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


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


Adalimumab Added to MTX & I.A. Glucocorticoid: DAS28 < 3.2 at 12 Months


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


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


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


Secukinumab for Rheumatoid Arthritis: Discontinuations


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


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


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 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


ACQUIRE Study Long-term Extension: Baseline Characteristics

CharacteristicShort-term population LTE Population

SC Abatacept + MTX (n=736)



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


ACQUIRE Study Long-term Extension: Efficacy – ACR 20/50/70 Over 24 Months


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


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) -


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


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 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


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


-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


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


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 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


Direct Comparison of Four Biologics:DAS28-ESR Scores at 6 Months


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


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


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 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


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


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


1

Comparative Tolerability of Biologic Therapies in RA: Discontinuations


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


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


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 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)


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


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


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


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


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 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


72%

28%Required step-up(DAS28 > 3.2)

Remained on MTXMonotherapy(DAS28 ≤ 3.2)

Validation of Methotrexate First Strategy: Mean DAS28 to Week 102


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)


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


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


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 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


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



IV abatacept

Temporary Withdrawal & Reintroduction of Abatacept in RA: Efficacy (DAS28)


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)


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


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 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


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


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


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


Patterns of DMARD Use for RA in Quebec

• 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 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


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?


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


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


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


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 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


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


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


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


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 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%


Risk of Malignant Melanoma inBiologic-naïve RA vs. General Population


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


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)


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


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 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


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


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 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


* 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)


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)


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)


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


• 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

international literature search in rheumatology

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