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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
7
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
Emery P et al. Lancet. 2008;372:375-382.
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
Emery P et al. Lancet. 2008;372:375-382.
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
Emery P et al. Lancet. 2008;372:375-382.
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 —
Emery P et al. Lancet. 2008;372:375-382.
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
Emery P et al. Lancet. 2008;372:375-382.
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
*
*
*
Emery P et al. Lancet. 2008;372:375-382.
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)
Emery P et al. Lancet. 2008;372:375-382.
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)
Emery P et al. Lancet. 2008;372:375-382.
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
Emery P et al. Lancet. 2008;372:375-382.
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)
Emery P et al. Lancet. 2008;372:375-382.
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
Emery P et al. Lancet. 2008;372:375-382.
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
Emery P et al. Lancet. 2008;372:375-382.
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
Emery P et al. Lancet. 2008;372:375-382.
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