International Literature Search in Rheumatology
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Transcript of International Literature Search in Rheumatology
International Literature Search in Rheumatology
Vol. 6, Number 2December 2011
In this issue:Highlights of the 2011 Annual Meeting of the
American College of RheumatologyNovember 5-9, Chicago, IL
Table of ContentsAuthor(s) Poster / presentation #s SlidesHørslev-Petersen K 394 3 – 10Genovese M 401 11 – 18Genovese M 402 19 – 26VanVollenhoven R 408 27 – 34Yonemoto Y 1236 35 – 42Yazici Y 124043 – 50Bakker M 1695 51 – 58O'Dell J 169659 – 66Kaine JL 2190 67 – 74Roussy J-P 2193 75 – 82Meissner B 2197 83 – 90Dirven L 2200 91 – 98Raaschou P 2523 99 – 106Galloway J 2524 107 – 114Mercer L 2525 115 – 122
Adalimumab Added to Methotrexate andIntra-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
Characteristic Methotrexate + Placebo
Methotrexate + Adalimumab
Number of patients 91 89
Women 69% 63%
Median age, years 54.4 56.2
Median disease duration, days 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
Median HAQ 1.0 1.1
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
CharacteristicMethotrexate
+ 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
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
Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394
100%
80%
60%
40%
20%
0%MTX + Placebo MTX + Adalimumab
81 84
p = 0.74
% o
f pati
ents
with
DAS
28 <
3.2
Adalimumab Added to MTX & I.A. Glucocorticoid: Remission
Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394
p = 0.059
p = 0.0017
p = 0.0235 p = 0.0095
64
78
% o
f pati
ents
100%
80%
60%
40%
20%
0% DAS28 < 2.6 ACR/EULARremission(28 joint)
SDAI < 3.3 ACR/EULARremission(40 joint)
38
63
31
49
28
48
MTX + PlaceboMTX + Adalimumab
Adalimumab + Methotrexate & Intra-articularGlucocorticoid 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 intra-articular 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
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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
R: Responder; NR: Non-Responder; pbo: Placebo; N: Number of patients; Wk: Week; MTX: MethotrexateAdapted from Genovese MC, et al: Presented at ACR 2011; Poster #401
Week 0 randomization N=237
N=47
75 mgN=49
150 mgN=43
300 mgN=41
pboN=50
Re-assignment at Week 16 based on ACR20 response: R and NR
25 mgN=54
N=47 N=43 N=38 N=45
Patients available for evaluation at Week 52
25/25R=18
25/150NR=27
75/75R=23
75/150NR=23
150/150R=20
150/300NR=23
300/300R=21
300/300NR=16
pbo/150R=18
pbo/150R=17
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
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401
50%
40%
30%
20%
10%
0% 25 mg 75 mg 150 mg 300 mg Total
% o
f pati
ents
38.9
14.813.0
8.2
4.1
22.4
14.012.0
7.0
30.0
4.9
0.0
24.4
9.8
6.0
Overall study discontinuationsDiscontinuations for AEsDiscontinuations for Unsatisfactory therapeutic effects
Secukinumab for Rheumatoid Arthritis: Adverse Events
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401
100%
80%
60%
40%
20%
0% Overall AEs Infections / infestations
% o
f pati
ents
31.928.3
34.8
26.133.3
64.868.3
63.565.261.1
25 mg75 mg150 mg300 mgTotal
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
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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 Abataceptin 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
CharacteristicShort-term population LTE Population
SC Abatacept + MTX (n=736)
SC Abatacept + MTX (n=721)
SC Abatacept + MTX (n=1372)
Mean age, years 49.9 ± 13.2 50.1± 12.6 49.7 ± 12.8
% female 84.4 80.4 82.4
Mean disease duration, years 7.6 ± 8.1 7.7 ± 7.8 7.6 ± 7.9
Mean TJC / SJC 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
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
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402
100.0
80.0
60.0
40.0
20.0
0.0015
2957
85113
141169
253 449365 729617533
Visit day
Patie
nts a
chie
ving
ACR
resp
onse
(%)
SC abataceptIV abatacept switched to SC abatacept
ACR 20
ACR 50
ACR 70
All patients switch toSC abatacept
ACQUIRE Study Long-term Extension: Efficacy – LDAS and DAS28 Remission
Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402
100.0
80.0
60.0
40.0
20.0
0.0015
2957
85113
141169
253 449365 729617533
Visit day
Patie
nts a
chie
ving
ACR
resp
onse
(%)
SC abataceptIV abatacept switched to SC abatacept
LDAS
DAS28-definedremission
All patients switch toSC abatacept
ACQUIRE Study Long-term Extension: Safety
ST Period: SC Abatacept + MTX (n=744)
ST Period: IV Abatacept + MTX (n=731)
LTEPeriod: SC Abatacept + MTX (n=1372)
Pts. with event (%)
Events / 100 pt-yrs
Pts. with event (%)
Events / 100 pt-yrs
Pts. with event (%)
Events / 100 pt-yrs
Serious adverse events (SAEs) 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
Discontinued due to SAEs 8 (1.1) - 14 (1.9) - 23 (1.7) -
Adverse events (AEs) 493 (67.0) - 470 (65.2) - 988 (72.0) -
Infections 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) -
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
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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
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
51.5 52.647.2
28.3
% o
f pati
ents
100%
80%
60%
40%
20%
0%Tofacitinib 5 mg Tofacitinib 10 mg Adalimumab 40 mg Placebo
Tofacitinib vs. Adalimumab or Placebo in RA Patients: DAS28 Remission at Month 6
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
7.3
12.5
6.2
1.1
% o
f pati
ents
14%
10%
8%
6%
2%
0%Tofacitinib 5 mg Tofacitinib 10 mg Adalimumab 40 mg Placebo
12%
4%
Tofacitinib vs. Adalimumab or Placebo in RA Patients: Mean HAQ Change at Month 6
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
-0.55
-0.61
-0.49
-0.24
Chan
ge in
HAQ
Sco
re fr
om b
asel
ine
0
-0.2
-0.3
-0.4
-0.6
-0.7
Tofacitinib 5 mg Tofacitinib 10 mg Adalimumab 40 mg Placebo
-0.1
-0.5
Tofacitinib vs. Adalimumab or Placebo in RA Patients on Methotrexate: Adverse Events
Treatment groupMonths 0-3 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
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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 0.65Age, years 59 59 63 60 0.33RA duration, months 105 131 149 132 0.28Concomitant MTX, % 100 54 41 87 <0.01
MTX dosage, mg/wk 6.6 6.3 5.3 6.2 <0.01Concomitant PSL, % 84 67 74 59 0.11
PSL dosage, mg/day 4.5 4.8 4.8 5.0 0.77CRP (mg/dL) 2.66 2.81 4.27 2.62 <0.01ESR (mm/hr) 53 54 71 52 0.41MMP-3 (ng/dL) 275.2 241.0 315.4 286.0 0.74DAS-28 (ESR) 4.9 4.8 5.5 4.8 0.73DAS-28 (CRP) 3.9 3.8 4.6 3.9 <0.05
Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Direct Comparison of Four Biologics:DAS28-ESR Scores at 6 Months
Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Biologic: IFX ETN TCZ ADA
6.0
5.0
4.0
3.0
2.0
1.0
0
DA28
-ESR
Baseline DAS28-ESR: 4.9 4.8 5.5 4.8
Direct Comparison of Four Biologics: MMP-3 at 6 Months
Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Biologic: IFX ETN TCZ ADA
1200.0
1000.0
800.0
600.0
400.0
200.0
0.0
MM
P-3
(ng/
ml)
Baseline MMP-3 (ng/mL): 275.2 241.0 315.4 286.0
Direct Comparison of Four Biologics: Drug Survival Rates at 6 Months
No significant difference between biologics in drug survival ratesAdapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236
Infliximab Etanercept Tocilizumab Adalimumab
100%
80%
60%
40%
20%
0%
% sti
ll ta
king
dru
g at
6 m
onth
s
8992
100
89
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
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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 COMET PREMIER AGREE GO-BEFORE
MTXIFX
3 mg/kg + MTX
MTXETN
50 mg+ MTX
MTXADA
40 mg+ MTX
MTXABA
10 mg/kg+ MTX
MTXGOL
50 mg+ MTX
N 282 359 263 265 257 268 253 256 160 159
ACR20 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 remission 15% 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
Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240
Odds Ratios (Log Scale)0.1 1 10 100
ACR 20
ETN 50mgADA 40mg
ABA 10mg/kgGOL 50mg
INF 3mg/kg
ACR 50
ETN 50mgADA 40mg
ABA 10mg/kgGOL 50mg
INF 3mg/kg
ACR 70
ETN 50mgADA 40mg
ABA 10mg/kgGOL 50mg
INF 3mg/kg
DAS-R
ETN 50mgADA 40mg
ABA 10mg/kgGOL 50mg
INF 3mg/kg
3.021.60
1.961.64
1.44
2.521.92
1.841.631.77
2.372.19
1.981.71
1.80
2.592.84
2.341.60
1.53
Random-effects modelFixed-effects model
Comparative Tolerability of Biologic Therapies in RA: Serious Infections and Serious AEs
Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240
SeriousInfections
ETN 50mg
ABA 10mg/kg
GOL 50mg
INF 3mg/kg
0.94
0.99
0.91
1.32
Odds Ratios vs. Placebo + MTX0.01 0.1 10 100
SeriousAE
ETN 50mg
ADA 40mg
ABA 10mg/kg
GOL 50mg
INF 3mg/kg
0.59
1.26
0.45
0.63
2.97
Random-effects modelFixed-effects model
1
Comparative Tolerability of Biologic Therapies in RA: Discontinuations
Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240
Odds ratios vs. Placebo + MTX0.01 0.1 10 100
Withdrawaldue to AE
ETN 50mg
ADA 40mg
ABA 10mg/kg
GOL 50mg
INF 3mg/kg
0.78
1.71
0.70
2.66
3.32
Random-effects modelFixed-effects model
1
0.57
0.61
0.90
0.76
0.85
AnyWithdrawal
ETN 50mg
ABA 10mg/kg
GOL 50mg
INF 3mg/kg
ADA 40mg
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
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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, placebo-controlled, 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)
Adapted from Bakker MF, et al: Presented at ACR 2011; Oral presentation #1695
40
20
00 60 80 100
67% 78%
Medianerosion score at 2yearsless in the MTX+prodstrategy, p=0.02
MTX-placeboMTX-prednisone
Low-dose Prednisone with MTX-based Tight Control in Early RA: Sustained Remission
Adapted from Bakker MF, et al: Presented at ACR 2011; Oral presentation #1695
p = 0.0972
100%
80%
60%
40%
20%
0%MTX + prednisone MTX + placebo
61
% o
f pati
ents
Low-dose Prednisone with MTX-based Tight Control in Early RA: Need for Biologic Therapy
Adapted from Bakker MF, et al: Presented at ACR 2011; Oral presentation #1695
p< 0.001
14
100%
80%
60%
40%
20%
0%MTX + prednisone MTX + placebo
36
% o
f pati
ents
requ
iring
bio
logi
c
Low-dose Prednisone with MTX-based Tight Control in Early RA: Adverse Events
Event MTX + Prednisone MTX + Placebo
Death 1 0Admission 1 5Cataract 1 0Glaucoma 0 0Nausea 51 152Epigastric pain 14 17ALT > ULN 30 87AST > ULN 16 38Pneumonitis 1 0Infections 6 7Antibiotics 1 0Peripheral fractures 1 0Hypertension 11 18Diabetes mellitus 1 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
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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
Adapted from O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
72%
28%Required step-up(DAS28 > 3.2)
Remained on MTXMonotherapy(DAS28 ≤ 3.2)
Validation of Methotrexate First Strategy: Mean DAS28 to Week 102
Adapted from O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
Primary Analysis: Weeks 48 to 102
Comparison p-valueGroups (IE, IT, SE, ST) 0.55
Time (I = S) 0.37Trt (ETN > TT) 0.18
7
6
5
4
3
2
1
0Week 0
(755)Week 12
(661)Week 24
(646)Week 36
(601)Week 48
(582)Week 60
(522)Week 72
(518)Week 84
(508)Week 96
(485)Week 102
(476)
DAS2
8
IEIT
SEST
Step-up to MultipleDMARD at Week24 if DAS28 ≥ 3.2
Validation of Methotrexate First Strategy:Radiographic Progression (Cumulative Probability)
Adapted from O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
100
80
60
40
20
0
-2010 20 30 40 50 60 70 80 90 1000
Initial EtanerceptInitial TripleStep-up EtanerceptStep-up Triple
Cumulative probability
Wee
k 10
2 Ch
ange
from
Bas
elin
e (%
)
Validation of Methotrexate First Strategy:MTX-only Patients Achieving DAS28 Reduction Thresholds
Adapted from O'Dell JR, et al: Presented at ACR 2011; Oral presentation #1696
70
60
50
40
30
20
10
0Week 12 Week 24
DAS > 1.2DAS > 1.8DAS > 2.4
Perc
enta
ge o
f pati
ents
(%)
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
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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 through15 months
Adapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
Temporary Withdrawal & Reintroduction of Abatacept in RA: Study Design
Adapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
Introduction PhasePeriod I: SC open-label
12 weeks
Withdrawal PhasePeriod II: double-blind
12 weeks
Re-introduction PhasePeriod III: SC open-label
12 weeks
Respondersrandomized
IV loading dose:placebo (blinded)Loading dose
IV abataceptDay 1
Long-term extension:SC open-label
Month 6 (Day 169)Primary endpoint:
ImmunogenicitySecondary endpoints:
SafetyEfficacy
Month 3 (Day 85) Month 9 (Day 253)Primary endpoint:
ImmunogenicitySecondary endpoints:
SafetyEfficacy
IV loading dose: abataceptor placebo (blinded)
SC abatacept + MTXn=167
SC abatacept + MTX†
n=40
SC placebo + MTX†
n=80
SC abatacept + MTXn=40
SC abatacept + MTXn=79
IV abatacept
Temporary Withdrawal & Reintroduction of Abatacept in RA: Efficacy (DAS28)
Adapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
0.5
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
85 169 253 449
Period I:Introduction
SC ABA, N=167
Period III:Re-Introduction
SC ABA, N=40SC PBO, N=79
Period II:Withdrawal
SC ABA, N=40vs. PBO, N=80
DAS2
8 m
ean
chan
ge fr
om b
asel
ine
Long-term extension:SC ABA open-labelPeriod I NRs, N=37
Period III completers, N=113(SC ABA, N=39; SC PBO, N=74)
Studyvisit day
Period I NRPeriod II SC ABAPeriod II SC PBO
Temporary Withdrawal & Reintroduction of Abatacept: Safety
Number of patients with event (%)
Treatment group prior to LTE entry
Total (n=150)Period I Non-responders
(n=37)
Period III Completers (n=113)Period II SC ABA (n=39)
Period II SC PBO (n=74)
Deaths 1 (2.7) 0 0 1 (0.7)AEs
URTIInfluenzaSinusitisBronchitis
24 (64.9)6 (16.2)6 (16.2)2 (5.4)2 (5.4)
22 (56.4)3 (7.7)
02 (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 0Autoimmune events 0 0 1 (1.4) 1 (0.7)
S.C. injection-site reactions 0 2 (5.1) 0 2 (1.3)
Adapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
Temporary Withdrawal & Reintroduction of Abatacept: Immunogenicity
NR: Non-responders; SC ABA: subcutaneous abataceptAdapted from Kaine JL, et al: Presented at ACR 2011; Poster #2190
Overall
Period I NR
Period II SC ABA
Period II placebo
0% 20% 40% 60% 80% 100%
2.8%
2.8%
2.6%
2.9%
% of patients with positive immunogenicity
Temporary Withdrawal & Reintroduction of Abatacept (ALLOW study): Conclusions
• In ALLOW, 3-month interruption and subsequentre-introduction of SC abatacept had no adverse impact on safety, immunogenicity or efficacy over15 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
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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
DMARD-t: Traditional DMARD; DMARB-b: Biologic DMARDAdapted from Roussy J-P, et al: Presented at ACR 2011; Poster #2193
50.0%
45.0%
40.0%
35.0%
30.0%
25.0%
20.0%
15.0%
10.0%
5.0%
0.0%Nov.2002
Nov.2003
Nov.2004
Nov.2005
Nov.2006
Nov.2007
Nov.2008
No treatmentNon-DMARD onlyDMARD - anyDMARD-tDMARD-b (+/- DMARD-t)
Perc
enta
ge o
f sub
ject
s
Time from Diagnosis to Initiation of Any DMARD, by Specialty
Adapted from Roussy J-P, et al: Presented at ACR 2011; Poster #2193
Rheumatologist
Internist
GPOther specialist
1.0
0.8
0.6
0.4
0.2
0.00 500 1000 1500 2000 2500
Survival days
Surv
ival
pro
babi
lity
Censored Log rank, p<0.0001
Predictors of DMARD Use for RA in Quebec: Multivariate Analysis (1 of 2)
Variable Reference AdjustedOdds Ratio 95% CI
Calendar year
2003
vs. 2002
1.112 0.955 – 1.296
2004 1.166 1.003 – 1.355
2005 1.209 1.035 – 1.412
2006 1.336 1.144 – 1.561
2007 1.474 1.254 – 1.734
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
Comorbidity score -- 0.986 0.976 – 0.997
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)
Variable Reference AdjustedOdds Ratio 95% CI
Specialty overseeing RA care
Rheumatologist
vs. GP
4.159 3.608 – 4.794
Internist 2.388 2.019 – 2.826
Other specialty 0.708 0.543 – 0.923
≥ 1 claim in the previous year for:
Opioid (≥ 1)
vs. no claim
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
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
• These findings further highlight the need for earlier access to rheumatologists for patients with RA
Commentary from International Literature Search in Rheumatology’s Canadian Editorial Panel
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 aReal-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 12-month 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
Adapted from Meissner B, et al: Presented at ACR 2011; Poster #2197
100%
80%
60%
40%
20%
0%Abatacept Adalimumab Etanercept Infliximab Overall
% o
f pati
ents
7.85.28.58.92.0
Which Type of Biologic Was Used As the 2nd Agent?
Adapted from Meissner B, et al: Presented at ACR 2011; Poster #2197
90.0
10.0100%
80%
60%
40%
20%
0%Adalimumab Etanercept Infliximab
% o
f pati
ents
8.5
94.8
5.2
44.6
55.4
First Biologic Agent
Non-anti-TNF biologicAnti-TNF biologic
Proportion of Patients Requiring Switch to 3rd Biologic Within 1st Year
Adapted from Meissner B, et al: Presented at ACR 2011; Poster #2197
100%
80%
60%
40%
20%
0%Abatacept Adalimumab Etanercept Infliximab
% o
f pati
ents
12.812.918.1
6.0
Second Biologic
Healthcare Utilization Differences Between Switchers and Nonswitchers (Prior to Biologic Initiation)
Hospitalizations Monthly Healthcare Costs
Adapted from Meissner B, et al: Presented at ACR 2011; Poster #2197
p = 0.015
100%
80%
60%
40%
20%
0%Switchers Nonswitchers
% o
f pati
ents
7.29.5
p< 0.001
$1,500
$1,200
$900
$600
$300
$0Switchers Nonswitchers
$ U
S 796
1,025
Switching Biologics for RA in a Real-World 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 RAin a Real-World Setting
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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
Adapted from Dirven L, et al: Presented at ACR 2011; Poster #2200
1.
2.
3.
4.
5.
Group 1:Sequential
Monotherapy
MTX
SSZ
LEF
MTX+ Biologic
Group 4:Initial combo
with infliximab
MTX+ Biologic
SSZ
LEF
MTX+ CSA + PRED
Group 3:Initial combo with
prednisone
MTX+ SSZ + PRED
MTZ+ CSA + PRED
MTX+ Biologic
Group 2:Step-upTherapy
MTX
MTX+ SSZ
MTX+ SSZ + HCQ
MTX + SSZ+ HCQ + PRED
MTX+ Biologic
8-Year Results of the BeSt Study:Patient Disposition
Status% of patients
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
*p < 0.05 for Group 4 vs. Group 2Adapted from Dirven L, et al: Presented at ACR 2011; Poster #2200
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
00 1 2 3 4 5 6 7 8
Sequential monotherapyStep-up combination therapyInitial combination with prednisoneInitial combination with infliximab
Year
HAQ
Sco
re
8-Year Results of the BeSt Study: Radiologic Progression
Adapted from Dirven L, et al: Presented at ACR 2011; Poster #2200
20
16
12
8
4
0Sequential
monotherapyStep-uptherapy
Initial combinationwith prednisone
Initial combinationwith infliximab
Mea
n SH
S pr
ogre
ssio
n
Year 8Year 7Year 6Year 5Year 4Year 3Year 2Year 1
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 aDAS-steered Treatment Study
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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
RAGeneral
populationAnti-TNF exposed No anti-TNF
Female 76% 72% 72%
Age at inclusion, yrs. Mean: 55Median: 57
Mean: 61Median: 62
Mean: 60Median: 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%
Adapted from Raaschou P, et al: Presented at ACR 2011; Oral Presentation #2523
Risk of Malignant Melanoma inBiologic-naïve RA vs. General Population
Adapted from Raaschou P, et al: Presented at ACR 2011; Oral Presentation #2523
RR: 1.1(95% CI: 0.9 – 1.4)
54
80
60
40
20
0RA General population
46
Inci
denc
e pe
r 100
,000
pati
ent-y
ears
Risk of Malignant Melanoma inAnti-TNF Patients vs. Biologic-naïve RA
Adapted from Raaschou P, et al: Presented at ACR 2011; Oral Presentation #2523
RR: 1.6(95% CI: 1.1 – 2.4)
7180
60
40
20
0Anti-TNF RA patients Biologic-naïve RA
54
Inci
denc
e pe
r 100
,000
pati
ent-y
ears
Time Since Treatment Start:Anti-TNF Exposed vs. Unexposed in RA
RR (95% CI)Malignant melanoma All sites
Overall 1.6 (1.1 – 2.4)
0.9(0.8 – 1.0)
Follow-up
< 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)
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 biologic-naïve 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
• In this study from Sweden, the relative risk for melanoma was increased in RA patients on anti-TNFs– 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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 anti-TNF 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 Allanti-TNF ETN IFX ADA
Subjects, n 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
ETN: etanercept; IFX: infliximab; ADA: adalimumabAdapted from Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
Summary of Opportunistic Infections in RA: DMARD vs. Anti-TNF
Adapted from Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
DMARD Anti-TNF
Exposure time (pyrs) 12,592 45,700
Events, n 4 37
Incidence rate / 100 000 years(95% CI)
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
Anti-TNF Agents and Risk of Opportunistic Infections (BSRBR)
*Adjusted for age, gender, disease activity, disease duration, disability, COPD, diabetes, baseline steroid use, year of entry into studyAdapted from Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
Haza
rd ra
tio (9
5% C
onfid
ence
inte
rval
)
2.8(1.0, 7.8)
1.5(0.3, 7.8)
8.0
4.0
2.0
1.0
0.5
Anti-TNF (Adjusted*)Anti-TNF (Unadjusted)DMARD
Risk of Opportunistic Infections: Comparison Among Anti-TNF Agents
*Adjusted for age, gender, disease activity, disease duration, disability, COPD, diabetes, baseline steroid use, year of entry into studyAdapted from Galloway JB, et al: Presented at ACR 2011; Oral Presentation #2524
ETN INF ADA
Exposure time (pyrs) 23,026 13,476 17,211
Events, n 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
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)
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
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 Arthritisfor 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)
* Adjusted for baseline age, gender, smoking, RA duration, NSAID use, comorbidity and year of registrationAdapted from Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525
Haza
rd ra
tio fo
r anti
-TN
F(9
5% C
I)
0.73
0.940.88
1.5
1.2
1.0
0.8
0.6
Fully adjusted*Age/gender adjustedUnadjusted
Anti-TNF Agents and Risk of Solid Cancers: Agent-specific Analysis (BSRBR)
* Adjusted for baseline age, gender, smoking, RA duration, NSAID use, comorbidity and year of registrationAdapted from Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525
Fully
adj
uste
d ha
zard
ratio
* (9
5% C
I)
1.5
1.2
1.0
0.8
0.6
AdalimumabInfliximabEtanerceptAnti-TNF
0.870.880.94
0.81
Anti-TNF Agents and Risk of Solid Cancers: Analysis by Duration of Follow-up (BSRBR)
* Adjusted for baseline age, gender, smoking, RA duration, NSAID use, comorbidity and year of registrationAdapted from Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525
Fully
adj
uste
d ha
zard
ratio
for a
nti-T
NF*
(9
5% C
I)
0.881.00
0.74
1.01
1.18
3.0
2.0
1.5
1.2
1.0
0.5
Overall 5th year4th year3rd year2nd year
Anti-TNF Agents and Risk of Most Common Solid Cancers (BSRBR)
* Adjusted for baseline age, gender, smoking, RA duration, NSAID use, comorbidity and year of registrationAdapted from Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525
All F
ully
adj
uste
d ha
zard
ratio
for a
nti-T
NF*
(9
5% C
I)
3.0
2.0
1.5
1.2
1.0
0.5
BreastColorectalLungAll Solid
1.21
0.88 0.890.99
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 site-specific 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)
• 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 from International Literature Search in Rheumatology’s Canadian Editorial Panel
Commentary on Mercer LK, et al: Presented at ACR 2011; Oral Presentation #2525