Transcript ASCO 2007 Breast Cancer Research

New Evidence reports on presentations given at EULAR 2009
Factors Affecting the Efficacy
and Safety of Rituximab
Given at Varying Points in the
Treatment of Rheumatoid Arthritis
Report on EULAR 2009 presentations
 Rituximab compared with further TNF inhibitor therapy in rheumatoid
arthritis patients who had previously failed TNF inhibitor therapy
(Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257)
 Inhibition of joint damage and improved clinical outcomes with a
combination of rituximab and methotrexate in patients with early active
rheumatoid arthritis who are naïve to methotrexate: a randomized, active
comparator placebo-controlled trial (IMAGE)
(Tak P-P, et al. EULAR 2009: Abstract OP-0022)
 Long-term safety of rituximab: follow-up of the rheumatoid arthritis clinical
trials and re-treatment population
(Van Vollenhoven R, et al. EULAR 2009: Abstract OP-0026)
 Rate of serious infections in rituximab-treated patients with rheumatoid
arthritis who subsequently received other biologic therapies
(Genovese MC, et al. EULAR 2009: Abstract SAT0097)
 Autoantibody-positive rheumatoid arthritis patients have enhanced clinical
response when compared with seronegative patients
(Isaacs J, et al. EULAR 2009: Abstract FRI0256)
EULAR = European League Against Rheumatism
TNF = tumour necrosis factor
Rituximab compared with further TNF inhibitor
therapy in rheumatoid arthritis patients who had
previously failed TNF inhibitor therapy
Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.
Background

Results of the REFLEX study showed that rituximab is effective and
well tolerated in patients who have had an inadequate response to
one or more TNF-Is.1

At EULAR 2009, Gómez-Reino and colleagues presented the results
of their prospective, observational study.

The study was designed to assess the efficacy of cycling to an
alternative TNF-I, compared with receiving rituximab, in RA patients
who had previously failed TNF-I therapy.2
1. Cohen SB, et al. Arthritis Rheum 2006;54(9):2793–2806.
2. Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.
EULAR = European League Against Rheumatism
RA = rheumatoid arthritis
TNF-I = tumour necrosis factor inhibitor
Study design

The study by Gómez-Reino and colleagues is an ongoing,
multicentre, prospective, three-year observational study of a cohort
of RA patients who received either rituximab or an alternative
TNF-I, having previously failed a TNF-I.

Results are based on the first follow-up of patients at 3–6 months
after treatment initiation.

Patients were included in the study if they had active RA that had
been previously treated with a TNF-I which did not provide an
adequate response, was contraindicated because of safety, or was
discontinued.
Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.
RA = rheumatoid arthritis
TNF-I = tumour necrosis factor inhibitor
Study design (cont’d)

Assessments were made at baseline, on treatment adjustment,
every 4 months, and on premature discontinuation.

Assessments included:
•
DAS28 to evaluate inflammatory status and ESR
•
evaluation of 66 joints for swelling and 68 joints for tenderness
•
response assessment using EULAR criteria
•
HAQ-DI score
•
VAS patient assessment of disease activity
Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.
DAS28 = 28-joint Disease Activity Score
ESR = erythrocyte sedimentation rate
EULAR = European League Against Rheumatism
HAQ-DI = Health Assessment Questionnaire Disability Index
VAS = Visual Analogue Scale
Key findings

At the time of this analysis, there were 226 evaluable patients:
•
•

69 had received rituximab
157 had received an alternative TNF-I
Compared with those receiving an alternative TNF-I, significantly
more patients receiving rituximab:
•
had received at least DMARDs
•
reported toxicity with DMARDs
•
used concomitant glucocorticoids
•
reported morning stiffness
•
were older
•
had disease duration of >4 years
•
had higher DAS28, SJC, TJC, ESR, and HAQ-DI scores
Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.
DAS28 = 28-joint Disease Activity Score
DMARD = disease-modifying anti-rheumatic drug
ESR = erythrocyte sedimentation rate
HAQ-DI = Health Assessment Questionnaire Disability Index
SJC = swollen joint count; TJC = tender joint count
TNF-I = tumour necrosis factor inhibitor
Key findings (cont’d)

The number of patients who were RF positive at baseline in each
group was not given.

In the first 3–6 months, rituximab-treated patients had a greater mean
change in DAS28 response of –1.54 (95% CI, –1.91 to –1.17)
versus the TNF-I–treated patients, who had a change of –0.87
(95% CI, –1.11 to –0.64) (p = 0.002).

A significantly greater proportion of rituximab-treated patients had a
decrease in DAS28 >1.2 than those receiving an alternative TNF-I
(57.6% versus 37.9%, respectively; p = 0.012).

In a subgroup of patients with only one TNF-I failure, mean change
from baseline in DAS28 was statistically significantly greater for those
receiving rituximab (n = 30; mean change in DAS28 –1.6) compared
with those receiving an alternative TNF-I (n = 107; mean change in
DAS28 –0.8) (p = 0.008).
Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.
CI = confidence interval
DAS28 = 28-joint Disease Activity Score
RF = rheumatoid factor
TNF-I = tumour necrosis factor inhibitor
Key findings (cont’d)

No statistically significant differences occurred in the mean change in
DAS28 between rituximab (n = 29; mean change in DAS28 –1.50) and
TNF-I (n = 17; mean change in DAS28 –0. 9) in a subgroup of patients
with two or more previous TNF-I failures.

Statistically significantly more rituximab-treated patients achieved a
moderate or good EULAR response compared with those receiving an
alternative TNF-I.

Changes from baseline in all other disease activity and patient-reported
outcome measures assessed were statistically significant in favour of
rituximab-treated patients over those treated with an alternative TNF-I,
with the exception of HAQ-DI.

Overall, both treatments were well tolerated.

In all, 28 AEs were reported (15 in the rituximab group and 13 in the TNF-I
group), with some patients experiencing more than one AE.

A total of 8 infections were reported: 3 infections in the rituximab group
and 5 in the TNF-I group.
AE = adverse event; DAS28 = 28-joint Disease Activity Score
Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.
EULAR = European League Against Rheumatism
HAQ-DI = Health Assessment Questionnaire Disability Index
TNF-I = tumour necrosis factor inhibitor
Figure 1. Proportion of patients who achieved a EULAR
response at first follow-up (3–6 months) following
treatment with rituximab or an alternative TNF-I
Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.
EULAR = European League Against Rheumatism
TNF-I = tumour necrosis factor inhibitor
Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.
Key conclusion
 Rituximab provides an alternative therapeutic option to
TNF cycling in RA patients who have failed previous
TNF inhibitor therapy.
Gómez-Reino JJ, et al. EULAR 2009: Abstract FRI0257.
RA = rheumatoid arthritis
TNF = tumour necrosis factor
Inhibition of joint damage and improved clinical
outcomes with a combination of rituximab and
methotrexate in patients with early active
rheumatoid arthritis who are naïve to
methotrexate: a randomized active comparator
placebo-controlled trial (IMAGE)
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
Background
 At EULAR 2009, Tak and colleagues presented data from
the IMAGE (International Study in Methotrexate-nAïve
Subjects InvestiGating Rituximab’s Efficacy) study.
 The IMAGE study was designed to evaluate clinical and
radiographic outcomes with a combination of rituximab and
MTX versus MTX alone in patients with early RA not
previously treated with MTX.1
1. Tak P-P, et al. EULAR 2009: Abstract OP-0022.
EULAR = European League Against Rheumatism
MTX = methotrexate; RA = rheumatoid arthritis
Study design

The IMAGE study was a prospective, double-blind, phase III,
randomized, controlled trial designed to assess the efficacy of
rituximab in combination with MTX compared to MTX monotherapy
in RA patients.

Patients included in the study:
•
had no prior exposure to MTX, with a disease duration
of <4 years
•
had an SJC and TJC of ≥8 each
•
had a CRP concentration of ≥1.0 mg/dL
•
were RF positive or exhibited erosive damage

Patients were randomized to receive placebo plus MTX, rituximab
(2 x 500 mg) plus MTX, or rituximab (2 x 1000 mg) plus MTX.

MTX was initiated in all groups at 7.5 mg/wk and titrated to 20 mg/wk
by week 8. Rituximab was given by intravenous infusion on
days 1 and 15.
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
CRP = C-reactive protein; MTX = methotrexate
RA = rheumatoid arthritis; RF = rheumatoid factor
SJC = swollen joint count; TJC = tender joint count
Study design (cont’d)

At week 24, patients with DAS28 ≥2.6 received a second course
of rituximab.

Patients with DAS28 <2.6 were re-treated if and when their DAS28
increased to ≥2.6.

Radiographs were taken at screening, and at weeks 24 and 52,
and centrally read using mTSS. Readers were blinded to the
sequence and treatment.

The primary endpoint was the change from screening in mTSS
at week 52.

Secondary endpoints included ACR and EULAR responses,
MCR (ACR70 maintained for at least 6 months), and change in
DAS28.
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
ACR = American College of Rheumatology
DAS28 = 28-joint Disease Activity Score
EULAR = European League Against Rheumatism
MCR = major clinical response
mTSS = Genant-modified sharp method
Key findings

A total of 755 patients were randomized, and 715 patients were
radiographically evaluable at 52 weeks.

Groups were well matched at baseline, with a mean RA duration of
0.9 years and DAS28 >7.

At 52 weeks, the rituximab (2 x 1000 mg) plus MTX group had a
significantly lower change in mTSS (p = 0.0003) compared with the
placebo plus MTX group.

This comparison was not significant for the rituximab (2 x 500 mg)
plus MTX group versus the placebo plus MTX group.

At 52 weeks, the rituximab (2 x 1000 mg) plus MTX group had a
significantly higher proportion of patients with no joint progression
(p <0.05) compared with the placebo plus MTX group.

This comparison was not significant for the rituximab (2 x 500 mg)
plus MTX group versus the placebo plus MTX group.
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
DAS28 = 28-joint Disease Activity Score
mTSS = Genant-modified sharp method
MTX = methotrexate; RA = rheumatoid arthritis
Figure 1. Mean change in mTSS score
after 52 weeks of treatment
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
mTSS = Genant-modified sharp method
Figure 2. Percentage of patients with an
mTSS score ≤0 after 52 weeks of treatment
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
mTSS = Genant-modified sharp method
Key findings (cont’d)

At 52 weeks, both doses of rituximab plus MTX improved ACR and
EULAR responses, compared with MTX monotherapy.

The proportion of patients with an MCR after 52 weeks was:

•
18.4% in the rituximab (2 x 1000 mg) plus MTX group
(n = 250; p = 0.0006 versus MTX)
•
17.3% in the rituximab (2 x 500 mg) plus MTX group
(n = 249; p = 0.0019 versus MTX)
•
8% in the placebo plus MTX group (n = 249)
The mean change in DAS28-ESR score was:
•
–3.21 in the rituximab (2 x 1000 mg) plus MTX group (n = 248)
•
–3.05 in the rituximab (2 x 500 mg) plus MTX group (n = 247)
•
–2.06 in the placebo plus MTX group (n = 244)
(p <0.0001 for all comparisons with MTX)
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
ACR = American College of Rheumatology
DAS28 = 28-joint Disease Activity Score; ESR = erythrocyte sedimentation rate
EULAR = European League Against Rheumatism; MCR = major clinical response
mTSS = Genant-modified sharp method; MTX = methotrexate
Figure 3. ACR response after 52 weeks of treatment
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
ACR = American College of Rheumatology
Figure 4. EULAR response after 52 weeks of treatment
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
EULAR = European League Against Rheumatism
Key findings (cont’d)

Serious adverse events occurred in:
•

10% of patients in the placebo plus MTX group
•
9% of patients in the rituximab (2 x 500 mg) plus MTX group
•
10% of patients in the rituximab (2 x 1000 mg) plus MTX group
The rate of serious infections (events per 100 patient-years) was:
•
6.09 events in the placebo plus MTX group
•
4.61 events in the rituximab (2 x 500 mg) plus MTX group
•
3.73 events in the rituximab (2 x 1000 mg) plus MTX group

Three deaths occurred: two from pneumonia and one from cerebral
infarction.

All deaths were in the placebo plus MTX group.
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
MTX = methotrexate
Key conclusions
 Using rituximab earlier in the treatment algorithm as a
first-line biologic aids in the prevention of joint damage in
rheumatoid arthritis.
 Both higher (2 x 1000 mg) and lower (2 x 500 mg) doses
of rituximab plus MTX improved clinical outcomes, as
compared with MTX alone, after 52 weeks of treatment.
 After 52 weeks of treatment in patients with early active
rheumatoid arthritis, only rituximab (2 x 1000 mg) plus MTX
significantly improved radiographic outcomes and inhibited
joint damage.
Tak P-P, et al. EULAR 2009: Abstract OP-0022.
MTX = methotrexate
Long-term safety of rituximab: follow-up
of the rheumatoid arthritis clinical trials
and re-treatment population
Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.
Background
 At EULAR 2009, Van Vollenhoven and colleagues
presented data from their study examining the long-term
safety of rituximab in combination with MTX
in patients with RA.1
1. Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.
EULAR = European League Against Rheumatism
MTX = methotrexate; RA = rheumatoid arthritis
Study design

The study by Van Vollenhoven and colleagues was a pooled analysis
of safety data from RA patients treated with rituximab in combination
with MTX in a global clinical trial program.

All patients were offered repeat treatment with rituximab, as
determined by clinical need.

Data were collected on AEs, including infusion reactions, infections,
and malignancies.

Serious infusion reaction events were defined as evidence of pruritus,
fever, urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic
oedema, throat irritation, cough, bronchospasm, hypotension,
or hypertension.
Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.
AE = adverse event; MTX = methotrexate
RA = rheumatoid arthritis
Key findings

The analysis (as of April 2008) was based on 5,964 patient-years of
rituximab exposure.

A total of 2,579 patients with RA received multiple courses of rituximab:
1,926; 1,228; 794; and 282 patients received ≥2, ≥3, ≥4, and ≥5 courses,
respectively.

A total of 2,417 patients were followed for >1 year, 1,198 for >2 years,
743 for >3 years, 564 for >4 years, and 109 for >5 years from start
of treatment.

Withdrawals from the trial due to AEs occurred in 138 patients (5%).

The most frequent AEs were infusion-related reactions. There were 15 serious
infusion-related events in 14 patients (0.5%), with 10, 4, 0, 1, and 0 events in
C1 to C5, respectively.

Twenty-five percent (25%) of patients reported infusion reactions for the first
infusion of the first course, and the percentage decreased for subsequent
infusions.
Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.
AE = adverse event; C = course
RA = rheumatoid arthritis
Key findings (cont’d)

Rates of AEs, serious AEs, and infections remained stable following
each course.

The overall serious infection event rate was 4.26/100 patient-years
(95% CI, 3.77–4.82).

Rates of infection and serious infection remained stable over time.

One case of progressive, multifocal leukoencephalopathy was
reported in a patient who also received cancer chemotherapy.

There were no cases of tuberculosis.

The malignancy rate was comparable to malignancy rates in the
general RA population.
Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.
AE = adverse event; CI = confidence interval
MTX = methotrexate; RA = rheumatoid arthritis
Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.
Figure 1. Serious infection event rates by rituximab treatment course
Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.
Key conclusions
 Overall rates of adverse events, serious adverse events,
and infections remained stable over time and by treatment
course.
 No cases of tuberculosis were reported.
 In long-term re-treatment trials, rituximab has remained
well tolerated with administration of up to five courses,
with a stable safety profile.
Van Vollenhoven RF, et al. EULAR 2009: Abstract OP-0026.
Rate of serious infections
in rituximab-treated patients with
rheumatoid arthritis who subsequently
received other biologic therapies
Genovese MC, et al. EULAR 2009: Abstract SAT0097.
Background

An increase in the number of treatment options for RA has meant
that patients may switch therapies a number of times during the
course of their disease.

After using rituximab, other biologic DMARDs may be given during
a period of B-cell depletion.

The safety implications, particularly those concerning infection, of
switching from rituximab to other biologic therapies have not been
examined.1

At EULAR 2009, Genovese and colleagues presented data from
their study examining the rate of serious infection events in
RA patients previously treated with rituximab and subsequently
receiving a biologic DMARD while peripherally B-cell (CD20+)
depleted.1
1. Genovese MC, et al. EULAR 2009: Abstract SAT0097.
DMARD = disease-modifying anti-rheumatic drug
EULAR = European League Against Rheumatism
RA = rheumatoid arthritis
Study design

Eligible patients were those with active RA who had received at least
one course of rituximab (either 2 x 500 mg or 2 x 1000 mg infusions
given 2 weeks apart) during participation in one of seven clinical trials
(SERENE, SUNRISE, MIRROR, SIERRA, REFLEX III, DANCER IIa,
and DANCER IIb) and 2 open-label extension trials (DANCER and
REFLEX).

Patients who completed the trial or withdrew from receiving further
courses of rituximab were required to enter a safety follow-up period
consisting of periodic visits approximately every 12 weeks for at least
one year, during which additional biologic DMARD RA therapies were
permitted.

Patients were examined based on the biologic DMARD therapy
received during the follow-up.
Genovese MC, et al. EULAR 2009: Abstract SAT0097.
DMARD = disease-modifying anti-rheumatic drug
RA = rheumatoid arthritis
Study design (cont’d)

All patients receiving biologic DMARD therapy in addition to
concomitant weekly MTX were assessed as 2 groups:
•
all patients receiving biologic DMARDs, including TNF-Is
•
patients receiving a TNF-I

Patients receiving a TNF-I in addition to or subsequent to receiving a
different biologic DMARD were included in the TNF-I sub-population.

Serious infection events (SIEs), peripheral CD19+ counts (a surrogate
marker for CD20+ B cells), and concomitant medications were
collected.

Due to limited data (cut-off date was April, 2008), only exploratory
descriptive analysis was performed, with no formal statistical testing.

The SIE rates (events per 100 patient-years) while on rituximab but
before initiation of a biologic DMARD were calculated and compared
to rates after initiating a biologic DMARD.
Genovese MC, et al. EULAR 2009: Abstract SAT0097.
DMARD = disease-modifying anti-rheumatic drug
MTX = methotrexate; RA = rheumatoid arthritis
TNF-I = tumour necrosis factor inhibitor
Key findings

To date, 2,579 patients have received rituximab treatment in the global
clinical trial program, representing 5,964.3 patient-years.

Of the rituximab-treated patients, 216 (8%) have switched to another
biologic DMARD following rituximab treatment:
•
178 patients (82%) received TNF-Is: 52 (25%) received etanercept,
54 (25%) received infliximab, and 69 (32%) received adalimumab as
their first biologic DMARD after rituximab
•
31 patients (14%) received abatacept, and 9 patients (4%) received
anakinra (included 2 patients who subsequently received a TNF-I)

Approximately 35% of the 216 patients received their biologic within
6 months of their last rituximab infusion.

Median and mean time from the last dose of rituximab to the first biologic
DMARD was 8 months (range: 0.5–37 months) and 9 (±6) months,
respectively.

Median and mean follow-up time after receipt of the subsequent biologic
was 11 months (range: 0–45 months) and 12 (±9) months, respectively.
Genovese MC, et al. EULAR 2009: Abstract SAT0097.
DMARD = disease-modifying anti-rheumatic drug
TNF-I = tumour necrosis factor inhibitor
Key findings (cont’d)

At the time of receiving further RA treatment, the majority (86.1%) of
patients had peripheral B-cell depletion, with CD19+ levels below the
LLN (<80 cells/μL).

The mean CD19+ B-cell count was 34.7 (±64.7) cells/μL
(range: 0–459 cells/μL).

The overall SIE rate in the all-exposure safety population was
4.26/100 patient-years (95% CI, 3.77–4.82).

Of the 216 patients who withdrew and received another biologic
DMARD, a total of 13 SIEs in 12 patients were reported during
treatment with rituximab and prior to receipt of another DMARD
(5.73/100 patient-years).

Following the initiation of the biologic DMARD, 12 SIEs in 12 patients
were reported (5.36/100 patient-years).
Genovese MC, et al. EULAR 2009: Abstract SAT0097.
CI = confidence interval
DMARD = disease-modifying anti-rheumatic drug
LLN = lower limit of normal; RA = rheumatoid arthritis
SIE = serious infection event
Genovese MC, et al. EULAR 2009: Abstract SAT0097.
Key findings (cont’d)

The median and mean time to the SIE after initiating another biologic
DMARD was 6 months (range: 0–23 months) and 9 (±8) months,
respectively.

The time to the specific SIE was highly variable and did not show any
specific temporal pattern.

Of the 12 patients reporting SIEs following another biologic DMARD,
10 patients had mean peripheral B-cell counts below the LLN at the
time of receiving the biologic DMARD and at the last measurement
prior to the SIE, with a mean of 23.6 (±26.9) cells/μL and a median of
10 cells/μL (range: 1–69 cells/μL).

Of these 10 patients, one patient had an IgG level below the LLN
(5.2 g/L) prior to the SIE.

This patient experienced a UTI while on adalimumab and
subsequently had an IgG level above the LLN 18 days following the
onset of infection.
Genovese MC, et al. EULAR 2009: Abstract SAT0097.
DMARD = disease-modifying anti-rheumatic drug
LLN = lower limit of normal; SIE = serious infection event;
UTI = urinary tract infection
Key findings (cont’d)

Three (3) patients experienced more than one SIE:
•
One patient had two cases of pneumonia (before and after
starting anakinra)
•
A second patient had pneumonia before starting adalimumab
and a UTI after starting adalimumab
•
A third patient experienced one case of bronchitis and one case of
UTI before starting etanercept

In the 31 patients receiving abatacept and 9 patients receiving
anakinra, there was one SIE before and one SIE after receiving each
of these biologics.

All but five of the patients with SIEs were also taking concomitant
glucocorticoids.

There were no opportunistic or fatal infections.
Genovese MC, et al. EULAR 2009: Abstract SAT0097.
SIE = serious infection event; UTI = urinary tract infection
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.
 Overall, the infections were variable and typical for
RA patients.
Genovese MC, et al. EULAR 2009: Abstract SAT0097.
RA = rheumatoid arthritis
Autoantibody-positive rheumatoid arthritis
patients have enhanced clinical response when
compared with seronegative patients
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
Background

Previous studies using rituximab in patients with an inadequate
response to TNF-Is have suggested that seropositivity for either
or both of the autoantibodies RF and anti-CCP is associated with
improved clinical benefit compared with seronegative patients.1

At EULAR 2009, Isaacs and colleagues presented data from a
pooled non-placebo controlled patient cohort from the MIRROR2
and SERENE3 trials, designed to examine the effect of patient
seropositivity on the efficacy of rituximab.1
1. Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
2. Rubbert-Roth A, et al. ACR 2008: Abstract 363.
3. Emery P, et al. ACR 2008: Abstract 364.
CCP = cyclic citrullinated peptide
EULAR = European League Against Rheumatism
RA = rheumatoid arthritis; RF = rheumatoid factor
TNF-I = tumour necrosis factor inhibitor
Study design

The study by Isaacs and colleagues was designed to examine whether
baseline seropositivity (RF and/or anti-CPP) enriches clinical responses
versus patients seronegative for both autoantibodies in a population of
RA patients from the MIRROR and SERENE trials.

The MIRROR and SERENE trials were randomized, double-blind,
placebo-controlled, phase III trials designed to evaluate the safety and
efficacy of various regimens of rituximab in combination with MTX in
patients who had had a previous inadequate response to MTX.

Both studies had the following inclusion criteria:
•
RA for at least 6 months, diagnosed according to the revised
1987 ACR criteria for the classification of RA
•
SJC ≥8 (66 joint count) and TJC ≥8 (68 joint count) at screening
and baseline
•
either CRP ≥0.6 mg/dL or ESR ≥28 mm/hour
•
background MTX 10–25 mg/week at a stable dose
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
ACR = American College of Rheumatology
CCP = cyclic citrullinated peptide; CRP = C-reactive protein
ESR = erythrocyte sedimentation rate; MTX = methotrexate
RA = rheumatoid arthritis; RF = rheumatoid factor
SJC = swollen joint count; TJC = tender joint count
Study design (cont’d)

Patients received rituximab by intravenous infusion on days 1 and 15 at
doses of 2 x 500 mg or 2 x 1000 mg.

At week 24, further courses of rituximab were permitted according to
individual study criteria.

All infusions of rituximab were preceded by 100 mg intravenous
methylprednisone.

Patients from low-dose rituximab (2 x 500 mg, 2 x 500 mg) and high-dose
rituximab (2 x 1000 mg, 2 x 1000 mg) groups were included from both
studies.

The first course of the dose escalation arm from the MIRROR study
(2 x 500 mg) was also included in the analysis, although second-course
data (2 x 1000 mg) were excluded to ensure alignment with other
treatment groups.

Clinical outcomes determined at weeks 24 and 48 included ACR and
EULAR responses, change from baseline in DAS28, low disease activity
(DAS28 <3.2), and remission (DAS28 ≤2.6).
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
ACR = American College of Rheumatology
DAS28 = 28-joint Disease Activity Score
EULAR = European League Against Rheumatism
Study design
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
Study design (cont’d)

Serological status for RF (positive: >20 IU/mL) and anti-CCP
(positive: >5 U/mL, DiastatTM, AxisShield, Dundee, Scotland) were
determined at baseline.

Patients positive for either or both autoantibodies were compared to
those who were seronegative for both.

The analyses were carried out in patients who completed 48 weeks in
their respective studies without imputation for missing values.

Association of serotype with clinical outcomes was assessed by
logistic regression analysis or by analysis of variance (ANOVA) as
appropriate at weeks 24 and 48.

A significance level of p <0.05 was adopted throughout.
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
CCP = cyclic citrullinated peptide
RF = rheumatoid factor
Key findings

A total of 670 patients were included (554 seropositive,116 seronegative).

Across all analyses, patients positive for only one autoantibody showed a
comparable response to patients positive for both autoantibodies.

As single-positive patients comprised a relatively small component of the
total seropositive population, all results are represented as a pooled
seropositive population.

Following the first and second courses of rituximab, both seronegative and
seropositive patients showed a decrease in DAS28-ESR.

Seropositive patients responded with a significantly greater decrease than
the seronegative patients at all time points.

After adjusting for initial change in DAS28 at week 24, there was statistical
evidence that seropositive patients showed a further enhanced reduction of
DAS28 at week 48 compared with seronegative patients (p <0.05).
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
DAS28 = 28-joint Disease Activity Score
ESR = erythrocyte sedimentation rate
Figure 1. Change from baseline in DAS28-ESR by serotype in
pooled samples from MIRROR and SERENE
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
DAS28 = 28-joint Disease Activity Score
ESR = erythrocyte sedimentation rate
Key findings (cont’d)

Proportions of patients achieving DAS28-ESR low disease activity or
remission were greater in the seropositive population at 24 weeks,
but not significantly different.

At 48 weeks, patients who were seropositive were significantly more
likely to achieve low disease activity (p <0.05).

Statistical significance was not achieved for remission.

Statistical analysis of ACR responses at week 24 indicated that
patients who were seropositive had significantly increased odds of
achieving ACR20 and ACR50 responses compared with seronegative
patients (p = 0.03 and p = 0.0096, respectively).

The probability of achieving an ACR70 response was not significantly
different between patients who were seropositive and patients who
were seronegative.
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
ACR = American College of Rheumatology
DAS28 = 28-joint Disease Activity Score
ESR = erythrocyte sedimentation rate
Figure 2. Proportion of patients with DAS28 low disease activity
by serotype in pooled samples from MIRROR and SERENE
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
DAS28 = 28-joint Disease Activity Score
Figure 3. Proportion of patients with DAS28 remission by
serotype in pooled samples from MIRROR and SERENE
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
DAS28 = 28-joint Disease Activity Score
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
ACR = American College of Rheumatology
Key findings (cont’d)

At week 48, seropositive patients had significantly increased odds
of achieving ACR20 and ACR50 responses when compared with
seronegative patients (p <0.05 and p <0.001, respectively).

Serapositive patients were also more likely to achieve ACR70
responses compared with seronegative patients (p = 0.0068).

At week 48, odds ratios for seropositive patients versus
seronegative patients of achieving ACR20, 50, and 70 responses
were 2.23 (95% CI, 1.38–3.58), 2.72 (95% CI, 1.58–4.70), and
3.29 (95% CI, 1.40–7.82), respectively.

The odds ratio for achieving low disease activity was 2.29
(95% CI, 1.20–4.38)

The odds ratio for achieving remission was 2.3 (95% CI, 0.93–6.10).
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
ACR = American College of Rheumatology
CI = confidence interval
Key conclusions
 After 48 weeks of treatment, responses to rituximab in
patients who were seropositive for RF and/or anti-CPP were
significantly enhanced.
 Seropositive patients were 2 to 3 times more likely to
achieve ACR responses compared with patients
seronegative for both autoantibodies.
Isaacs JD, et al. EULAR 2009: Abstract FRI0256.
ACR = American College of Rheumatology
CCP = cyclic citrullinated peptide
RF = rheumatoid factor