Rheumatoid Arthritis:
Expanding Treatment Options
HIGHLIGHTS FROM
EULAR 2008 PRESENTATIONS
June 11-14, 2008
Paris, France
Rituximab is Approved
After Failure with 1 anti-TNFa Inhibitor
• Is there a benefit to using Rituximab, instead of another
TNFa-inhibitor, when a patient has already failed a
TNFa-inhibitor?
• What are long-term results of its use in the real World?
• What are the options when Rituximab doesn’t work?
• Can you use a TNFa-inhibitor with Rituximab?
Switching to rituximab vs. alternative second or third
TNF-inhibitor after treatment failure to first TNF-inhibitor
Rationale
• About 30% of patients on anti-TNF agents do not
respond to treatment and large numbers of responders
eventually lose their response
• When patients fail one anti-TNF agent, switching to
another class of agent such as rituximab may be more
effective than opting for a second or third TNF inhibitor
Finckh et al. EULAR 2008, abstract OP-0249.
Decreased effectiveness to a Second anti-TNF
EULAR response rates 3 months after anti-TNF initiation
Adapted from Navarro et al. Arthritis Rheum 2006;54:abstract 873 (Spanish RA cohort)
Switching to Rituximab vs. alternative second or third
TNF-inhibitor after treatment failure to First TNF-inhibitor
Patients and treatment
300 patients had failed at least one anti-TNF agent
• 101 patients received a first cycle of rituximab
• 199 an alternative anti-TNF agent
Primary outcome:
Evolution of DAS28 scores over the 1st year
Finckh et al. EULAR 2008, abstract OP-0249.
Initiate treatment with a biological agent with a different
mechanism of action: Lasting change in DAS28 over 24
weeks with rituximab
Mean change in DAS28
Weeks
In RA patients with an inadequate response to anti-TNFs, the REFLEX
trial has demonstrated that rituximab is more effective than placebo
Adapted from Cohen et al. Arthritis Rheum 2006; 54: 2793–806
Results
• Overall evolution of DAS28 was more favourable in the rituximab
group than in the anti-TNF group (P=0.01)
DDAS28 score after six months
according to reason for switching
Rituximab
Ineffectiveness to previous antiTNF agent
-1.55
-1.03
Significant
Adverse event
-0.86
-0.77
Non-significant
Alternate anti-TNF
This study suggests that rituximab is more effective than switching
to an alternative anti-TNF agent in patients who have persistent
active disease despite anti-TNF therapy
Finckh et al. EULAR 2008, abstract OP-0249.
The STURE Registry
(Stockholm TNFa uppföljningsergister)
• The STURE registry is a comprehensive registry in the larger Stockholm
area of patients receiving biological therapies for RA
• The registry described experience with rituximab in 114 of these patients
• EULAR disease activity: 78% high, 19% moderate
Baseline demographics
Female
83%
Age
57 ± 14 Female; 58 ± 11 Male
Disease duration (years)
12 ± 14
Rheumatoid Factor
(RF)-positive antibodies
91%
Number of prior anti-TNF
2.01 ± 0.81
DAS28
6.03 ± 1.26 (Female: 5.96 ±1.22; male: 6.42 ±1.41)
HAQ disability index
1.57 ±0.59
van Vollenhoven et al. EULAR 2008, abstract FRI0168.
(Female: 1.64 ±0.58; male: 1.21 ±0.54, P=0.01)
The STURE Registry: DAS28 Response
P=0.002
P<0.001
van Vollenhoven et al. EULAR 2008, abstract FRI0168.
The STURE Registry EULAR Response
n=71
n=51
n=27
• At 3 months 64% of patients achieved a good/moderate response; 19% a good response and 14% a DAS28 <2.6
• At 6 months, 62% achieved a good/moderate response; 23% a good response and 18% a DAS28 <2.6
van Vollenhoven et al. EULAR 2008, abstract FRI0168.
The STURE Registry Conclusions
• After 9 months of follow-up, there was no difference in
efficacy between patients treated with or without MTX
• Efficacy appears similar in RF+ and RF– patients
• Results in this registry were consistent with clinical trials
• Rituximab is a useful therapy in patients with very active,
TNF-refractory RA, with 60-70% having a EULAR
response and 20-30% achieving low disease activity or
remission
van Vollenhoven et al. EULAR 2008, abstract FRI0168.
A UK Single-centre Experience
• Real-world” clinical experience with any drug does not always
reflect that of clinical trials
• It is important to understand if general use of rituximab offers
patients similar efficacy and safety as reported in clinical trials
• Investigators describe a single-centre experience in which the
long-term effects of rituximab were documented for their first
100 patients
Characteristics for all patients:
• DAS28 >5.1
• RF-positive or anti-CCP antibody
• Inadequate response or contraindication to anti-TNF agents
• Clinical outcome was determined at 6 months by EULAR criteria
Dass et al. EULAR 2008, abstract AB0352
Mean DAS 28 scores at 6 months improved
with each cycle
A UK Single-centre Experience
• Mean DAS28 scores at 6 months improved with
each cycle
• Only 6 patients out of the 100 treated did not
respond to Rituximab therapy (94% response rate)
• All good responses were maintained after the
second cycle and 18% of previously moderate
responders improved further and achieved good
responses
• Initial non-response does not preclude response to
further therapy
Dass et al. EULAR 2008, abstract AB0352
A UK Single-centre, Real-world Experience
• Rituximab appears to be well tolerated, even in
those patients with complex disease
• 19% were on leflunomide instead of
methotrexate, 6% were not on a DMARD
– No differences in duration of response
observed in any of these groups
Dass et al. EULAR 2008, abstract AB0352
A Real-world Experience in a Canadian Centre
• Investigators reviewed the use of rituximab in severe
RA patients refractory to DMARD and anti-TNF
therapy
• A total of 21 patients from a prospective longitudinal
database in Calgary were included
Hazlewood et al. EULAR 2008, abstract AB0362
A Real-world experience in a Canadian Centre
Assessment at 3 months
Good or moderate
EULAR response
Average DAS28 score
Average mHAQ
82%
-2.6
-0.63
Eight patients required a second course of rituximab after an average
of 10.4 months, and one required a third course
• 2 cases of serious infections and 4 of non-serious infections
• Three infusion reactions occurred in 2 patients
• Nonspecific reactions occurred in 3 patients
Hazlewood et al. EULAR 2008, abstract AB0362
A Real-world Experience in a Canadian Centre
Conclusions
• Rituximab is efficacious in the treatment of patients with
severe RA who are intolerant or resistant to anti-TNF
therapy
• Results support evidence that depletion of B cells with
rituximab is efficacious in RA
• Adverse events did occur but none were fatal
Hazlewood et al. EULAR 2008, abstract AB0362
Optimizing response to retreatment with rituximab
• It was previously reported that for every 1.0 point the
DAS28 was allowed to worsen before a 2nd course of
rituximab, patients had a 0.32 point higher DAS28 postretreatment
• Investigators explored whether the more clinically
accessible Simplified Disease Activity Index (SDAI) and
the Clinical Disease Activity Index (CDAI) might also be
predictive of retreatment outcome
• Analysis was based on the REFLEX trial (Arthritis &
Rheumatism 2006;54(9):2793-806) and subsequent
open-label extension study
Mease et al. EULAR 2008, abstract THU0188
REFLEX Study design and open-label
extension phase
Screen/TNF
and/or DMARD
withdrawal
period
Open-label
Extension study
Double-blind
course 1
Randomization
•
•
•
•
•
•
Rituximab + MTX
(Group A)*
Methotrexate
(MTX) x
≥ 3 months
Placebo + MTX
(Group B)*
Screen
Day
1
Week Week Week Week Week Week Week
2
4
8
12
16
20
24
Rituximab: 1000 mg or placebo iv infusion
Methylprednisolone: 100 mg iv before rituximab infusion
Prednisone: 60mg day 2-7, 30mg day 8-14
•
Clinic visit
Rescue
Standard of care
Primary efficacy time point
Rituximab +MTX
*Note: The group A and B ITT populations were 298 and 201, respectively.
Mease et al. EULAR 2008, abstract THU0188
Timing of course
2 was at
physician
discretion
SDAI and CDAI for Predicting Outcome of a
Second Course of Rituximab for Patients with RA
Mean disease activity scores by time to course 2 intervals
BSE (Day 1C1)
Week 24 C1
Prior to C2
Week 24 C2
≤36 weeks
50.00
30.26
37.27
23.71
37-52 weeks
51.48
17.23
43.09
15.75
>52 weeks
47.55
16.35
39.04
18.36
≤36 weeks
46.25
28.11
34.96
23.17
37-52 weeks
47.31
15.66
39.76
14.98
>52 weeks
44.08
15.20
37.15
17.06
SDAI
CDAI
Mease et al. EULAR 2008, abstract THU0188
Percentage change from baseline for
A) SDAI, B) CDAI and C) DAS28
Mease et al. EULAR 2008, abstract THU0188
SDAI and CDAI for Predicting Outcome of a Second
Course of Rituximab for Patients with RA
• Every 1.0 point that SDAI was allowed to worsen before
C2 resulted in a 0.21 point higher SDAI score post-C2
• Every 1.0 point that CDAI was allowed to worsen before
C2 resulted in a 0.24 point higher CDAI score post-C2
• These data suggest that outcome following a second
course of rituximab is better the less that disease activity
is allowed to worsen before repeating treatment
• Retreatment before patients are allowed to flare results
in improved disease activity after C2 rituximab
Mease et al. EULAR 2008, abstract THU0188
Early use of rituximab in patients with
severe RA refractory to DMARDS
Patient Characteristics
13 women and 2 men with severe RA and poor response to
conventional therapy with multiple DMARDS, corticosteroids and
NSAIDs.
The average age was 52 years old with an average disease
duration of 3 years.
Marked extra-articular manifestations
RF-positive at high titers
DAS28 >5.6
HAQ = 1.4
No prior use of anti-TNF therapy
Guzman et al. EULAR 2008, abstract AB0358
Results and Conclusion
80% of improvement in clinical parameters was observed at an
average of three weeks after initiation of treatment.
Response
ACR20
ACR50
ACR70
Week 24
62%
42%
21%
Average HAQ score remained low at 0.5
Median improvement in DAS28 score -2.4 in 13 patients
No serious adverse events reported at 2 years follow-up
Rituximab may be an excellent alternative as a first-line
biological agent in patients with aggressive disease
Guzman et al. EULAR 2008, abstract AB0358
Rituximab ACR and DAS28 response after 24 weeks in RA
patients with inadequate response to one TNFa inhibitor:
The RESET trial
An open-label, single-arm, multicentre, international study
(26 sites in Canada, 9 in Sweden) of safety and efficacy of a
combination of rituximab with methotrexate in patients with
active RA with an inadequate response or intolerance to only
one prior TNF-inhibitor
Interim analysis in 50 patients with a follow-up of 24 weeks
after 2 infusions of rituximab 1000 mg
Mean DAS28 at baseline 6.4 ±1.2
Haraoui et al. EULAR 2008, abstract AB0360
Results
Response at Week 24
ACR20
ACR50
ACR70
60%
28%
8%
Baseline
Week 24
Swollen joint count
13.7
6.8
Tender joint count
15.5
6.2
Patient global
67.3
36.4
Physician global
65.5
28.9
HAQ
1.8
1.3
CRP mg/dL
3.0
1.2
ESR mm/hr
39.0
20.4
Haraoui et al. EULAR 2008, abstract AB0360
Results
• FACIT-F scores decreased by 34% by week 24
• EULAR good/moderate response at 4, 12, and 24 weeks
were 54%, 74% and 78%, respectively
• DAS remission was seen in 8% of patients and low disease
activity in 20% by week 24
• Mean DDAS28 of -2.2 at Week 24 from a baseline of
6.4 ±1.2
Haraoui et al. EULAR 2008, abstract AB0360
Conclusions
• A single course of rituximab with MTX provided clinically
significant improvements in disease activity by week 24
in patients with active, long-standing RA who had an
inadequate response to one prior anti-TNF agent
• Small improvements in HAQ are probably due to
irreversible damage seen in a cohort with long-standing
disease
Haraoui et al. EULAR 2008, abstract AB0360
Combination therapy with rituximab
and etanercept for patients with RA
• Six patients with long-standing refractory RA who failed
rituximab were treated with etanercept two months after
receiving rituximab
• Over 6 months, DAS28 significantly decreased to 4.2
and high serum CRP levels of 68.9 mg/L prior to
receiving the combination decreased to 7.4 mg/L
• No severe infections occurred over a mean of 10.7
months and the frequency of mild bronchitis or influenza
was not increased with the combination
• Short-term results are promising but without long-term
experience, the rituximab/etanercept combination cannot
yet be recommended
Blank et al. EULAR 2008, abstract THU0165.
Safety and efficacy of rituximab in patients
with chronic infection
• Five patients with active chronic infections not eligible for antiTNF therapy were treated with rituximab.
• Mean treatment duration: 15.6 months
• ACR20 at six months was 59% and 45% at 12 months.
• Patients did not experience any adverse events or worsening
of their chronic infection, suggesting that rituximab may be a
safe and effective therapy in patients with chronic infections in
whom anti-TNF therapy is contraindicated
Continuous courses of rituximab do not increase the
frequency of severe infections and for patients with
contraindications to anti-TNF agents, B-cell depletion
may be an attractive alternative
Casas et al. EULAR 2008, abstract AB0378
Summary of Findings
•Rituximab may more effective than switching to an alternative antiTNF agent in patients with persistent active disease
•Rituximab is a useful therapy in patients with very active, TNFrefractory RA and efficacy appears similar in RF+ and RF–
patients
•Duration of response with Rituximab is at least 6 months
•Subsequent courses of Rituximab continue top provide added
benefit
•Rituximab appears to be well tolerated even by patients with
complex disease
•Continuous courses of rituximab do not increase the frequency of
serious infections
•Rituximab is an excellent alternative as a first-line biological agent
in patients with aggressive disease