were somewhat higher than those in both the RD and DE
arms, but the difference was not statistically significant.

The proportion of patients achieving ACR50 and ACR70 was also higher in the SD arm,
but no statistically significant difference between the treatment arms was achieved.

Distribution of EULAR responses was significantly better in the SD group, compared with
the RD group, with 89.2% versus 73% achieving a EULAR good or moderate response,
respectively (p = 0.0495).
Rubbert-Roth A, et al. ACR/ARHP 2008; Abstract 363.
ACR = American College of Rheumatology; DE = dose escalation group;
EULAR = European League Against Rheumatism
RD = reduced dose group; SD = standard dose group
Figure 1. ACR responses at week 48 following treatment with
reduced dose, dose escalation, or standard dose rituximab
Figure 2. EULAR responses at week 48 following treatment with
reduced dose, dose escalation, or standard dose rituximab
Key findings (cont’d)

A subgroup analysis examined the effect at week 48 of repeat treatment on
patients who had not achieved an ACR20 response to the initial course of
rituximab.

In total, 42% to 48% of these patients achieved an ACR20 response after a second
course of treatment. The dose regimen did not appear to have a significant impact;
however, response rates were higher in those patients who had received initial
treatment and repeated treatment with 2 x 1000 mg.

Over 80% of patients who achieved at least an ACR20 response to their first
course of treatment maintained this response during the second course of
treatment, irrespective of dose.

A comparison of ACRn score by category (<20, >20) using a shift analysis showed
that 28% to 37% of patients who achieved an ACRn ≥20 at week 24 improved their
ACR response category at week 48.

Conversely, 35% of patients receiving RD had a worse ACR response at week 48,
compared with 22% of SD patients.

Regardless of prior biologic therapy, ACR and EULAR outcomes for the SD
regimen were consistently higher than those of the RD regimen. But patient
numbers are small and no statistical significance was observed.
Rubbert-Roth A, et al. ACR/ARHP 2008; Abstract 363.
ACR = American College of Rheumatology; DE = dose escalation group;
EULAR = European League Against Rheumatism
RD = reduced dose group; SD = standard dose group
Figure 3. ACR responses at 48 weeks: prior/no prior biologic subgroups (mITT)
Figure 4. EULAR moderate/good responses at 48 weeks:
prior/no prior biologic subgroups (mITT)
Key findings (cont’d)
Safety

All three rituximab regimens were well tolerated and demonstrated comparable
safety through 48 weeks.

The most common adverse events (AEs) were infusion-related reactions (IRRs)
at 39%, 30%, and 30% for RD, DE, and SD, respectively.

The proportion of patients experiencing infusion reactions was highest with the
first infusion of the first course, lower with subsequent infusions, and similar
across dosing regimens.

Other common AEs included RA flares (18%, 20%, and 15%, for RD, DE, and
SD, respectively), and upper respiratory tract infections (12%, 14%, and 11% for
RD, DE, and SD, respectively).

Incidences of serious AEs leading to withdrawal, infections, lower gastrointestinal
events, cardiac events, vascular events, and malignancies, were similar across
treatment arms.

Overall rate of infections (non-serious and serious) across the three treatment
groups was 120.81–159.16 infections per 100 patient-years; the rate of serious
infection was 2.36–4.73 per 100 patient-years. No clear difference in rates of
infections was observed across the dosing regimens.

No deaths were reported during this study.
Rubbert-Roth A, et al. ACR/ARHP 2008; Abstract 363.
DE = dose escalation group; RA = rheumatoid arthritis
RD = reduced dose group; SD = standard dose group
Key conclusions

Rituximab is effective and well tolerated in patients with an
inadequate response to methotrexate, including patients receiving
one prior biologic agent.

The reduced dose and standard dose could not be clearly
differentiated after 48 weeks of treatment, although some efficacy
outcomes suggest improved outcomes in the standard dose group.

Dose escalation did not appear to be associated with improved
responses.

Overall, repeat treatment maintained response to the first course and
may have incremental benefits.

Repeat treatment may also elicit response in patients non-responsive
to their initial treatments.
Rubbert-Roth A, et al. ACR/ARHP 2008; Abstract 363.
Safety of other biologic therapies following
rituximab treatment in RA patients
Genovese M, et al. ACR/ARHP 2008; Abstract 1671.
Background

ACR/ARHP 2008: Genovese and colleagues presented results of a
study to assess the rate of serious infection events (SIEs) in
rheumatoid arthritis (RA) patients previously treated with rituximab
and who subsequently received a further biologic RA therapy.
Genovese M, et al. ACR/ARHP 2008; Abstract 1671.
Study design

Patients with moderate-to-severe active RA who had been treated with rituximab
plus methotrexate within an international clinical trial program were included in the
study.

Following withdrawal from their respective studies, patients entered a safety followup (SFU) during which peripheral B-cell counts were monitored at regular intervals
for ≥48 weeks.

During SFU, patients were permitted to receive addition biologic therapies.

Data on all serious infection events (SIEs) were collected throughout the SFU
period.

SIEs were defined as infections that required intravenous antibiotics or where at
least one of the following applied:
•
patient required hospitalization or existing hospitalization was prolonged;
•
infection was immediately life-threatening;
•
infection caused persistent or significant disability or incapacity;
•
intervention was required to prevent one of the previously mentioned outcomes;
•
infection was fatal.
Genovese M, et al. ACR/ARHP 2008; Abstract 1671.
Key findings

At the time of data cut-off (November 2007), 2578 RA patients had received at least one
course of rituximab (some patients may have received multiple courses), providing 5013
patient-years of follow-up.

Overall rate of SIE in this population was 4.31 (95% CI, 3.77–4.92) per 100 patient-years.

Of patients who withdrew into SFU, 185 patients were subsequently treated with another
biologic (150 received tumour necrosis factor (TNF) inhibitors, 25 received abatacept, and
10 received anakinra or experimental biologics).

Median follow-up time after receipt of the subsequent biologic was 11 months
(range: 0–45 months).

Majority of patients had peripheral B-cell depletion with CD19 levels below the lower limit
of normal at the time of receiving further RA treatment.

This group of patients reported a total of 13 SIEs in 186.05 patient-years follow-up
(6.99 events/100 patient-years; 95% CI, 4.06–12.03) during treatment with rituximab and
prior to the receipt of the biologic.

Ten SIEs in 182.31 patient-years were reported following the initiation of the biologic (5.49
events/100 patient-years; 95% CI 2.95–10.19).

Median time to SIE after initiating biologic therapy was 4 months (range: 0–23 months).

Overall, infections were variable and typical for RA patients.

No opportunistic or fatal infections occurred.
Genovese M, et al. ACR/ARHP 2008; Abstract 1671.
CI = confidence interval
RA = rheumatoid arthritis
Figure 1. Subsequent treatment with another biologic
Key conclusions

In this updated, exploratory analysis, the use of other biologic
therapies in RA patients previously treated with rituximab was not
associated with an increase in the rate of serious infections.

Controlled trials of combination therapy of rituximab and other
biologics is ongoing.
Genovese M, et al. ACR/ARHP 2008; Abstract 1671.
RA = rheumatoid arthritis
Improved quality of life (QoL) with
rituximab (RTX) as first-line biologic therapy in
patients (pts) with active rheumatoid arthritis (RA):
results from a phase III randomized
controlled study (SERENE)
Deodhar A, et al. ACR/ARHP 2008; Abstract 365.
Background

Rituximab, a monoclonal antibody that selectively targets CD20positive B cells, has demonstrated significant efficacy and a good
safety profile in clinical trials conducted in patients with active
rheumatoid arthritis (RA).1–3

RA is associated with progressive functional decline and decreased
quality of life (QoL), making the use of patient-reported outcomes
(PROs) of interest in evaluating patient response to rituximab.

ACR/ARHP 2008: Deodhar and colleagues presented data from
the SERENE study evaluating the effect of rituximab on physical
function, disability, and health-related QoL in patients with active RA
who have had an inadequate response to methotrexate, and have
not received prior biologic therapy.4
1. Edwards JC, et al. N Engl J Med 2004;350(25):2572–2581.
2. Smolen JS, et al. Ann Rheum Dis 2007;66:143–150.
3. Cohen SB, et al. Arthritis Rheum 2006;54(9):2793–2806.
4. Deodhar A, et al. ACR/ARHP 2008; Abstract 365.
ACR = American College of Rheumatology
ARHP = Association of Rheumatology Health Professionals
Study design

The SERENE study was a multicentre, randomized, double-blind, placebocontrolled, phase III trial conducted at 105 centres in 11 countries.

Key eligibility criteria was as follows:
•
age 18–80 years with active RA for ≥6 months according to ACR
criteria;
•
SJC and TJC ≥8 at screening and baseline with C-reactive protein
(CRP) ≥0.6 mg/dL and/or erythrocyte sedimentation rate (ESR ) ≥28
mm/h at screening;
•
IR to methotrexate (MTX) (10–25 mg/week for at least 12 weeks) and
no prior biologic therapy for RA;
•
Absolute neutrophil count ≥1500 μL, hemoglobin level ≥8 g/dL,
immunoglobulin (Ig)M and IgG levels ≥40 and 500 mg/dL, respectively.

Patients received prophylactic treatment with intravenous methylprednisone
(100 mg) to reduce the incidence and severity of infusion reactions.

All patients continued to receive MTX (10–25 mg/week) at a stable dose
with folic acid (≥5 mg/week or equivalent).
Deodhar A, et al. ACR/ARHP 2008; Abstract 365.
ACR = American College of Rheumatology
IR = inadequate response; RA = rheumatoid arthritis
SJC = swollen joint count; TJC = tender joint count
Study design (cont’d)
Study design (cont’d)

From week 24, all eligible patients (DAS ≥2.6 and all safety criteria met)
were re-treated with rituximab.

Patients who received placebo for the first 24 weeks were switched to
rituximab (2 x 500 mg), while patients in the original active arms were
re-treated with the same dose of rituximab (2 x 500 mg or 2 x 1000 mg).

The study remained double-blinded to treatment and dose through week 48.

Clinical assessments were made according to the ACR core set of diseaseactivity measures at baseline every 4 weeks from week 4 to week 24, and
every 8 weeks thereafter.

Primary endpoint was assessment of the proportion of patients in each
treatment arm achieving an ACR20 response.

Secondary endpoints included the PRO measures presented in this report.
Deodhar A, et al. ACR/ARHP 2008; Abstract 365.
ACR = American College of Rheumatology
DAS = Disease Activity Score
PRO = patient-reported outcome
Study design (cont’d)

Patient-reported outcomes (PROs) included:
•
Health Assessment Questionnaire-Disability Index (HAQ-DI) score;
•
patient rating of fatigue, assessed using the Functional Assessment of
Chronic Illness Therapy-Fatigue (FACIT-Fatigue);
•
health-related QoL, assessed using the Medical Outcomes Study Short
Form (36-item) health survey (SF-36).

HQ-DI score was collected at every visit, FACIT-Fatigue at weeks 12, 24, and
48, and SF-36 at weeks 24 and 48.

Minimal clinically important differences (MCIDs) from individual patient
baselines were defined as ≥0.22, ≥4, >5.42, and >6.33 for HAQ-DI,
FACIT-Fatigue, and physical and mental component scores (PCS and MCS)
of the SF-36, respectively.
Deodhar A, et al. ACR/ARHP 2008; Abstract 365.
QoL = quality of life
Key findings

Demographic and baseline disease characteristics were generally
well balanced across the three arms.

Primary intent-to-treat (ITT) population comprised 509 patients:
•
167 patients receiving 2 x 500 mg rituximab;
•
170 patients receiving 2 x 1000 mg rituximab;
•
172 patients receiving placebo.

Of these patients, 487 completed 24 weeks of treatment and 468
completed 48 weeks.

After week 24, 460 patients (90%) received a second course of
treatment, and 451 of them completed 48 weeks of the study.
Deodhar A, et al. ACR/ARHP 2008; Abstract 365.
Key findings (cont’d)
Week 24 results (placebo-controlled period)

Mean decrease from baseline in HAQ-DI was significantly greater (p <0.0001) in both
rituximab arms, compared with the placebo arm, resulting in a clinically meaningful
improvement in HAQ-DI (≥MCID of 0.22).

A significantly greater mean increase from baseline in SF-36 PCS score was observed in
the two rituximab arms compared with the placebo arm.

Mental component scores (MCS) were also improved in both rituximab arms, but
achieved statistical significance at the 5% level only with the 2 x 1000 mg dose, compared
with the placebo arm.

Significantly greater proportions of patients treated with rituximab plus MTX achieved
clinically relevant improvements in SF-36 PCS (>MCID of 5.42) compared with those
receiving placebo plus MTX.

A significantly greater proportion of patients treated with rituximab 2 x 1000 mg plus MTX
achieved clinically relevant improvements in SF-36 MCS (>MCID of 6.33), compared with
those treated with placebo plus MTX.

A significantly greater mean increase from baseline in the FACIT-Fatigue score was
observed in the two rituximab arms, compared with the placebo arm.

A significantly greater proportion of patients in the rituximab 2 x 1000 mg arm and the
rituximab 2 x 500 mg arm (p <0.01 and p <0.05, respectively) showed a clinically
meaningful improvement in the FACIT-Fatigue score (≥MCID of 4.0).
Deodhar A, et al. ACR/ARHP 2008; Abstract 365.
MTX = methotrexate
Key findings (cont’d)
Week 48 results

Improvements in HAQ-DI with rituximab plus methotrexate (MTX)
was first observed by week 8 of treatment.

MCID improvements for HAQ-DI, SF-36 physical and mental
components, and FACIT-Fatigue endpoints were sustained at week
48 with both rituximab arms.

Of the rituximab-treated patients with an MCID improvement in
HAQ-DI at week 24, ≥93% had sustained improvement at week 48.

Of the rituximab-treated patients with an MCID improvement in SF36, >78% and >67% had sustained improvement at week 48 in the
PCS and MCS, respectively.
Deodhar A, et al. ACR/ARHP 2008; Abstract 365.
FACIT = Functional Assessment of Chronic Illness Therapy
HAQ-DI = Health Assessment Questionnaire-Disability Index
MCID = minimal clinically important difference
MCS = mental component score; PCS = physical component score
SF-36 = Medical Outcomes Study Short Form (36-item) health survey
Key conclusions

Rituximab as a first-line biologic therapy in patients with active RA
taking a stable dose of methotrexate (MTX) resulted in statistically
significant and sustained clinically important improvements for both
doses over a 48-week period.

Improvements were seen in physical function, as indicated by the
HAQ-DI score, and in the fatigue and health-related QoL
parametres assessed by the FACIT-Fatigue and SF-36 physical
and mental component summary scores.
Deodhar A, et al. ACR/ARHP 2008; Abstract 365.
FACIT = Functional Assessment of Chronic Illness Therapy
HAQ-DI = Health Assessment Questionnaire-Disability Index
MTX = methotrexate ; RA = rheumatoid arthritis;
SF-36 = Medical Outcomes Study Short Form (36-item) health survey
Prospective follow-up of rituximab treatment
in 965 patients with refractory
rheumatoid arthritis (630 patients/year):
tolerance and efficacy data from the French
Registry AIR (autoimmunity and rituximab)
Gottenberg J-E, et al. ACR/ARHP 2008; Abstract 1190.
Background

ACR/ARHP 2008: Gottenberg and colleagues presented data from
the French AIR (Autoimmunity and Rituximab) Registry, the
objective of which is to prospectively assess the safety and efficacy
of rituximab in off-trial patients with rheumatoid arthritis (RA) and
other autoimmune diseases over a period of 5 years.
Gottenberg J-E, et al. ACR/ARHP 2008; Abstract 1190.
Study design

The French Society of Rheumatology has developed an electronic
registry named AIR (Autoimmunity and Rituximab), which is
available online at www.air-cri.org.

The registry has been collecting data on tolerance and efficacy of
rituximab in RA and in other refractory autoimmune diseases (AID)
since September 2005.
Gottenberg J-E, et al. ACR/ARHP 2008; Abstract 1190.
Key findings
Patients with RA


Demographical data:
•
RA patients (n = 965 ), of whom 78.7% were women and 72.7% were RF-positive;
•
mean age was 57.5 years; disease duration was 11.7 years; number of prior
disease-modifying anti-rheumatic drugs (DMARDs) was 3.4;
•
21 .8% of patients had not previously received any anti-TNF (tumour necrosis
factor) inhibitors; 21.4% had received one anti-TNF; 32.7% had received
2 anti-TNFs; 24.1% had received 3 anti-TNFs;
•
3.3% had received abatacept;
•
mean baseline DAS28 was 5.7 ± 1.2;
•
81.3% of patients received prednisone (mean dose: 12.6 ± 10.7 mg/day);
•
mean gammaglobulin level, assessed in 56.3% of the patients, was 11.9 ± 8.5
g/l.
Treatment:
•
monotherapy with rituximab was prescribed in 31.8% of patients;
•
68.2% of patients received a concomitant immunosuppressant.
Gottenberg J-E, et al. ACR/ARHP 2008; Abstract 1190.
Key findings (cont’d)
Patients with RA (cont’d)



Follow-up:
•
729 patients have already had at least one follow-up visit;
•
mean follow-up duration is currently 44.9 weeks (630 patients/year).
Tolerance:
•
157 infusion-reactions;
•
three deaths (related to infection in two patients and worsening of a preexisting lymphoma in one patient) occurred;
•
43 severe infections occurred (6.8 severe infections/100 patients/year,
including 19 broncho-pulmonary, 6 osteo-articular, 8 skin/soft tissues, 6
pyelonephritis, 2 digestive, and 2 ENT), mainly (81.3%) within the 6 months
following rituximab;
•
5 venous thromboses, 3 pulmonary embolisms, and 10 cancers were
observed.
Efficacy:
•
EULAR response was observed in 53.5% of 316 patients who already had
a 6-month follow-up visit;
•
remission was observed in 5% of patients.
Gottenberg J-E, et al. ACR/ARHP 2008; Abstract 1190.
Key findings (cont’d)
Patients with RA (cont’d)

Re-treatment:
•
328 patients (34%) were re-treated after a mean period of 10
months since the last infusion of the first rituximab cycle;
•
76 patients had 3 cycles or more.
Patients with other refractory autoimmune diseases

195 patients (systemic lupus: 41; primary Sjögren’s syndrome: 45;
vasculitis: 24; myositis: 21; other: 64) were included in the registry.

5 deaths (worsening of pre-existing cancer: 2; infection: 1;
worsening of AID: 2) and 9 severe infections occurred.
Gottenberg J-E, et al. ACR/ARHP 2008; Abstract 1190.
AID = autoimmune disease
Key conclusions

Results show good short-term tolerance of rituximab in daily
rheumatological practice, comparable to data from clinical trials,
which has to be confirmed in the long-term by the ongoing
prospective follow-up.
Gottenberg J-E, et al. ACR/ARHP 2008; Abstract 1190.
ACR and DAS28 response over 24 wks in
RA patients treated with rituximab after
an inadequate response to one TNF
Haraoui B, et al. ACR/ARHP 2008; Abstract 762.
Background

Despite the use of tumour necrosis factor (TNF) inhibitors and diseasemodifying anti-rheumatic drugs (DMARDs), many patients with rheumatoid
arthritis (RA) do not respond adequately to treatment.

Rituximab, a monoclonal antibody that selectively targets CD20 B-cells, is
currently approved for use in patients who have failed treatment with an
anti-TNF agent. A post-hoc analysis of the REFLEX study1 suggested that
the efficacy of rituximab is optimized if used after one TNF agent.2

Prospective studies in RA patients that have failed treatment with only one
TNF inhibitor are needed to provide additional evidence to guide the optimal
use of rituximab in this refractory group of patients.

ACR/ARHP 2008: Haraoui and colleagues presented interim data from a
study designed to evaluate the safety of rituximab in combination with
methotrexate (MTX) in RA patients who had an inadequate response (IR) or
were intolerant to treatment with only one prior anti-TNF inhibitor.3
1. Cohen SB, et al. Arthritis Rheum 2006;54(9):2793–2806.
2. Kremer MJ, et al. Ann Rheum Dis 2006;65(Suppl II):326.
3. Haraoui B, et al. ACR/ARHP 2008; Abstract 762.
Study design

The study was an open-label, multicentre clinical trial conducted in
26 centres in Canada and 9 centres in Sweden.

Results are from a pre-defined interim analysis of 50 patients who
had 24 weeks of follow-up.

Patients with an IR to one prior TNF inhibitor received rituximab
(1000 mg on days 1 and 15) in accordance with approved labelling.

Primary safety endpoints were evaluated at days 1 and 15 (rituximab
infusions) and at 4, 8, 12, and 24 weeks after the initial infusion.

Efficacy was evaluated at 4, 12, 24, 36, and 48 weeks after the
initial infusion.

Intensity of adverse events (AEs) was graded according to the scale
detailed in the National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE), version 3.0.
Haraoui B, et al. ACR/ARHP 2008; Abstract 762.
IR = inadequate response
TNF = tumour necrosis factor
Study design (cont’d)
Key findings

Of the 50 patients, 68% were female with a mean age of 55.6 years and a
mean disease duration of 13.6 years. All patients received 2 infusions on days
1 and 15.

Ninety-two percent of patients had discontinued their previous TNF inhibitor
because of inadequate efficacy (25% due to lack of initial response, 64% due
to loss of response over time), and 8% because of AEs/tolerability. Thirty-two
percent of patients were using concomitant glucocorticoids.

Robust ACR responses were achieved at week 24 by the refractory patient
population with long-standing disease.

Improvements in DAS28 were significant (p <0.0001) at week 4 (-1.1 versus
baseline) with an absolute decrease of -2.2 at week 24.

Seventy-eight percent of patients achieved a moderate to good DAS
response, 20% had low disease activity and 8% were in DAS remission
(DAS28 <2.6).

Major improvements (>50%) were observed in all ACR core components with
the exception of the Health Assessment Questionnaire (HAQ) score (28%)
and the erythrocyte sedimentation rate (ESR) (48%).
Haraoui B, et al. ACR/ARHP 2008; Abstract 762.
ACR = American College of Rheumatology
AE = adverse event; DAS = Disease Activity Score
IR = inadequate response; TNF = tumour necrosis factor
Figure 1. ACR response at week 24
Figure 2. EULAR/DAS response at week 24
Key findings (cont’d)

The mean baseline values versus week 24, respectively, were as follows:
•
•
•
•
•

swollen joint count (SJC): 13.7 versus 6.8;
tender joint count (TJC): 15.5 versus 6.2;
patient global: 67.3 versus 36.4;
physician global: 65.5 6 versus 28.9;
•
HAQ: 1.8 versus 1.3;
C-reactive protein (CRP) (mg/dL): 3.0 versus 1.2;
•
ESR (mm/hour): 39.0 versus 20.4.
Improvements were also observed in the level of fatigue as measured by the
FACIT-Fatigue score with a decrease of 34% in fatigue by week 24 (baseline of
28.3; week 24: 18.6).
Safety

Only 3 patients (6%) experienced a serious AE. No patients withdrew from the
primary treatment period because of an AE.

Forty-four infections were observed in 54% of patients during the 24-week
observation period. Only one serious infection (urinary tract) occurred during the
24-week period.
Haraoui B, et al. ACR/ARHP 2008; Abstract 762.
AE = adverse event; ESR = erythrocyte sedimentation rate
FACIT = Functional Assessment of Chronic Illness Therapy
HAQ = Health Assessment Questionaire
Figure 3. Significant improvements across ACR core set at 6 months (ITT)
Key conclusions

At 24 weeks, a single course of rituximab (2 x 1000 mg) with
methotrexate (MTX) provided clinically significant improvements in
disease activity in patients with active, long-standing RA who had
an inadequate response (IR) to one prior TNF inhibitor.

Improvements were observed in DAS28 and the proportion of ACR
responders in this patient population.

Smaller improvements in HAQ are probably due to the irreversible
damage seen in this cohort with long-standing disease.

These data confirm early findings that rituximab is an effective
treatment option for RA patients.
Haraoui B, et al. ACR/ARHP 2008; Abstract 762.
ACR = American College of Rheumatology
DAS = Disease Activity Score
HAQ = Health Assessment Questionaire
RA = rheumatoid arthritis; TNF = tumour necrosis factor
Efficacy, safety, and dose frequency of
retreatment with rituximab in RA: results from
a randomized, controlled trial (SUNRISE)
Mease PJ, et al . ACR/ARHP 2008; Abstract 1212.
Background

Clinical trials using rituximab as selective B-cell–targeted therapy
have demonstrated significant efficacy and safety in modifying the
signs and symptoms of rheumatoid arthritis (RA).1,2,3

In open-label extension studies, sustained efficacy has been
observed over multiple courses of treatment,4 but an optimal
re-treatment paradigm has not been established.

ACR/ARHP 2008: Mease and colleagues presented results of the
phase III, randomized, placebo-controlled SUNRISE study,
designed to assess the efficacy and safety of one versus two
courses of rituximab over 48 weeks.5
1. Cohen SB, et al. Arthritis Rheum 2006;54(9):2793–2806.
2. Edwards JC, et al. N Engl J Med 2004;350(25):2572–2581.
3. Emery P, et al. Arthritis Rheum 2006;54(5):1390–1400.
4. Keystone EC, et al. ACR/ARHP 2008; Abstract 367.
5. Mease PJ, et al. ACR/ARHP 2008; Abstract 1212.
Study design

The SUNRISE study was a controlled re-treatment study of one
versus two courses of rituximab.

Adult patients (n = 550) with active RA on stable methotrexate
(MTX) (10–12 mg/week ≥12 weeks) and with a previous inadequate
response to ≥1 tumour necrosis factor (TNF) inhibitor were enrolled.

All enrolled patients received one course of open-label rituximab
(1000 mg IV on days 1 and 15) at baseline.

From week 24, patients not in DAS28 remission (< 2.6) were
randomized in a 2:1 ratio to receive an additional course of
re-treatment with rituximab or to receive re-treatment with placebo.

Re-treatment could occur until week 40.

Primary endpoint was ACR20 response in re-treated patients at
week 48, relative to baseline.

An intention-to-treat analysis was used for efficacy.
Mease PJ, et al. ACR/ARHP 2008; Abstract 1212.
ACR = American College of Rheumatology
DAS = Disease Activity Score; RA = rheumatoid arthritis
Study design (cont’d)
Key findings

The study enrolled 550 patients, who received the first course of
rituximab at baseline.

At week 24, 42 patients were in DAS remission, and 475 patients
were randomized to a second course in two arms:
•
re-treatment with rituximab (n = 318);
•
re-treatment with placebo (n = 157).

Most randomized patients (n= 426, 90%) were re-treated between
weeks 24 and 28.

In both groups at baseline, approximately 80% of patients were
female, mean age was 54, disease duration was 11–12 years,
baseline DAS28-ESR was 6.7, and HAQ-DI was 1.5.

Relative to baseline, patients re-treated with rituximab had
significantly improved efficacy at week 48 compared with those
re-treated with placebo, respectively (ACR20: 53.5% versus 44.6%,
p = 0.0195; change in DAS28 mean: -1.9 versus -1.5, p= 0.0058).
Mease PJ, et al. ACR/ARHP 2008; Abstract 1212.
ACR = American College of Rheumatology
DAS = Disease Activity Score; ESR = erythrocyte sedimentation rate
HAQ-DI = Health Assessment Questionnaire-Disability Index
Figure 1. ACR20 response at week 48 (ITT)
Figure 2. Change in DAS28-ESR at week 48 (ITT)
Key findings (cont’d)

Differences in efficacy between groups were first observed following
weeks 28 to 32, at which time worsening disease activity was
observed in the patients re-treated with placebo. Patients
re-treated with rituximab maintained efficacy responses.

Patients with strong initial clinical responses were most likely to
benefit from a second course.

Randomized patients who achieved ACR70 following the first
course (n = 45) had more than 4-fold greater odds of maintaining
response if re-treated with rituximab, compared with placebo
(OR: 4.5, p = 0.037).

Following re-treatment, the proportion of patients experiencing any
adverse events (AEs) were comparable between the placebo
versus rituximab re-treatment groups, respectively: total AEs
(76.8% versus 70.6%), serious AEs (7.1% versus 6.9%), infections
(38.1% versus 37.5%), and serious infections (1.9% versus 2.2%)
Mease PJ, et al. ACR/ARHP 2008; Abstract 1212.
ACR = American College of Rheumatology
OR = overall response
Key conclusions

Two courses of rituximab approximately 6 months apart resulted in
improved and sustained efficacy at one year, as compared with a
single course.

Safety profile with two courses of rituximab was comparable to that
of a single course.
Mease PJ, et al. ACR/ARHP 2008; Abstract 1212.