International Literature
Search in Rheumatology
Vol. 6, Number 2
December 2011
In this issue:
Highlights of the 2011 Annual Meeting of the
American College of Rheumatology
November 5-9, Chicago, IL
Table of Contents
Author(s)
Hørslev-Petersen K
Genovese M
Genovese M
VanVollenhoven R
Yonemoto Y
Yazici Y
Bakker M
O'Dell J
Kaine JL
Roussy J-P
Meissner B
Dirven L
Raaschou P
Galloway J
Mercer L
Poster / presentation #s
394
401
402
408
1236
124043 – 50
1695
169659 – 66
2190
2193
2197
2200
2523
2524
2525
Slides
3 – 10
11 – 18
19 – 26
27 – 34
35 – 42
51 – 58
67 – 74
75 – 82
83 – 90
91 – 98
99 – 106
107 – 114
115 – 122
Adalimumab Added to Methotrexate and
Intra-Articular Glucocorticoid Increases
Remission Rates At One Year In Early,
DMARD-Naïve Patients with Rheumatoid
Arthritis - An Investigator-Initiated
Randomized, Controlled, Double-Blinded Study
Hørslev-Petersen K, et al:
Presented at ACR 2011;
Poster #394
Adalimumab + Methotrexate & Intra-articular
Glucocorticoid in DMARD-naïve, Early RA
• Objective: To assess the efficacy and safety of adding adalimumab
(ADA) to methotrexate (MTX) and intra-articular glucocorticoid
• Subjects: 180 DMARD-naïve RA patients, disease duration < 6
months
• Methodology:
– Subjects were randomized to MTX 7.5 mg weekly + ADA 40 mg every
other week or MTX + placebo
– All patients had triamcinolone injections into swollen joints at weeks
0, 4, 8, and 12, then every third month up to 12 months
– If DAS28 > 3.2 at 3 months, sulfasalazine & hydroxychloroquine were
added
– Assessments: DAS28 (CRP), SDAI and ACR/EULAR remission criteria
– Primary outcome: Frequency of DAS28 (CRP) < 3.2
Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394
Adalimumab + Methotrexate & Intra-articular
Glucocorticoid in DMARD-naïve, Early RA: Baseline
Characteristics
Methotrexate +
Placebo
Methotrexate +
Adalimumab
91
89
Women
69%
63%
Median age, years
54.4
56.2
83
84
Anti-CCP positive
70%
60%
IgM-RF positive
74%
70%
Median DAS28 (CRP)
5.4
5.3
Median TJC / SJC (40)
16 / 11
15 / 10
1.0
1.1
Characteristic
Number of patients
Median disease duration, days
Median HAQ
Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394
Adalimumab + Methotrexate & Intra-articular
Glucocorticoid in DMARD-naïve, Early RA:
Treatment Characteristics During the Study
Methotrexate
+ Placebo
(n=91)
Methotrexate
+ Adalimumab
(n=89)
p value
Median MTX dose, mg/week
20
20
0.33
Median triamcinolone,
mL 0-12 months
7.0
5.4
0.084
Characteristic
Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394
Adalimumab Added to MTX & I.A.
Glucocorticoid: DAS28 < 3.2 at 12 Months
% of patients with DAS28 < 3.2
100%
p = 0.74
84
81
80%
60%
40%
20%
0%
MTX + Placebo
MTX + Adalimumab
Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394
Adalimumab Added to MTX & I.A.
Glucocorticoid: Remission
100%
MTX + Placebo
MTX + Adalimumab
p = 0.059
78
80%
p = 0.0017
% of patients
64
63
p = 0.0235
60%
p = 0.0095
49
48
38
40%
31
28
20%
0%
DAS28 < 2.6
SDAI < 3.3
ACR/EULAR
remission
(28 joint)
ACR/EULAR
remission
(40 joint)
Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394
Adalimumab + Methotrexate & IntraarticularGlucocorticoid in DMARD-naïve, Early RA:
Conclusions
• In DMARD-naïve patients with early RA, excellent
disease control was achieved by a targeted step-up
strategy using methotrexate and intra-articular
glucocorticoid injections
• Addition of adalimumab to methotrexate and intraarticular glucocorticoid improved the remission rates
considerably
• The treatments were well tolerated
Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394
Adalimumab + Methotrexate & Intra-articular
Glucocorticoid in DMARD-naïve, Early RA
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• This study used methotrexate doses of 20 mg
per week, which reflects current practice in
Canada; the use of intra-articular injections also
applies to rheumatology standard-of-care in
Canada
– This study is, therefore, very applicable in our context
• The only issue is availability of biologics in very
early disease, but this study helps to corroborate
the need for early treatment with biologics in RA
Commentary on Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394
One Year Efficacy and Safety Results of a
Phase II Trial of Secukinumab in Patients
with Rheumatoid Arthritis
Genovese MC, et al:
Presented at ACR 2011;
Poster #401
Phase II Study of Secukinumab in
Rheumatoid Arthritis
• Objective: To assess the efficacy and safety of secukinumab in
patients with active RA despite stable MTX
• Subjects: 237 adults with RA, taking MTX therapy
• Methodology:
– Subjects were randomized to receive monthly s.c. secukinumab
25 mg, 75 mg, 150 mg, 300 mg or placebo
– After Week 16, dose adjustments were made if necessary and
placebo patients were switched to active therapy
– Primary endpoint: ACR 20 at week 16 (previously reported)
– Key efficacy measures evaluated in this analysis: Long-term results
from week 24 to week 52
• No placebo arm during this period: all patients were receiving
secukinumab
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401
Secukinumab for Rheumatoid Arthritis:
Study Design
Week 0 randomization N=237
25 mg
N=54
75 mg
N=49
150 mg
N=43
300 mg
N=41
pbo
N=50
Re-assignment at Week 16 based on ACR20 response: R and NR
N=47
N=47
N=43
N=38
N=45
Patients available for evaluation at Week 52
25/25
R=18
25/150
NR=27
75/75
R=23
75/150
NR=23
150/150 150/300
R=20
NR=23
300/300 300/300
R=21
NR=16
pbo/150 pbo/150
R=18
R=17
R: Responder; NR: Non-Responder; pbo: Placebo; N: Number of patients; Wk: Week; MTX: Methotrexate
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401
Secukinumab for Rheumatoid Arthritis:
ACR and DAS28 Responses
• Responders who remained on secukinumab 150 mg
showed further improvement in ACR50 and ACR70
over time up to week 52
• Placebo patients who were responders by week 16
also had high ACR50 and ACR70 response rates by
week 52
• DAS28 (CRP) reductions were sustained through
week 52 in responders across dose groups, with
lowest responses in those who remained on 25 mg
throughout the trial
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401
Secukinumab for Rheumatoid Arthritis:
Discontinuations
50%
% of patients
40%
Overall study discontinuations
Discontinuations for AEs
Discontinuations for Unsatisfactory therapeutic effects
38.9
30.0
30%
24.4
22.4
20%
14.8
14.0
13.0
10%
8.2
9.8
7.0
6.0
4.9
4.1
0%
12.0
0.0
25 mg
75 mg
150 mg
300 mg
Total
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401
Secukinumab for Rheumatoid Arthritis:
Adverse Events
100%
25 mg
75 mg
150 mg
300 mg
Total
% of patients
80%
60%
61.1
65.2
68.3
63.5
40%
64.8
34.8
33.3
26.1
28.3
31.9
20%
0%
Overall AEs
Infections / infestations
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401
Phase II Study of Secukinumab in
Rheumatoid Arthritis: Conclusions
• The primary efficacy endpoint was not achieved in this trial
• ACR20 responders at Week 16 experienced maintenance or
improvement of efficacy through week 52 with highest efficacy in
patients who remained on secukinumab 150 mg throughout the
trial
• DAS28 and HAQ scores improved through week 52 in responders
who remained on secukinumab 150 mg
• Patients on secukinumab who were non-responders at week 18 did
not gain much additional efficacy benefit through week 52 after
dose escalation
• Infection was the most frequently reported adverse event, with
nasopharyngitis and pharyngitis reported most commonly
• The rate of adverse events, including infections, was not dose
dependent
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401
Phase II Study of Secukinumab in
Rheumatoid Arthritis
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• The success of biologic agents for the treatment of RA over the
past 10 years has generated ongoing research to find drugs that
target new pathways
• A Phase 2 study previously reported that targeting IL-17 with
secukinumab did not achieve its primary endpoint at week 16
• This paper reports further data up to 1 year from that study and
shows that although the group that did respond maintained their
response, those who were non-responders did not improve with
dose escalation
• As reported elsewhere at this meeting, there are positive data
treating spondyloarthropathies with this agent, particularly
ankylosing spondylitis, but it remains to be seen whether targeting
IL-17 will turn out to be a useful addition to treat RA
Commentary on Genovese MC, et al: Presented at ACR 2011; Poster #401
Subcutaneous (SC) Abatacept (ABA) Versus
Intravenous (IV) ABA in Patients (pts) with
Rheumatoid Arthritis: Long-Term Data From
the ACQUIRE (Abatacept Comparison of
Sub[QU]cutaneous versus Intravenous in
Inadequate Responders to MethotrexatE) Trial
Genovese MC, et al:
Presented at ACR 2011;
Poster #402
Subcutaneous vs. Intravenous Abatacept
in RA: Long-term Data (ACQUIRE study)
• Objective: To evaluate the efficacy and safety of the subcutaneous
(SC) formulation of abatacept compared to the intravenous (IV)
formulation over 24 months
• Subjects:1372 patients from the ACQUIRE study
• Methodology: Long-term extension (LTE) study of the ACQUIRE
trial
– In the initial 6-month study, SC abatacept (125 mg/week) and IV
abatacept showed comparable safety and efficacy
– After 6 months, patients could enter the LTE and receive SC abatacept
125 mg/week for an additional 18 months
– LTE assessments: safety, immunogenicity, efficacy
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402
ACQUIRE Study Long-term Extension:
Baseline Characteristics
Short-term population
Characteristic
LTE Population
SC Abatacept +
MTX (n=736)
SC Abatacept +
MTX (n=721)
SC Abatacept +
MTX (n=1372)
49.9 ± 13.2
50.1± 12.6
49.7 ± 12.8
84.4
80.4
82.4
7.6 ± 8.1
7.7 ± 7.8
7.6 ± 7.9
30.1 / 20.4
29.1 / 19.4
29.6 / 19.9
Mean HAQ-DI score
1.7 ± 0.7
1.7 ± 0.7
1.7 ± 0.7
Mean DAS28 (CRP)
6.2 ± 0.9
6.2 ± 0.8
6.2 ± 0.9
Mean MTX dose, mg/week
16.3 ± 3.6
16.5 ± 3.8
16.5 ± 4.0
Mean age, years
% female
Mean disease duration, years
Mean TJC / SJC
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402
ACQUIRE Study Long-term Extension:
Efficacy – ACR 20/50/70 Over 24 Months
Patients achieving ACR response (%)
100.0
All patients switch to
SC abatacept
SC abatacept
IV abatacept switched to SC abatacept
80.0
ACR 20
60.0
ACR 50
40.0
ACR 70
20.0
0.0
0 29
85
141
15 57
113
169
253
365
449
533
617
729
Visit day
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402
ACQUIRE Study Long-term Extension:
Efficacy – LDAS and DAS28 Remission
Patients achieving ACR response (%)
100.0
All patients switch to
SC abatacept
SC abatacept
IV abatacept switched to SC abatacept
80.0
60.0
LDAS
40.0
DAS28defined
remission
20.0
0.0
0 29
85
141
15 57
113
169
253
365
449
533
617
729
Visit day
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402
ACQUIRE Study Long-term Extension:
Safety
ST Period: SC Abatacept ST Period: IV Abatacept LTEPeriod: SC Abatacept
+ MTX (n=744)
+ MTX (n=731)
+ MTX (n=1372)
Pts. with
event (%)
Events /
100 pt-yrs
Pts. with
event (%)
Events /
100 pt-yrs
Pts. with
event (%)
Events /
100 pt-yrs
31 (4.2)
9.02
35 (4.9)
10.82
154 (11.2)
9.0
Deaths
2 (0.3)
-
5 (0.7)
-
11 (0.8)
-
Serious infections
5 (0.7)
1.48
10 (1.4)
3.05
35 (2.6)
1.97
8 (1.1)
-
14 (1.9)
-
23 (1.7)
-
493 (67.0)
-
470 (65.2)
-
988 (72.0)
-
237 (31.9)
84.62
227 (31.1)
82.91
609 (44.4)
47.64
Malignancies
2 (0.3)
0.59
5 (0.7)
1.52
18 (1.3)
1.01
Autoimmune events
6 (0.8)
1.78
6 (0.8)
1.83
22 (1.6)
1.23
Discontinued due to AE
15 (2.0)
-
25 (3.5)
-
33 (2.4)
-
Serious adverse events (SAEs)
Discontinued due to SAEs
Adverse events (AEs)
Infections
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402
ACQUIRE Study Long-term Extension:
Conclusions
• Over 24 months, subcutaneous abatacept showed
acceptable safety, with high patient retention,
similar to the IV experience
• Efficacy was comparable between SC and IV groups
• ACR and HAQ responses and DAS28 remission rates
were maintained in the LTE
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402
Subcutaneous vs. Intravenous
Abatacept in RA: Long-term Results
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• In this trial, patients with relatively longstanding RA
(8 years) did well on either i.v. or s.c. abatacept, with
similar retention, efficacy and safety in both groups
• It remains to be seen whether patients who are
currently receiving i.v .abatacept monthly will be
interested in switching to weekly s.c. dosing, but this
study does provide reassurance that, for those who
wish to make the switch, the medication is effective
Commentary on Genovese MC, et al: Presented at ACR 2011; Poster #402
Tofacitinib (CP-690,550), An Oral Janus
Kinase Inhibitor, or Adalimumab Versus
Placebo in Patients with Rheumatoid
Arthritis on Background Methotrexate:
A Phase 3 Study
van Vollenhoven RF, et al:
Presented at ACR 2011;
Poster #408
Tofacitinib vs. Adalimumab or Placebo
in RA Patients on Methotrexate
• Objective: To compare the efficacy and safety of tofacitinib to
adalimumab and to placebo in active RA
• Subjects: 717 patients with active RA and inadequate response to
methotrexate
• Methodology:
– Subjects were randomized (4:4:4:1:1 ratio) to:
• Tofacitinib 5 mg BID SC Q2W);
• Tofacitinib 10 mg BID SC Q2W;
• Adalimumab 40 mg SC Q2W;
• Placebo  tofacitinib 5 mg BID SC Q2W; or
• Placebo  tofacitinib 10 mg BID SC Q2W
– Efficacy assessments: ACR response, HAQ-DI, DAS28
– Safety was also evaluated
Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408
Tofacitinib vs. Adalimumab or Placebo
in RA: ACR20 Responses at Month 6
100%
% of patients
80%
60%
51.5
52.6
47.2
40%
28.3
20%
0%
Tofacitinib 5 mg
Tofacitinib 10 mg Adalimumab 40 mg
Placebo
All comparisons of active therapies vs. placebo were statistically significant (p<0.001)
Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408
Tofacitinib vs. Adalimumab or Placebo in RA
Patients: DAS28 Remission at Month 6
14%
12.5
12%
% of patients
10%
8%
7.3
6.2
6%
4%
2%
0%
1.1
Tofacitinib 5 mg
Tofacitinib 10 mg Adalimumab 40 mg
Placebo
All comparisons of active therapies vs. placebo were statistically significant (p<0.05)
Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408
Tofacitinib vs. Adalimumab or Placebo in RA
Patients: Mean HAQ Change at Month 6
Change in HAQ Score from baseline
0
Tofacitinib 5 mg
Tofacitinib 10 mg Adalimumab 40 mg
Placebo
-0.1
-0.2
-0.24
-0.3
-0.4
-0.5
-0.6
-0.49
-0.55
-0.61
-0.7
All comparisons of active therapies vs. placebo were statistically significant (p<0.0001)
Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408
Tofacitinib vs. Adalimumab or Placebo in RA
Patients on Methotrexate: Adverse Events
Months 0-3
Treatment group
Months 3-6
AEs, n (%)
SAEs , n
(%)
AEs, n (%)
SAEs , n
(%)
Tofacitinib 5 mg BID
(n=204)
106 (52.0)
12 (5.9)
67 (32.8)
10 (4.9)
Tofacitinib 10 mg BID
(n=201)
94 (46.8)
10 (5.0)
62 (30.8)
7 (3.5)
Adalimumab 40 mg SC Q2W
(n=204)
105 (51.5)
5 (2.5)
68 (33.3)
6 (2.9)
Placebo
(n=108 at mo. 3; n=59 mos. 3-6)
51 (47.2)
2 (1.9)
16 (27.1)
2 (3.4)
Placebo to tofacitinib 5 mg BID
(n=28)
NA
NA
7 (25.0)
0
Placebo to tofacitinib 10 mg BID
(n=21)
NA
NA
9 (42.9)
0
Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408
Tofacitinib vs. Adalimumab or Placebo in RA
Patients on Methotrexate: Conclusions
• Tofacitinib demonstrated rapid, significant, and
clinically meaningful reductions in signs and
symptoms of RA and improvements in physical
function
• No new tofacitinib safety signals were detected
• Efficacy results with tofacitinib and adalimumab
(both given on MTX background) were similar
Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408
Tofacitinib vs. Adalimumab or Placebo
in RA Patients on Methotrexate
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• Tofacitinib will be a useful addition to our
armamentarium for the treatment of RA, especially
as it is an oral medication
• The SAEs are, however, of some concern; larger
studies should be carried out to further assess this
Commentary on van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408
Direct Comparison of Four Biologics in
Biologic-naïve Rheumatoid Arthritis
Patients
Yonemoto Y, et al:
Presented at ACR 2011;
Poster #1236
Direct Comparison of Four Biologics in
Biologic-naïve RA
• Objective: To compare treatment response to four biologics in
biologic-naïve RA patients in a real-life, clinical setting
• Subjects: 142 biologic-naïve RA patients who were started on a
biologic
–
–
–
–
Infliximab (n=37)
Etanercept (n=39)
Tocilizumab (n=27)
Adalimumab (n=39)
• Methodology:
– A number of variables were analyzed at baseline and at six months:
ESR, CRP, MMP-3, SJC/TJC, DAS28-ESR
– Drug survival rate was also assessed
Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Direct Comparison of Four Biologics:
Baseline Characteristics
Characteristic
IFX (n=37) ETN (n=39) TCZ (n=27) ADA (n=39)
p
Male, %
16
21
22
28
0.65
Age, years
59
59
63
60
0.33
RA duration, months
105
131
149
132
0.28
Concomitant MTX, %
100
54
41
87
<0.01
6.6
6.3
5.3
6.2
<0.01
84
67
74
59
0.11
4.5
4.8
4.8
5.0
0.77
CRP (mg/dL)
2.66
2.81
4.27
2.62
<0.01
ESR (mm/hr)
53
54
71
52
0.41
275.2
241.0
315.4
286.0
0.74
DAS-28 (ESR)
4.9
4.8
5.5
4.8
0.73
DAS-28 (CRP)
3.9
3.8
4.6
3.9
<0.05
MTX dosage, mg/wk
Concomitant PSL, %
PSL dosage, mg/day
MMP-3 (ng/dL)
Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Direct Comparison of Four Biologics:
DAS28-ESR Scores at 6 Months
6.0
5.0
DA28-ESR
4.0
3.0
2.0
1.0
0
Biologic:
IFX
ETN
TCZ
ADA
Baseline DAS28-ESR:
4.9
4.8
5.5
4.8
Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Direct Comparison of Four Biologics:
MMP-3 at 6 Months
1200.0
MMP-3 (ng/ml)
1000.0
800.0
600.0
400.0
200.0
0.0
Biologic:
Baseline MMP-3 (ng/mL):
IFX
ETN
TCZ
ADA
275.2
241.0
315.4
286.0
Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Direct Comparison of Four Biologics:
Drug Survival Rates at 6 Months
100
100%
% still taking drug at 6 months
89
92
89
80%
60%
40%
20%
0%
Infliximab
Etanercept
Tocilizumab
Adalimumab
No significant difference between biologics in drug survival rates
Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Comparison of Four Biologics in
Biologic-naïve RA: Conclusions
• In this study, there was a larger fall in MMP-3 with
tocilizumab than with the other two agents
• The study suggests that tocilizumab may provide
therapeutic efficacy at least comparable to TNF
inhibitors in biologic-naïve RA patients
Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Direct Comparison of Four Biologics in
Biologic-naïve RA
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• This confirms that all the TNF inhibitors are equally
clinically effective and that tocilizumab is at least as
effective in biologic-naïve RA patients
Commentary on Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Comparative Efficacy and Tolerability of
Biologic Therapies in Early Rheumatoid
Arthritis Utilizing a Bayesian Approach
Yazici Y, et al:
Presented at ACR 2011;
Poster #1240
Comparative Efficacy and Tolerability of
Biologic Therapies in RA
• Objective: To determine the relative efficacy and tolerability of
biologic agents approved for the treatment of MTX-naïve early RA
• Methodology: Agents were compared using an indirect approach
(mixed treatment comparison [MTC])
– Systematic literature review identified RCTs that measured efficacy
and safety endpoints in MTX-naïve, early RA with:
• Abatacept, adalimumab, etanercept, golimumab, and infliximab
– Assessments: ACR20/50/70, DAS28 remission, SAEs, serious infections
and withdrawals at 1 year
Adapted from YaziciY, et al: Presented at ACR 2011; Poster #1240
Comparative Efficacy of Biologic
Therapies in RA: Efficacy Measures
ASPIRE
IFX
MTX 3 mg/kg
+ MTX
N
282
ACR20
COMET
PREMIER
AGREE
GO-BEFORE
MTX
ETN
50 mg
+ MTX
MTX
ADA
40 mg
+ MTX
ABA
MTX 10 mg/kg MTX
+ MTX
GOL
50 mg
+ MTX
359
263
265
257
268
253
256
160
159
54%
62%
67%
86%
63%
73%
62%
76%
49%
62%
ACR50
32%
46%
49%
71%
46%
62%
42%
57%
29%
40%
ACR70
21%
32%
28%
48%
28%
46%
27%
43%
16%
24%
DAS28
15%
remission
21%
28%
50%
21%
43%
23%
41%
28%
38%
Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240
Comparative Efficacy of Biologic Therapies in RA:
Odds Ratios for ACR Responses and DAS28
Remission
Fixed-effects model
Random-effects model
0.1
ACR 20
ETN 50mg
ADA 40mg
ABA 10mg/kg
GOL 50mg
INF 3mg/kg
ACR 50
ETN 50mg
ADA 40mg
ABA 10mg/kg
GOL 50mg
INF 3mg/kg
ACR 70
ETN 50mg
ADA 40mg
ABA 10mg/kg
GOL 50mg
INF 3mg/kg
DAS-R
ETN 50mg
ADA 40mg
ABA 10mg/kg
GOL 50mg
INF 3mg/kg
Odds Ratios (Log Scale)
1
10
100
3.02
1.60
1.96
1.64
1.44
2.52
1.92
1.84
1.63
1.77
2.37
2.19
1.98
1.71
1.80
2.59
2.84
2.34
1.60
1.53
Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240
Comparative Tolerability of Biologic Therapies in
RA: Serious Infections and Serious AEs
Fixed-effects model
Random-effects model
0.01
ETN 50mg
Serious ABA 10mg/kg
Infections
GOL 50mg
INF 3mg/kg
ETN 50mg
0.1
Odds Ratios vs. Placebo + MTX
1
GOL 50mg
INF 3mg/kg
100
0.94
0.99
0.91
1.32
0.59
ADA 40mg
Serious
AE ABA 10mg/kg
10
1.26
0.45
0.63
2.97
Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240
Comparative Tolerability of Biologic
Therapies in RA: Discontinuations
Fixed-effects model
Random-effects model
0.01
ETN 50mg
ADA 40mg
0.1
Odds ratios vs. Placebo + MTX
1
0.61
0.90
GOL 50mg
0.76
INF 3mg/kg
0.85
ETN 50mg
0.78
ADA 40mg
GOL 50mg
INF 3mg/kg
100
0.57
Any
Withdrawal ABA 10mg/kg
Withdrawal
due to AE ABA 10mg/kg
10
1.71
0.70
2.66
3.32
Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240
Comparative Efficacy of Biologic
Therapies in RA: Conclusions
• In general, all biologic agents used in MTX-naïve
early RA demonstrated similar efficacy and
tolerability
– Except for infliximab, which appeared to have less
favorable efficacy and tolerability
• For specific outcomes studied, etanercept and
abatacept were not significantly different from each
other and were the only biologics that did not
demonstrate a significantly decreased likelihood of
efficacy or tolerability compared with any of the
other agents
Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240
Comparative Efficacy and Tolerability of
Biologic Therapies in RA
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• All of the biologics analyzed in this Bayesian analysis
were comparable with regards to efficacy and safety
in an ERA, MTX-naïve population
• However, only etanercept and abatacept did not
show any decreased likelihood of efficacy or
tolerability compared to other agents
Commentary on Yazici Y, et al: Presented at ACR 2011; Poster #1240
Double-Blind Randomized CAMERA-II
Trial: Better Control of Disease and
Erosive Joint Damage with Inclusion of
Low-Dose Prednisone Into a MTX-Based
Tight Control Strategy for Early
Rheumatoid Arthritis
Bakker MF, et al:
Presented at ACR 2011;
Oral presentation #1695
Low-dose Prednisone with MTX-based Tight
Control in Early RA: CAMERA II Study
• Objective:To evaluate efficacy and safety of 10 mg/day
prednisone from the start of treatment with a methotrexate
(MTX)-based, tight-control strategy for early RA
• Subjects: 236 patients with early RA (<1 year)
• Methodology: 2-year, prospective randomized, placebocontrolled, double-blind, multi-centre study
– Subjects were randomized to a MTX-based tight control strategy with
either prednisone (MTX-pred) or placebo (MTX-plac)
– MTX treatment was tailored to the individual patient, aiming for
remission
– Primary endpoint: radiographic erosive joint damage after 2 years
Adapted from Bakker MF, et al: Presented at ACR 2011; Oral presentation #1695
Low-dose Prednisone with MTX-based Tight
Control in Early RA: Erosion Score After 2 Years
(Cumulative Probability Plot)
MTX-placebo
MTX-prednisone
40
Medianerosion score at 2
yearsless in the MTX+prod
strategy, p=0.02
20
67%
78%
0
0
60
80
100
Adapted from Bakker MF, et al: Presented at ACR 2011; Oral presentation #1695
Low-dose Prednisone with MTX-based Tight
Control in Early RA: Sustained Remission
100%
% of patients
80%
p = 0.09
72
61
60%
40%
20%
0%
MTX + prednisone
MTX + placebo
Adapted from Bakker MF, et al: Presented at ACR 2011; Oral presentation #1695
Low-dose Prednisone with MTX-based Tight
Control in Early RA: Need for Biologic Therapy
% of patients requiring biologic
100%
80%
60%
p< 0.001
36
40%
20%
0%
14
MTX + prednisone
MTX + placebo
Adapted from Bakker MF, et al: Presented at ACR 2011; Oral presentation #1695
Low-dose Prednisone with MTX-based Tight
Control in Early RA: Adverse Events
Event
Death
Admission
Cataract
Glaucoma
Nausea
Epigastric pain
ALT > ULN
AST > ULN
Pneumonitis
Infections
Antibiotics
Peripheral fractures
Hypertension
Diabetes mellitus
MTX + Prednisone
MTX + Placebo
1
1
1
0
51
14
30
16
1
6
1
1
11
1
0
5
0
0
152
17
87
38
0
7
0
0
18
1
Adapted from Bakker MF, et al: Presented at ACR 2011; Oral presentation #1695
Low-dose Prednisone in Early RA:
Conclusions from the CAMERA II Study
• Inclusion of low-dose prednisone from the start into
a two-year MTX-based tight control treatment
strategy for early RA:
–
–
–
–
Increases effectiveness (i.e., disease activity variables)
Improves outcome (i.e., erosive joint damage)
Does not increase toxicity
Reduces the need for (early) treatment with biologics
Adapted from Bakker MF, et al: Presented at ACR 2011; Oral presentation #1695
Low-dose Prednisone with MTX-based
Tight Control in Early RA
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• In this study, a methotrexate-based, treat-to-target
approach in an early RA population showed that
adding low dose prednisone had a “biologic sparing”
effect
• The addition of prednisone appeared to be disease
modifying, without added side effects
• However, the use of long-term corticosteroids may
not be a widely accepted strategy
Commentary on Bakker MF, et al: Presented at ACR 2011; Oral presentation #1695
Validation of Methotrexate First Strategy
in Early Rheumatoid Arthritis:
A Randomized, Double-Blind, 2-Year Trial
O'Dell JR, et al:
Presented at ACR 2011;
Oral presentation #1696
Validation of Methotrexate First
Strategy
• Objective: To compare initial methotrexate (MTX)
therapy with initial MTX-based combination therapy in
early RA
• Subjects: 755 patients with early RA and a poor
prognosis
• Methodology:
– Subjects were randomized to initial MTX or immediate
combination therapy (MTX/etanercept or MTX/SSZ/HCQ)
– Primary efficacy assessment: DAS28
Adapted from O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
Validation of Methotrexate First Strategy:
Proportion of MTX Subjects Requiring Step-up
Required step-up
(DAS28 > 3.2)
Remained on MTX
Monotherapy
(DAS28 ≤ 3.2)
28%
72%
Adapted from O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
Validation of Methotrexate First
Strategy: Mean DAS28 to Week 102
7
SE
ST
6
IE
IT
DAS28
5
4
3
Step-up to Multiple
DMARD at Week
24 if DAS28 ≥ 3.2
2
1
0
Week 0
(755)
Primary Analysis: Weeks 48 to 102
Comparison
Groups (IE, IT, SE, ST)
Time (I = S)
Trt (ETN > TT)
p-value
0.55
0.37
0.18
Week 12 Week 24 Week 36 Week 48 Week 60 Week 72 Week 84 Week 96 Week 102
(661)
(646)
(601)
(582)
(522)
(518)
(508)
(485)
(476)
Adapted from O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
Validation of Methotrexate First Strategy:
Radiographic Progression (Cumulative Probability)
Week 102 Change from Baseline
(%)
100
Initial Etanercept
Initial Triple
Step-up Etanercept
Step-up Triple
80
60
40
20
0
-20
0
10
20
30
40
50
60
70
80
90
100
Cumulative probability
Adapted from O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
Validation of Methotrexate First Strategy:
MTX-only Patients Achieving DAS28 Reduction
Thresholds
Percentage of patients (%)
70
60
DAS > 2.4
DAS > 1.8
DAS > 1.2
50
40
30
20
10
0
Week 12
Week 24
Adapted from O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
Validation of Methotrexate First
Strategy: Conclusions
• These data validate the oft-recommended strategy
of starting with MTX monotherapy
• If this is done, approximately 30% of patients will
not need combination therapy and the 70% who
need add-on therapy will be:
– Clinically indistinguishable from those that received
immediate combination therapy 3 months after step-up
– Radiographically indistinguishable at 2 years
Adapted from O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
Validation of Methotrexate First
Strategy
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• In this study, one-third of patients did well on
methotrexate monotherapy
– This has significant implications for cost avoidance
• The main message of the study is that if you treat to
target, patients do well
Commentary on O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
SC Abatacept Is Effective and Well Tolerated
with Low Immunogenicity Following Temporary
Withdrawal and Reintroduction in the ALLOW
LTE (Evaluation of ABA Administered
SubcutaneousLy in AduLts With Active RA:
Impact of Withdrawal and Reintroduction)
Kaine JL, et al:
Presented at ACR 2011;
Poster #2190
Temporary Withdrawal &
Reintroduction of Abatacept in RA
• Objective: To assess the impact of withdrawal and re-introduction
of subcutaneous (SC) abatacept (ABA) on safety, immunogenicity
and efficacy
• Subjects: 150 patients with mild-to-moderate RA on MTX, from
the long-term extension of the ALLOW study
• Methodology:
– The ALLOW study consisted of four phases:
• Period I: 3 months, open-label SC ABA 125 mg Q2W
• Period II: 3 months, randomized to SC ABA 125 mg Q2W or
placebo
• Period III: 3 months, open-label SC ABA 125 mg Q2W
• Long-term extension: 6 months open-label SC ABA 125 mg Q2W
– This analysis assessed efficacy, safety, and immunogenicity through
15 months
Adapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
Temporary Withdrawal & Reintroduction of
Abatacept in RA: Study Design
Introduction Phase
Withdrawal Phase
Re-introduction Phase
Period I: SC open-label
12 weeks
Period II: double-blind
12 weeks
Period III: SC open-label
12 weeks
Responders
randomized
Loading dose
IV abatacept
Day 1
IV loading dose:
placebo (blinded)
SC abatacept + MTX†
n=40
SC abatacept + MTX
n=40
IV abatacept
SC abatacept + MTX
n=167
SC placebo +
n=80
MTX†
Long-term extension:
SC open-label
SC abatacept + MTX
n=79
IV loading dose: abatacept
or placebo (blinded)
Month 3 (Day 85)
Month 6 (Day 169)
Primary endpoint:
Immunogenicity
Secondary endpoints:
Safety
Efficacy
Month 9 (Day 253)
Primary endpoint:
Immunogenicity
Secondary endpoints:
Safety
Efficacy
Adapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
Temporary Withdrawal & Reintroduction of
Abatacept in RA: Efficacy (DAS28)
DAS28 mean change from baseline
Period I:
Introduction
SC ABA, N=167
0.5
85
Period II:
Period III:
Withdrawal Re-Introduction
SC ABA, N=40
SC ABA, N=40
vs. PBO, N=80 SC PBO, N=79
169
253
Long-term extension:
SC ABA open-label
Period I NRs, N=37
Period III completers, N=113
(SC ABA, N=39; SC PBO, N=74)
449
Study
visit day
0.0
-0.5
Period I NR
Period II SC ABA
Period II SC PBO
-1.0
-1.5
-2.0
-2.5
Adapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
Temporary Withdrawal &
Reintroduction of Abatacept: Safety
Treatment group prior to LTE entry
Number of patients with
event (%)
Period I Nonresponders
(n=37)
Period III Completers (n=113)
Total (n=150)
Period II SC
ABA (n=39)
Period II SC
PBO (n=74)
1 (2.7)
0
0
1 (0.7)
AEs
URTI
Influenza
Sinusitis
Bronchitis
24 (64.9)
6 (16.2)
6 (16.2)
2 (5.4)
2 (5.4)
22 (56.4)
3 (7.7)
0
2 (5.1)
2 (5.1)
40 (54.1)
3 (4.1)
5 (6.8)
7 (9.5)
6 (8.1)
86 (57.3)
12 (8.0)
11 (7.3)
11 (7.3)
10 (6.7)
SAEs
4 (10.8)
2 (5.1)
6 (8.1)
12 (8.0)
Infections / infestations
17 (45.9)
16 (41.0)
25 (33.8)
58 (38.7)
Malignancies
0
0
0
0
Autoimmune events
0
0
1 (1.4)
1 (0.7)
S.C. injection-site reactions
0
2 (5.1)
0
2 (1.3)
Deaths
Adapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
Temporary Withdrawal & Reintroduction of
Abatacept: Immunogenicity
Overall
2.8%
Period I NR
2.8%
Period II SC ABA
2.6%
Period II placebo
2.9%
0%
20%
40%
60%
80%
100%
% of patients with positive immunogenicity
NR: Non-responders; SC ABA: subcutaneous abatacept
Adapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
Temporary Withdrawal & Reintroduction of
Abatacept (ALLOW study): Conclusions
• In ALLOW, 3-month interruption and subsequent
re-introduction of SC abatacept had no adverse
impact on safety, immunogenicity or efficacy over
15 months
• This treatment pattern was well-tolerated by the
patients continuing treatment in the LTE
Adapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
Temporary Withdrawal &
Reintroduction of Abatacept in RA
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• Patients frequently ask if they can safely stop their medications
• Rheumatologists have been leery of advising this, in part because
of experiences and published data from gold withdrawal studies
where 2/3 of patients flared within a year of ceasing drug, as well
as poor response rates upon reintroduction of the medication
• In this study, a 3-month interruption and subsequent
reintroduction of s.c. abatacept recaptured efficacy and was not
associated with immunogenicity
• This has important real-life implications for patients and their
rheumatologists when drug interruption is required
Commentary on Kaine JL, et al: Presented at ACR 2011; Poster #2190
Use of Disease-Modifying Anti-Rheumatic
Drugs for Rheumatoid Arthritis in
Quebec, Canada
Roussy J-P, et al:
Presented at ACR 2011;
Poster #2193
Patterns of DMARD Use for RA in
Quebec
• Objectives:
– To describe the characteristics of RA subjects in Quebec
– To evaluate trends in DMARD use
– To assess potential factors associated with DMARD use in newly
diagnosed RA
• Subjects: 37,399 subjects from Quebec public healthcare system
databases between January 1, 2002 and December 31, 2008
• Methodology: Analyses included:
– Patient characteristics
– Patterns of DMARD use and their evolution over time
– Probability and correlates of DMARD initiation at 12 months
Adapted from Roussy J-P, et al: Presented at ACR 2011; Poster #2193
Treatment Patterns for RA in Quebec
50.0%
Percentage of subjects
45.0%
40.0%
35.0%
30.0%
25.0%
No treatment
Non-DMARD only
DMARD - any
DMARD-t
DMARD-b (+/- DMARD-t)
20.0%
15.0%
10.0%
5.0%
0.0%
Nov.
2002
Nov.
2003
Nov.
2004
Nov.
2005
Nov.
2006
Nov.
2007
Nov.
2008
DMARD-t: Traditional DMARD; DMARB-b: Biologic DMARD
Adapted from Roussy J-P, et al: Presented at ACR 2011; Poster #2193
Time from Diagnosis to Initiation of Any
DMARD, by Specialty
1.0
Other specialist
Survival probability
0.8
GP
Internist
0.6
Rheumatologist
0.4
0.2
Log rank, p<0.0001
Censored
0.0
0
500
1000
1500
2000
2500
Survival days
Adapted from Roussy J-P, et al: Presented at ACR 2011; Poster #2193
Predictors of DMARD Use for RA in
Quebec: Multivariate Analysis (1 of 2)
Adjusted
Odds Ratio
95% CI
2003
1.112
0.955 – 1.296
2004
1.166
1.003 – 1.355
1.209
1.035 – 1.412
2006
1.336
1.144 – 1.561
2007
1.474
1.254 – 1.734
Variable
Calendar year
Reference
2005
vs. 2002
Age/ 10 years
--
0.955
0.925 – 0.986
Sex (female)
vs. male
0.906
0.821 – 1.000
SSE (low)
vs. high
1.010
0.918 – 1.110
--
0.986
0.976 – 0.997
Comorbidity score
Adapted from Roussy J-P, et al: Presented at ACR 2011; Poster #2193
Predictors of DMARD Use for RA in
Quebec: Multivariate Analysis (2 of 2)
Adjusted
Odds Ratio
95% CI
4.159
3.608 – 4.794
2.388
2.019 – 2.826
Other specialty
0.708
0.543 – 0.923
Opioid (≥ 1)
1.112
1.003 – 1.233
Acetaminophen
(≥ 1)
0.797
0.706 – 0.899
NSAID (≥ 1)
2.175
1.959 – 2.414
Corticosteroid
(≥ 1)
1.223
1.109 – 1.349
Variable
Reference
Rheumatologist
Specialty
overseeing RA
care
≥ 1 claim in
the previous
year for:
Internist
vs. GP
vs. no claim
Adapted from Roussy J-P, et al: Presented at ACR 2011; Poster #2193
Patterns of DMARD Use for RA in
Quebec: Conclusions
• From 2002 to 2008, the use of RA treatment in
Quebec has evolved
• Despite indications that practice is moving toward
earlier and more aggressive management of the
disease, initiation of DMARD therapies still appears
sub-optimal
• Improving access to rheumatologists could be an
area of focus in order to enhance the quality of RA
care
Adapted from Roussy J-P, et al: Presented at ACR 2011; Poster #2193
Patterns of DMARD Use for RA in
Quebec
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• These findings further highlight the need for earlier
access to rheumatologists for patients with RA
Commentary on Roussy J-P, et al: Presented at ACR 2011; Poster #2193
Switching of Biologic Disease-Modifying
Antirheumatic Drugs During the First Year
in Patients with Rheumatoid Arthritis in a
Real-World Setting
Meissner B, et al:
Presented at ACR 2011;
Poster #2197
Switching Biologics for RA in a
Real-World Setting
• Objective: To characterize biologic switching in a real-world
RA population in the first year following initiation of therapy
• Subjects: 9,757 RA patients newly initiated on abatacept,
etanercept, infliximab, or adalimumab
• Methodology: Observational, retrospective study
– Data were from American administrative medical and pharmacy
claims from 2004 through 2010
– Switching of biologic therapy was characterized during the 12month period following biologic initiation
– Analyses were conducted to examine the characteristics of
switchers versus non-switchers
Adapted from Meissner B, et al: Presented at ACR 2011; Poster #2197
Proportion of RA Patients Switching
Biologics in the First Year
100%
% of patients
80%
60%
40%
20%
8.9
8.5
Adalimumab
Etanercept
2.0
5.2
7.8
Infliximab
Overall
0%
Abatacept
Adapted from Meissner B, et al: Presented at ACR 2011; Poster #2197
Which Type of Biologic Was Used As the
2nd Agent?
Non-anti-TNF biologic
Anti-TNF biologic
100%
10.0
5.2
80%
% of patients
55.4
60%
90.0
94.8
40%
44.6
20%
8.5
0%
Adalimumab
Etanercept
Infliximab
First Biologic Agent
Adapted from Meissner B, et al: Presented at ACR 2011; Poster #2197
Proportion of Patients Requiring Switch
to 3rd Biologic Within 1st Year
100%
% of patients
80%
60%
40%
18.1
20%
12.9
12.8
Etanercept
Infliximab
6.0
0%
Abatacept
Adalimumab
Second Biologic
Adapted from Meissner B, et al: Presented at ACR 2011; Poster #2197
Healthcare Utilization Differences Between
Switchers and Nonswitchers
(Prior to Biologic Initiation)
100%
Hospitalizations
$1,500
80%
p = 0.015
$1,200
Monthly Healthcare Costs
p< 0.001
60%
$900
796
$ US
% of patients
1,025
40%
$600
20%
$300
9.5
7.2
0%
$0
Switchers
Nonswitchers
Switchers
Nonswitchers
Adapted from Meissner B, et al: Presented at ACR 2011; Poster #2197
Switching Biologics for RA in a RealWorld Setting: Conclusions
• Less than 10% of RA patients who initiated therapy
on adalimumab, etanercept, infliximab or abatacept
switched to a second biologic in their first year of
therapy
• Switching was associated with significantly more
hospitalizations and healthcare costs than not
switching
• Further studies are required to determine why
abatacept-treated patients had a lower frequency of
switching than the other three biologics studied
Adapted from Meissner B, et al: Presented at ACR 2011; Poster #2197
Switching Biologics for RA
in a Real-World Setting
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• Overall, in this database, switching biologics was
rather low in the first year after initiation (<10%)
• Abatacept was the least likely biologic to generate a
switch and the reason for this is unclear
• One might presume that either this drug
demonstrated increased sustainability or,
alternatively, might have been selected as a first
choice to avoid anti-TNF’s, thereby making it less
likely to switch to an anti-TNF if a change was
needed
Commentary on Meissner B, et al: Presented at ACR 2011; Poster #2197
Eight Year Results of Disease Activity
Steered Treatment in a Large Recent
Rheumatoid Arthritis Cohort:
Clinical and Radiological Outcomes
Dirven L, et al:
Presented at ACR 2011;
Poster #2200
8-Year Results of a DAS-steered
Treatment Study (BeSt)
• Objective: To compare 8-year outcomes of four dynamic DAS
steered treatment strategies (from the BeSt study)
• Subjects: 508 patients with recent onset rheumatoid arthritis (RA)
• Methodology:
– Subjects were randomized to one of four treatment strategies:
• Sequential monotherapy,
• Step-up combination therapy,
• Initial combination with prednisone, or
• Initial combination with infliximab.
– Every three months, treatment adjustments were made based on DAS
measurements
– Assessments included HAQ and progression of joint damage
Adapted from Dirven L, et al: Presented at ACR 2011; Poster #2200
BeSt Study: Treatment Groups
Group 1:
Sequential
Monotherapy
Group 2:
Step-up
Therapy
Group 3:
Initial combo with
prednisone
Group 4:
Initial combo
with infliximab
1.
MTX
MTX
MTX
+ SSZ + PRED
MTX
+ Biologic
2.
SSZ
MTX
+ SSZ
MTZ
+ CSA + PRED
SSZ
3.
LEF
MTX
+ SSZ + HCQ
MTX
+ Biologic
LEF
4.
MTX
+ Biologic
MTX + SSZ
+ HCQ + PRED
5.
MTX
+ CSA + PRED
MTX
+ Biologic
Adapted from Dirven L, et al: Presented at ACR 2011; Poster #2200
8-Year Results of the BeSt Study:
Patient Disposition
% of patients
Status
Group 1
(n=126)
Group 2
(n=121)
Group 3
(n=133)
Group 4
(n=128)
p value
DAS < 1.6
49%
56%
57%
47%
0.48
DAS < 1.6 drug free
18%
19%
17%
15%
0.90
Still on initial treatment
29%
22%
45%
66%
< 0.001
Infliximab, current use
21
10
13
24
0.06
Drop-out / lost to follow-up
33
36
35
23
0.13
Adapted from Dirven L, et al: Presented at ACR 2011; Poster #2200
8-Year Results of the BeSt Study:
Mean HAQ Over Time
1.6
Sequential monotherapy
Step-up combination therapy
Initial combination with prednisone
Initial combination with infliximab
1.4
HAQ Score
1.2
1.0
0.8
0.6
0.4
0.2
0
0
1
2
3
4
5
6
7
8
Year
*p < 0.05 for Group 4 vs. Group 2
Adapted from Dirven L, et al: Presented at ACR 2011; Poster #2200
8-Year Results of the BeSt Study:
Radiologic Progression
Mean SHS progression
20
Year 8
Year 7
Year 6
Year 5
Year 4
Year 3
Year 2
Year 1
16
12
8
4
0
Sequential
monotherapy
Step-up
therapy
Initial combination Initial combination
with prednisone
with infliximab
Adapted from Dirven L, et al: Presented at ACR 2011; Poster #2200
8-Year Results of the BeSt Study:
Conclusions
• Improvement was maintained in all groups without
deterioration over time
• Radiological damage was very low, even after 8
years
• The percentages of patients in clinical remission and
in drug-free remission were stabilized
Adapted from Dirven L, et al: Presented at ACR 2011; Poster #2200
BeSt: 8-Year Results of a
DAS-steered Treatment Study
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• This study's powerful message is that if you treat to
target (with whatever works for your patient) they
will do well
– Some will even be able to come off pharmacotherapy
entirely
• Despite the push to use biologics early, studies like
the BeSt trial demonstrated the cost avoidance of
the more expensive therapies does not come at the
expense of clinical or radiologic control
Commentary on Dirven L, et al: Presented at ACR 2011; Poster #2200
RA, Anti-TNF Therapy, and Risk of
Malignant Melanoma –a Nationwide
Population-Based Study From Sweden
Raaschou P, et al:
Presented at ACR 2011;
Oral Presentation #2523
RA, Anti-TNF Agents and Risk of
Malignant Melanoma
• Objectives:
– To investigate the risk of malignant melanoma in patients with RA
compared to the general population
– To investigate whether anti-TNF treatment influences melanoma risk
in RA
• Subjects: 56,336 patients with RA from the national Swedish
outpatient registry
– Included 8,453 patients taking biologics
– General-population controls were matched for age, sex, and county of
residence
• Methodology:
– Relative risks for malignant melanoma and all-site cancer were
assessed overall and by time since start of anti-TNF therapy
Adapted from Raaschou P, et al: Presented at ACR 2011; Oral Presentation #2523
Study Population Characteristics
RA
Anti-TNF
exposed
No anti-TNF
General
population
76%
72%
72%
Age at inclusion, yrs.
Mean: 55
Median: 57
Mean: 61
Median: 62
Mean: 60
Median: 61
Nordic origin of birth
95%
95%
93%
Family history of melanoma
2%
2%
2%
COPD
2%
3%
2%
NMSC
0.5%
0.8%
0.5%
Diabetes
5%
6%
4%
Ischemic heart disease
6%
10%
7%
Previous joint surgery
28%
21%
4%
Female
Adapted from Raaschou P, et al: Presented at ACR 2011; Oral Presentation #2523
Risk of Malignant Melanoma in
Biologic-naïve RA vs. General Population
Incidence per 100,000 patient-years
80
RR: 1.1
(95% CI: 0.9 – 1.4)
60
54
46
40
20
0
RA
General population
Adapted from Raaschou P, et al: Presented at ACR 2011; Oral Presentation #2523
Risk of Malignant Melanoma in
Anti-TNF Patients vs. Biologic-naïve RA
Incidence per 100,000 patient-years
80
71
RR: 1.6
(95% CI: 1.1 – 2.4)
60
54
40
20
0
Anti-TNF RA patients
Biologic-naïve RA
Adapted from Raaschou P, et al: Presented at ACR 2011; Oral Presentation #2523
Time Since Treatment Start:
Anti-TNF Exposed vs. Unexposed in RA
RR (95% CI)
Malignant
melanoma
All sites
1.6
(1.1 – 2.4)
0.9
(0.8 – 1.0)
< 1 year
1.1
(0.4 – 3.1)
1.0
(0.8 – 1.2)
1 - <2 years
2.2
(1.0 – 4.7)
0.8
(0.6 – 1.0)
1 - <5 years
1.3
(0.7 – 2.5)
1.0
(0.8 – 1.2)
5+ years
1.8
(0.9 – 3.6)
0.9
0.8 – 1.1)
Overall
Follow-up
Adapted from Raaschou P, et al: Presented at ACR 2011; Oral Presentation #2523
RA, Anti-TNF Agents and Risk of
Malignant Melanoma: Conclusions
• In the absence of anti-TNF therapies, RA patients do
not appear to be at elevated risk of malignant
melanoma
• Patients selected for and treated with anti-TNF have
a higher risk of malignant melanoma than biologicnaïve RA patients
• Malignant melanoma is a rare outcome
Adapted from Raaschou P, et al: Presented at ACR 2011; Oral Presentation #2523
RA, Anti-TNF Agents and Risk of
Malignant Melanoma
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• In this study from Sweden, the relative risk for
melanoma was increased in RA patients on antiTNFs
– The absolute risk, however, was low, and in fact the
number needed to treat was more than 1000
• The overall cancer risk was not increased
• Is the glass half empty or half full?
– Most patients should be reassured by these data, but
cancer-phobic patients may not be
Commentary on Raaschou P, et al: Presented at ACR 2011; Oral Presentation #2523
Opportunistic Infections in Patients
Exposed to Anti-Tumour Necrosis
Factor Therapy:
Results From the British Society for
Rheumatology Biologics Register
Galloway JB, et al:
Presented at ACR 2011;
Oral Presentation #2524
Anti-TNF Agents and Opportunistic
Infections (BSRBR)
• Objective: To establish the risk and pattern of
opportunistic infections (OI) during treatment with antiTNF agents in RA
• Subjects: 11,864 anti-TNF and 3,666 non-biologic
DMARD patients from the British Society for
Rheumatology Biologics Register (BSRBR)
• Methodology:
– The BSRBR drew up a list of OI at its outset
– For this analysis, infection rates were compared using Cox
proportional hazards, adjusted for confounders
Adapted from Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
Anti-TNF Agents and Opportunistic
Infections: Patient Characteristics
DMARD
All
anti-TNF
ETN
IFX
ADA
3,666
11,864
4,136
3,472
4,256
Mean age, years
60
56
56
56
57
Female, %
72
76
77
76
76
Median disease duration, years
6
11
12
12
10
Baseline steroid use, %
23
44
48
46
39
Mean DAS28
5.1
6.6
6.6
6.6
6.5
Subjects, n
ETN: etanercept; IFX: infliximab; ADA: adalimumab
Adapted from Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
Summary of Opportunistic Infections in
RA: DMARD vs. Anti-TNF
DMARD
Anti-TNF
12,592
45,700
4
37
32
(8, 81)
81
(57, 111)
Invasive fungal infection, n
1
3
Pneumocytis pneumonia, n
1
6
Multidermatomal shingles, n
–
8
Listeriosis, n
1
8
Legionellosis, n
–
6
Salmonellosis, n
1
6
Exposure time (pyrs)
Events, n
Incidence rate / 100 000 years
(95% CI)
Adapted from Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
Hazard ratio (95% Confidence interval)
Anti-TNF Agents and Risk of
Opportunistic Infections (BSRBR)
8.0
4.0
2.8
(1.0, 7.8)
2.0
1.5
(0.3, 7.8)
1.0
0.5
DMARD
Anti-TNF (Unadjusted)
Anti-TNF (Adjusted*)
*Adjusted for age, gender, disease activity, disease duration, disability, COPD, diabetes, baseline steroid use, year of entry into study
Adapted from Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
Risk of Opportunistic Infections:
Comparison Among Anti-TNF Agents
ETN
INF
ADA
23,026
13,476
17,211
9
18
10
Incidence rate / 100 000 years
(95% CI)
45
(21, 86)
159
(94, 251)
66
(33, 127)
Adjusted hazard ratio*
(95% CI)
Referent
4.5
(1.9, 10.9)
1.7
(0.7, 4.3)
Adjusted hazard ratio*
(95% CI)
0.6
(0.2, 2.7)
2.7
(1.1, 6.5)
Referent
Exposure time (pyrs)
Events, n
*Adjusted for age, gender, disease activity, disease duration, disability, COPD, diabetes, baseline steroid use, year of entry into study
Adapted from Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
Anti-TNF Agents and Risk of
Opportunistic Infections: Conclusions
• The absolute rate of opportunistic infections (OI)
was non-significantly higher in anti-TNF exposed
patients
– The infliximab cohort accounted for 44% of these cases
– The absolute risk of OI was very low
• The pattern of risk seen in this analysis has also
been reported by other registries
• This adds weight to the evidence that infliximab may
carry a greater risk of OI than other anti-TNF agents
Adapted from Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
Anti-TNF Agents and Risk of
Opportunistic Infections (BSRBR)
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• These findings corroborate previous studies and add
weight to the evidence that infliximab may carry a
greater risk of opportunistic infection than either
etanercept or adalimumab
Commentary on Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
The Risk of Solid Cancer in Patients
Receiving Anti-Tumour Necrosis Factor
Therapy for Rheumatoid Arthritis
for up to 5 Years:
Results From the British Society for
Rheumatology Biologics Register
Mercer LK, et al:
Presented at ACR 2011;
Oral Presentation #2525
Anti-TNF Agents and Risk of Solid
Cancers (BSRBR)
• Objective: To determine whether anti-TNF use influences the risk
of cancer when used in routine clinical practice for RA
• Subjects: 3,543 DMARD patients and 11,719 anti-TNF patients
from the British Society for Rheumatology Biologics Register
(BSRBR)
– Patients with history of solid cancer were excluded
• Methodology:
– Rates of solid cancer in the anti-TNF and DMARD cohorts were
compared using adjusted multivariate Cox proportional hazards
models
– Site specific analyses were also performed for the most common
sites: colorectal, lung/bronchus and female breast
Adapted from Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525
Anti-TNF Agents and Risk of Solid
Cancers (BSRBR)
Hazard ratio for anti-TNF
(95% CI)
1.5
1.2
1.0
0.94
0.88
0.8
0.73
0.6
Unadjusted
Age/gender adjusted
Fully adjusted*
* Adjusted for baseline age, gender, smoking, RA duration, NSAID use, comorbidity and year of registration
Adapted from Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525
Anti-TNF Agents and Risk of Solid Cancers:
Agent-specific Analysis (BSRBR)
Fully adjusted hazard ratio*
(95% CI)
1.5
1.2
1.0
0.94
0.88
0.87
0.81
0.8
0.6
Anti-TNF
Etanercept
Infliximab
Adalimumab
* Adjusted for baseline age, gender, smoking, RA duration, NSAID use, comorbidity and year of registration
Adapted from Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525
Anti-TNF Agents and Risk of Solid Cancers:
Analysis by Duration of Follow-up (BSRBR)
Fully adjusted hazard ratio for anti-TNF*
(95% CI)
3.0
2.0
1.5
1.2
1.18
1.0
1.01
1.00
0.88
0.74
0.5
Overall
2nd year
3rd year
4th year
5th year
* Adjusted for baseline age, gender, smoking, RA duration, NSAID use, comorbidity and year of registration
Adapted from Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525
All Fully adjusted hazard ratio for anti-TNF*
(95% CI)
Anti-TNF Agents and Risk of Most
Common Solid Cancers (BSRBR)
3.0
2.0
1.5
1.2
1.21
1.0
0.99
0.88
0.89
0.5
All Solid
Lung
Colorectal
Breast
* Adjusted for baseline age, gender, smoking, RA duration, NSAID use, comorbidity and year of registration
Adapted from Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525
Anti-TNF Agents and Risk of Solid
Cancers (BSRBR): Conclusions
• In this UK national cohort of RA patients treated
with TNF inhibitors when followed for up to 5 years:
– No increase in solid cancer risk was seen in patients
without prior solid cancer
• Further follow up is warranted to further assess sitespecific risk and allow for longer latency
Adapted from Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525
Anti-TNF Agents and Risk of Solid
Cancers (BSRBR)
Commentary from International Literature Search in Rheumatology’s
Canadian Editorial Panel
• The strengths of this study are that:
– It is a large cohort, linked to a national cancer register
– It attempted to distinguish risk between the agents
• It adds to the reassuring data emerging from RCTs
and other observational studies (e.g., ARTIS from
Sweden) that the risk of solid cancers is not
increased in patients receiving any of the anti-TNF
agents
Commentary on Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525