achieving remission in early ra dubai, united arab emirates 19. january 2009 professor joachim...

Achieving remission in early RA

Dubai, United Arab Emirates19. January 2009

Professor Joachim Kalden

Friedrich-Alexander University Erlangen-Nuremberg

Erlangen, Germany

2

Achieving remission in early RAOverview

• Definition of remission• Why early treatment. Window of opportunity• Using DMARDs to induce remission• Using TNF antagonists to induce remission• The COMET study

3

Definition of Remission

• Clinical Remission• ACR/DAS criteria, or normal acute phase response, no clinical

synovitis

• Imaging Remission • No radiographic damage progression• No significant synovitis on sensitive imaging

• True Remission• A state of low disease activity with no progression of structural

damage

4

Clinical Remission by DAS28

Based on VAS of 100mm

Prevoo MLL et al. Arthritis Rheum 1995;38:44-8. van Gestel AM et al. J Rheumatol 1999;26:705-11.

DAS28 Score

5.1

3.22.6

Severe

Moderate

Low

Remission

Disease Activity

DAS28 <2.6

5

For achieving remission early treatment for RA is necessary

Since:

• Damage is an early feature of RA (93 % of Ra patients have radiographic damage within less than two years)

• Erosions can be demonstrated within four months after the onset of symptoms by MRI or ultrasound

• The rate of progression is significantly faster within the first year as compared to the second and third year

• Osteoclasts are involved in early tissue destruction

Plant. J. Rheumatol. 1998

Brook. Ann Rheum Dis. 1977

Wolfe. Arthritis Rheum. 1998

Molenaar et al. Arthritis Rheum. 2004;50:35-42

6

Erosion MTP I

OnsetRespiratory

Infection

NSARSingle shot

steroid

0 2 4 6 8 10 weeks

CASE31y female

11

69060

44

105095

21

38077

TJC

SJC

RF

ESR

Non- destructive phase Destructive phase

Kinetics of bone destruction in arthritis I

By t

he c

ourt

esy

of

Georg

Sch

ett

8

Early treatment reduces disability 5 years later

according to: Wiles NJ, et al. Arthritis Rheum 2001; 44: 1033 - 42

* Odds ratio of HAQ ≥1

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Degre

e o

f D

isabili

ty*

aft

er

5 Y

ears

<6 months(n = 60)

6-12 months(n = 47)

>12 months(n = 76)

0.9

2.4 2.3

9

Schematic Representation of the Course of RA Over 30 Years

0 5 10 15 20 25 30

Disease duration (years)

Se

ve

rity

(A

rbit

rary

Un

its

)

Inflammation

Disability

Radiographic Scores

Kirwan J. J Rheumatol. 1999;26:720-5.

10

Relationship Between X-ray Progression and Physical Function - TEMPO Trial

• X-ray progression and HAQ scores were determined at baseline, Year 1 and Year 2

• After adjustment for co-variates, Sharp-score was a statistically significant determinant of HAQ-score (P<0.0001)

• Progression of radiographic damage over a relatively short period of time leads to deterioration of physical function

van der Heijde D, et al. Abstract 1456, ACR 2005.

Negative Zero Mild Severe

Progression

11

Therapeutic options for early RA*

Steroids

systemical

intraarticular

in combination with DMARD‘s

* Besides NSAID‘s

DMARD‘s

as monotherapy

as combination therapy

Biologics

in combination with MTX

12

Using DMARDS to Induce Remission

Have we reached the limit of conventional therapies?

13

Combination DMARD step-down therapy: COBRA trial (6 months)

Boers M et al. Lancet. 1997;350:309-318.

Po

ole

d I

nd

ex

SSZ alone

SSZ with MTX + Pred

MTX 7.5 mg/week

Weeks

16 2800.0

0.4

0.8

1.2

1.6

Prednisolone 7.5 mg/day

Prednisolone60 mg/day

SSZ 2000 mg/day

14

Early combination DMARD therapy led to sustained slowing of progression in early RA

P =0.008

0

10

20

30

40

0 1 2 3 4 5

Rad

iog

rap

hic

pro

gre

ssio

n

(Mea

n

VdH

TS

S)

Years

COBRA:COBRA:5.45.4

points/yearpoints/year

SSZ alone: SSZ alone: 8.68.6

points/yearpoints/year

Landewe RB et al. Arthritis Rheum 2002:46:347-356

COBRA

SSZ alone

SSZ vs. COBRA

15

34

7

12

8

0

43

0

41

3

5

7

6

5

3

3

0

2

4

6

8

10

12

14

16

18

0 1 2 3 4 5 6 7 8Total no. of joints with US synovitis

Brown, Arthritis Rheum 2006; 54: 3761

Pat

ien

ts (

n)

Patients NOTsatisfying ACRRemission Criteria (n)Patientssatisfying ACRRemission Criteria (n)

Clinical Remission on DMARDs in 100 RA patients: # of Patients with US Synovitis

(ACR Remission vs non ACR Remission)

16Grigor C et al. Lancet 2004; 364: 263

NO:Tight Control in RA

6

5

4

3

2

1

0

0 3 6 9 12 15 18Month

Dis

ease

act

ivit

y sc

ore

Intensive

Routine

The TICORA Trial

17* P<0.02, ** P<0.002, Mann-Whitney

Radiographic Progression: 0 and 18 Months

3

4.5

8.5

0.5

3.25

4.5

0

1

2

3

4

5

6

7

8

9

Erosion score Narrowing score Total Sharp score

Routine Intensive

**

*

Median change in erosion, joint space narrowing and total Sharp score

Grigor C et al. Lancet 2004; 364: 263

18

Lessons from DMARD studies

• MTX is more efficacious at higher than lower dosages• DMARDs are efficacious, but do not completely arrest radiographic

progression• Combination DMARD therapy is more efficacious than monotherapy• Radiographic progression is reduced the most effectively, over the

long-term, when DMARD therapy is initiated:

• Early• Intensively

Targeting Remission with Biologic Therapy

20

Biologics in combination with MTX in early RA

PERMIER trial

ASPIRE trial

TEMPO trial

BEST trial

MTX + Adalimumab vs.

either drug alone

MTX + infliximab vs. MTX alone

MTX + Etanercept vs.

either drug alone

4 treatment strategies including

MTX + infliximab

St. Clair et al. Arthritis Rheum 2004, 50:3432Klareskog et al. Arthritis Rheum 2004, 50:238Breedveld et al. Arthritis Rheum 2005, 54:26Goekoop-Ruiterman et al. Arthritis Rheum 2005, 52:3381

21Breedveld FC, et al. Arthritis Rheum 2006;54:26-37

The PREMIER trial: Remission as measured by DAS28 ≤2.6

23* 2125* 25

43*

49*

0

10

20

30

40

50

60

Adalumimab+ MTX

Adalumimab alone

MTXalone

Pts

w/D

AS28 <

2.6

(%

)

Wk 52

Wk 104

*P <.001 ADA + MTX alone and ADA alone.

22

ASPIRE: Proportion of Patients Achieving Remission at Week 54

MTX alone

IFX 3 mg/kg + MTX

IFX 6 mg/kg + MTX

St Clair W, et al. Arthritis Rheum. 2004;50:3432-43.

DAS28 <2.6

15.0%

21.2%

31.0%

0%

5%

10%

15%

20%

25%

30%

35%

P=0.065

P <0.001

Median baseline: 6.8

The COMET Trial

Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe

rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial.

Emery P et al., Lancet. 2008; 372-382.

24

The COMET Trial

• The COmbination of Methotrexate and Etanercept in early rheumatoid arthriTis (RA) trial compared the effects of a combination of etanercept (ETN) and methotrexate (MTX) with MTX alone in patients with early RA (≥3 months and ≤2 years)

• COMET is a 24-month, double-blind, randomised, parallel-group, multicentre, outpatient study

• The aim was to investigate aggressive early combination therapy as the regimen of choice to achieve clinical and radiographic targets and normalisation of function

Emery P et al. Lancet. 2008;372:375-382.

25

Key End Points

• Primary clinical end point:• DAS28 remission (<2.6) at week 52 • Primary radiographic end point:

• Change in modified Total Sharp Score (mTSS) from baseline to week 52

• Secondary end points• DAS44 remission (<1.6) • ACR 20%, 50%, and 70% responses • HAQ-DI • Employment questionnaire/stopping working

ACR, American College of RheumatologyDAS, disease activity scoreHAQ-DI, Health Assessment Questionnaire – Disability Index


26

Study Design for COMET TrialDouble-blind randomised clinical trial

ETN + MTX(n=274)

Period 1

ETN (1b)

MTX (2b)

104 wk

Randomise(n=542)

Placebo ETN + MTX(n=268)

52 wk

ETN + MTX(1a)

ETN + MTX(2a)

Period 2


Results

28

92% of patients were considered to have severe rheumatoid arthritis (DAS28 >5.1)

Patient Baseline Disease Characteristics Modified ITT Population

MTXn=263

ETN + MTXn=265

Total n=528

Disease duration (months) 9.3 8.8 9.0

DAS28 6.5 6.5 6.5

No. of total swollen joints (0-68) 17.6 17.1 17.3

No. of total tender joints (0-71) 24.8 25.1 25.0

HAQ (0-3) 1.6 1.7 1.7

ESR (mm/h) 49.3 47.8 48.5

CRP (mg/L) 36.5 37.0 36.7

Anti-CCP positive (%) 70 67 69

Anti-CCP, anticyclic citrullinated peptide


29*After titration

Patient Disposition

MTX

n=268

ETN + MTX

n=274

Total

n=542

Completed 52 wks, n (%) 189 (70.5) 221 (80.7) 410 (75.6)

Total withdrawals, n (%) 79 (29.5) 53 (19.3) 132 (24.4)

Adverse event, n (%) 34 (12.7) 28 (10.2) 62 (11.4)

Lack of efficacy, n (%) 24 (9.0) 9 (3.3) 33 (6.1)

Protocol violation, n (%) 9 (3.4) 4 (1.5) 13 (2.4)

Patient request, n (%) 8 (3.0) 9 (3.3) 17 (3.1)

Other, n (%) 4 (1.5) 3 (1.1) 7 (1.3)

Median MTX dose at 8 weeks, mg/wk*

19.6 16.8 —


DAS28 Remission

31

DAS28 Remission Over Time

* P=0.002; † P<0.0001; LOCF

50%

28%

†

†

†

†

†

††

*

0

20

40

60

0 4 8 12 16 20 24 28 32 36 40 44 48 52Time (weeks)

Pro

po

rtio

n w

ith

DA

S28

re

mis

sio

n (

%)

MTX (n=263)ETN + MTX (n=265)

• A significant difference between the study groups was seen as early as 2 weeks

Emery P et al. Lancet. 2008;372:375-382. Data on file, Wyeth Pharmaceuticals.

†

2

32

DAS28 Remission

*P<0.0001; LOCFDAS28 remission=DAS28 <2.6; DAS44 remission=DAS<1.6; DAS28 LDA=≤3.2; DAS LDA=DAS<2.4

28% 28%

41%

49%50% 51%

64%

73%

0

20

40

60

80

100P

ati

en

ts (

%)

MTX (n=263)

ETN + MTX (n=265)

* *

DAS28 LDA

DAS44 Remission

DAS44 LDA

*

*

DAS28 and DAS44 Remission and Low Disease Activity (LDA) at Week 52


ACR Responses

34

ACR Responses at Week 52

67%

49%

28%

86%

71%

48%

0

20

40

60

80

100

ACR20 ACR50 ACR70

Pat

ien

ts (

%)

(mIT

T)

MTX (n=243)ETN + MTX (n=256)

*P<0.0001; LOCF

*

*

*


Radiographic Progression

36

Radiographic Changes at Week 52

2.44

0.27

0

0.5

1

1.5

2

2.5

3

Ch

an

ge

fro

m b

as

eli

ne

in

mT

SS

MTX (n=230)

ETN + MTX (n=246)


37

*

mTSS Definition of Nonprogression *P<0.001

Radiographic Nonprogression at Week 52

*

59%54%

80% 75%

0

20

40

60

80

100

≤0.5 ≤0

Pat

ien

ts (

%)

MTX (n=230) ETN+MTX (n=246)

Adapted from Emery P et al. Lancet. 2008;372:375-382.

Quality of Life

39

39%

55%

0

10

20

30

40

50

60

Week 52

Pat

ien

ts (

%)

MTX (n=241)

ETN + MTX (n=256)

*

*P=0.0004

HAQ-DI Scores Comparable to a Healthy Population (≤0.5)


Work Productivity

411. Puolakka K et al. Arthritis Rheum. 2004;50:55-62. 2. Verstappen SMM et al. Arthritis Rheum. 2004;51:488-497. 3. Data on file, Wyeth Pharmaceuticals. 4. Emery P et al. Lancet. 2008;372:375-382.

Work Productivity in RA – Background

Background• Absence from work and job loss can occur relatively early in RA1,2

• A patient who stops work due to arthritis is unlikely to return3

• Work productivity data is important for estimating economic burden of disease

Objective of the Work Productivity Analysis in COMET• To compare the secondary end point impact of combination ETN and MTX vs.

MTX alone on work stoppage among MTX naïve patients with active early RA4

42

How Many Patients With RA Are Unable to Work Over Time?

Rates of Work Disability in RA:• ~20% the first year• 32% to 50% after 10 years• Up to 90% after 30 years

Lacaille D. J Rheumatol 2005; 32: 42-45Puolakka K. Arthritis Rheum 2005; 52: 36Eberhardt K et al. J Rheumatol 2007; 34: 481

Working part-time

Working full-time

Work disabled

100

20

60

0

80

40

90

10

30

50

70

1 2 3 4 5 6 157 8 9 10 11 12 13 140

Development of work disability over 15 years in 148 patients with early RA

43

Methods Used for Work Productivity Analysis

• Employment questionnaire administered at weeks 12, 24, 36, and 52

• Analyses restricted to patients who reported working part-time or full-time at baseline

• Assumed that once patients reported stopping work, they did not restart working

• First-time work stoppage was compared using Fisher’s exact test with LOCF


44

Work Disability: Proportion of Patients Reporting First-time Work Stoppage

Pat

ien

ts s

top

pin

g w

ork

(%

)

*P=0.004

0

5

10

15

20

25

30

*

24%

9%

Week 52

MTX (n=100)

ETN + MTX (n=105)


Safety Data

46

Safety Summary Through Year 1

• The most common AE was nausea (19% in both groups) • The second most common AE was nasopharyngitis (16% in both

groups)

• The proportion of patients experiencing serious AEs was similar between the 2 groups

• No malignant diseases were considered related to the treatments received

• There were no new safety signals reported


Summary & Conclusions

48

COMET Summary

• 50% of patients treated with ETN + MTX achieved DAS28 remission• A significantly greater proportion achieved remission at Week 2 than those

receiving MTX alone

• Almost two thirds achieved low disease activity

• 80% of patients receiving ETN + MTX achieved radiographic non-progression compared with 59% of those in the MTX-alone group

• HAQ-DI scores within the norm were achieved by 55% of patients treated with ETN + MTX

• Treatment with ETN + MTX significantly reduced first-time work stoppage

• The safety profile of combination treatment was comparable to the safety profile of MTX alone


49

COMET Conclusions

• ETN in combination with MTX was superior to MTX-alone in providing • Clinical remission• Radiographic nonprogression• Normalised function

• Remission is an achievable therapeutic goal when combination therapy is initiated early in the RA disease process

© 2008, Wyeth Pharmaceuticals September 2008 235993-02


achieving remission in early ra dubai, united arab emirates 19. january 2009 professor joachim...

Documents

arthritis rheum

remission early treatment

early feature of ra

early radubai

ra patients

early tissue destructionplant

ann rheum

rate of progression