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Transcript of Treatment of Ankylosing Spondylitis Enbrel RA MENA Speaker Bureau Dubai, United Arab Emirates...
Treatment of Ankylosing Spondylitis
Enbrel RA MENA Speaker Bureau
Dubai, United Arab Emirates
January 2009
Prof. Joachim R. Kalden
Director emeritus
Medical Department III
Div. for Molecular Immunology
University of Erlangen-Nuremberg
Ankylosing Spondylitis Overview
– A type of arthritis that causes inflammation and eventually fusion of the spine and the spinal joints. Involvement of peripheral joints and extraarticular manifestations.
– AS causes pain, stiffness, disability, decreased spinal mobility, and decreased quality of life
– The prevalence ranges from 0.1 to 1 percent of the population
– Men are affected three times more than women– Commonly develops between the ages of 15 and
40
– 95 percent of people with AS share the genetic marker HLA-B27
Treatment of Ankylosing SpondylitisOverview
• Treatment goals• Use of traditional therapies• Clinical results with TNFalpha antagonists• Guidelines for the management of TNFalpha antagonists
Treatment goals in Ankylosing Spondylitis
Reduce and or prevent deleterious effects of:• Inflammation• Ankylosis• Abnormal posture
Dougados et al. J.Rheumatol 2001;28-62:16-20.
Inhibition of osteoblastogenesis
Development of Ankylosis in Ankylosing Spondylitis
From: Cruickshank and Path, Pathology of Ankylosing Spondylitis
• The earliest change seen was a sub acute osteitis in the immediately adjacent bone.
• This was followed by extensive replacement of the fibrocartilage and adjacent bone by fibrous tissue in which there was often little remaining evidence of inflammation.
• The late stage of the disease in this joint consisted of assification.
Late Stage Reparation Mechanism - Dense Formation of
Osteoblasts
bone marrow
bone
Appel H, Loddenkemper C, Sieper J; unpublished
ASAS/EULAR Recommendations for the Management of AS
Education, exercise, physical therapy,
rehabilitation, patient
associations, self help groups
NSAIDs
Peripheral disease
Axial disease
Sulfasalazine
TNF blockers
Analgesics
Local corticosteroids
Surgery
Zochling J, et al. Ann Rheum Dis. 2006;65:442-52 (excerpt)
Celecoxib Versus Naproxen in AS:Improvements in Primary Efficacy Measures
Barkhuizen et al. Ann Rheum Dis 2005;64(supplementIII);338(Abs).
Reduction of Radiographic Progression by NSAIDs in Ankylosing Spondylitis
Wanders et al. Arthritis Rheum 2005;52:1756-65.
Inhibition of proliferation and migration of
osteoblasts in a rat bone healing model by
diclofenac
GD Krischak et al. Arch Orthop Traum Surg 2007, 127:453-458
Sulphasalazine in the Treatment of Spondylarthropathy
20
40
60placebo
Sulphasalazine
% patients
43 40 42
59
Clegg et al. Arthritis Rheum 1999;42:2325-9.
Axialn=187
Periphraln=187
Placebo (n=39) Sulphasalazine (n=45)
Pain -17 -26
Swollen joints -1.6 -4.4
Tender joints -4.0 -8.8 Dougados et al. Arthritis Rheum 2005;38:618-27.
0
2
4
6
8
0 4 8 12 16Week
BA
SD
AI (
mea
n)
All patients (n=20)
*Braun J, …, Sieper Jl. Ann Rheum Dis 2006 Apr 10; Epub **Haibel H, ..., Sieper J. Ann Rheum Dis 2005;64:124-6. †Haibel H, .... Sieper J. 2006; Aug 10; Epub.
0
2
4
6
8
0 4 8 12 16 20 24Week
BA
SD
AI (
mea
n)
All patients (n=20)
Peripheral arthritis (n=10)
Non-arthritis (n=10)
Leflunomide**20 mg/day
Methotrexate†
20 mg/week sc
012345678
0 4 8 12 16 20 24Week
BA
SD
AI (
mea
n)
Placebo (n=60)
Sulfasalzine (n=60)
Sulfasalazine*2 g/day
P=0.03
Conventional DMARDs in the Treatment of Ankylosing Spondylitis
Conclusions from treatment experiences in Ankylosing Spondylitis with traditional therapies
Traditional therapy options are not sufficient to treat active disease
• Physiotherapy important to maintain function • NSAIDs alleviate pain in some but not all patients• Steroids and immunomodulators have little/no effect• No drugs which impede disease progression
Unmet medical need in the treatment of severe AS
Infliximab Monotherapy Study In Active Ankylosing Spondylitis
54
BaselinePeriod
70 Patients
Placebo (N=35)
0,2,6
Infliximab 5 mg/kg Q 6 Wks (N=35)
LoadingPeriod
12
Infliximab 5mg/kg Q 6 Wks
Week
Double-Blind Open Label
Infliximab 5 mg/kgQ 6 Wks
Study Design
Braun et al. Lancet 2002;359:1187-93.
Reduction of Disease Activity Was Rapid and Durable
Through 12 Weeks
Weeks
Percentage of Patients With Improvement of 50% in BASDAI
0
20
40
60
80
100
0 2 4 6 8 10 12
Pat
ien
ts r
esp
on
din
g,
%
Placebo
Infliximab 5 mg / kg
P<0.001
P<0.001 P<0.001
Intent-to-Treat Population
Braun et al. Lancet 2002;359:1187-93.
Maintenance of Efficacy of Infliximab in Ankylosing Spondylitis. Two year extension of a 3 months RCT
Braun et al. Ann. Rheum Dis 2005;64:229-34.
BASDAI 50% ASAS 40% ASAS 20% 5 out of 6
Radiographic Progression in Patients with Ankylosing Spondylitis treated for 2 years with Infliximab
Baraliakos et al. Ann Rheum Dis 2005;64:1462-6.
Control group Control group
Progression in total groupProgression in group with damage at baseline
Anti-TNF therapy in AS: Continuous improvement of spinal mobility and function over 2 years
-3
-2
-1
0
1
Weeks
Mean
Cha
nge i
n BAS
FI
Placebo-patientsCrossed-over
24 102
2
54
-2
-1
0
1
WeeksMe
an C
hang
e in
BASM
I
24 10254
Placebo-patientsCrossed-over
Braun J, et al. Arthritis Rheum 2008, in press
A randomized controlled clinical trial of infliximab shows clinical and MRI efficacy in patients with pos.
HLA B27 and very early AS
• 49 pat. with early inflammatory back pain, HLA B27 pos. and known oedema on MRI were randomized
• No demographic changes between the two groups
Result• Infliximab appears to be an effective therapy in very
early inflammatory back pain (significant change from baseline: MRI score of sacroiliac joints resolving of SI-joint lesions. Improvement of clinical parameters)
N. Barkham et al. ACR 2007. L11
Adalimumab in Ankylosing Spondylitis. The ATLAS trial: a RPCT on 315 patients treated for 24 weeks
25
50
75
100
21
58
14
41
19
51
14
39
Davis et al. Arthritis Rheum 2005;S208 (abs.483).
12 weeks 24 weeks
placebo
Adalimumab 40 mg eow
% patients
ASAS 20ASAS 40 ASAS 40ASAS 20
Adalimumab in Ankylosing Spondylitis. The ATLAS Trial: a RPCT on 315 patients Treated for 24 weeks
25
50
75
100
4
21
6
22
Davis et al. Arthritis Rheum 2005;S208 (abs.483).
12 weeks 24 weeks
placebo
Adalimumab 40 mg eow
Remission
% patients
Adalimumab in patients with total spine ankylosis
• Randomized, placebo-controlled trial (ratio 2:1)
• In patients with TSA adalimumab treatment resulted in rapid and clinically significant improvement in signs and symptoms of active disease– At week 12: 50% of adalimumab treated patients achieved
ASAS 20, 33% ASAS 40, ASAS 5/6 and BASDAI 50 as compared to non of placebo treated patients
– After 1 year: 8/11 adalimumab treated patients achieved ASAS 20
– After 2 years: 6/11 adalimumab treated patients achieved ASAS10
van der Heijde D et al, Ann Rheum Dis, Dec 2007
Etanercept for Ankylosing Spondylitis. Results of a 24-weeks RPCT on 277 patients
Davis et al. Arthritis Rheum 2003;48:3230-6.
Sustained Durability of Etanercept in Ankylosing Spondylitis for 96 weeks
Davis et al. Ann Rheum Dis 2006;64:1557-62.
Longterm anti-TNF therapy in AS - persistent low
disease activity over 4 years M
ean
BA
SD
AI
Weeks
0 24* 48 72 96 120 144 168 192
BASDAI (0–100)
0
10
20
30
40
50
60
70
Etanercept/EtanerceptPlacebo/Etanercept
*Week 24 represents the baseline of the OLE as well as the point of initial etanercept treatment for the patients switched from placebo to etanercept.
RCT
Davis J et al. Ann Rheum Dis 2008
0 24* 48 72 96 120 144 168 192
BASFI (0–100)
0
10
20
30
40
50
60
*Week 24 represents the baseline of the OLE as well as the point of initial etanercept treatment for the patients switched from placebo to etanercept.
Etanercept/EtanerceptPlacebo/Etanercept
Mea
n B
AS
FI
Weeks
Long-term anti-TNF therapy in AS - continuous improvement of function
Davis J et al. Ann Rheum Dis 2008
Assessment of Clinical Efficacy in a Randomized Double-Blind Study of Etanercept and Sulfasalazine in
Patients With Ankylosing Spondylitis
October 27, 2008American College of Rheumatology Annual Scientific MeetingACR 2008
J. Braun,1 F. Huang,2 R. Burgos-Vargas,3 I.E. van der Horst-Bruinsma,4
B. Freundlich,5 B. Vlahos,5 A.S. Koenig5
1Ruhr University, Bochum, Germany; 2Chinese PLA General Hospital, Beijing China; 3Hospital General de México and Universidad Nacional Autónoma de México, Mexico City, Mexico; 4VU University Medical Center, Department of Rheumatology, Amsterdam, Netherlands; 5Wyeth Research, Collegeville, PA, USA
Objective
To compare the efficacy and safety of etanercept 50 mg once weekly with sulfasalazine 1.5 to 3 g daily over 16 weeks in patients with active ankylosing spondylitis (AS)1
1van der Linden S. et al. Arthritis Rheum 1984;27:361–8.
Key Endpoints
• Primary
– Proportion of patients achieving ASAS 20 (20% improvement by Assessment of AS criteria) at 16 weeks
• Select Secondary
– ASAS 20, ASAS 40, ASAS 5/6, partial remission1 – BASMI (Bath Ankylosing Spondylitis Metrology Index) – BASFI (Bath Ankylosing Spondylitis Functional Index) – BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) – C-Reactive Protein through 16 weeks – Back pain– Modified Schober’s test
1Anderson et al. Arthritis Rheum 2001; 441876-86
Proportion of Patients Who Achieved ASAS 20 (LOCF)
54.163.9
73.3 70.975.9
52.952.449.242.3
28.1
0
10
20
30
40
50
60
70
80
90
0 2 4 6 8 10 12 14 16
Weeks
Pa
tie
nts
(%
)
Etanercept (n=378) Sulfasalazine (n=187)
*P<0.001, etanercept versus sulfasalazine
Primary Endpoint: Proportion of Patients Who Achieved ASAS 20 at week 16
*
*
* **
Proportion of Patients Who Achieved Partial Remission* (LOCF)
0
11.7
18.3
26.4
31.133.3
15.513.911.8
7.03.2
0
10
20
30
40
0 2 4 6 8 10 12 14 16
Weeks
Pa
tie
nts
(%
)
Etanercept (n=379) Sulfasalazine (n=187)
*Anderson et al. Arthritis Rheum 2001; 441876-86; †P<0.001, etanercept versus sulfasalazine
†
†
†
†
†
Mean BASMI Scores (LOCF)
3.7
2.82.82.9
3.13.2
3.53.4
3.33.2 3.2
3.3
2.5
3
3.5
4
0 2 4 6 8 10 12 14 16
Weeks
Me
an
Sc
ore
Etanercept (n=379) Sulfasalazine (n=187)
*P<0.001, etanercept versus sulfasalazine
**
* **
Conclusions
• In this 16-week study – Etanercept therapy was superior to sulfasalazine
therapy in the treatment of subjects with ankylosing spondylitis.
– There were no unexpected safety findings
Etanercept Shows Persistent clinical Efficacy over 5 Years
According to: Baraliakos X et al., FRI0291, EULAR 2008
No. Achieving at 12 weeks
No. Achieving at
< 90% of all visits (%)
Clinical Remission 6 5 (83)
BASDAI < 3 11 8 (73)BASFI < 3 9 8 (89)BASFI < 4 11 11 (100)
BASDAI + global physician‘s < 4 12 10 (83)
At 5 Years (n = 18): 33% were in partial remission according to ASAS criteria 38% achieved a BASDAI 50% response 62% achieved a ASAS 40% response 65% achieved a ‘5 out of 6’ response
Effectiveness of Adalimumab after failure of infliximab or etanercept in patients with PsA and AS
• Open-label phase IIb studies• PsA „STEREO“ 66 of 442 patients discontinued and
were switched to adalimumab• AS „RAPSODY“ 309 of 1186 patients discontinued
and were switched to adalimumab• PsA: Significant improvement in ACR 20, 50, 70 and
HAQ• AS: Significant improvement in ASAS 20, 50, 70 and
BASDAI
Burmester et al. Arthritis Rheum 2007; 56, 393
Rudwaleit et al. Ann Rheum Dis 2004;63:665-70.
Prediction of Response to TNF Antagonists in Ankylosing Spondylitis:
Infliximab n=69, Etanercept n=30
<4.5, 4.5-6.5, >6.5<10, 11-20 years, >20 years
Median percentage changefrom baseline
Interferon-γ Interleukin-6
CRPVEGF
Visvanathan Set al., Ann Rheum Dis, 2008
73
58
31
0
20
40
60
80
<10 years, N=37 11-20 years, N=33 >20 years, N=29
%
Patients with Ankylosing Spondylitis (n=99) treated with TNF-Blockers
Rudwaleit M, et al. Ann Rheum Dis. 2004; 63:665-70
Better Response if AS Patients Treated Early in the Disease Course (n=100)
(as judged by BASDAI 50 response)
Discontinuation of anti-TNF Therapy in Ankylosing Spondylitis
Baraliakos X et al., Arthritis Res Ther, 2005
Effects of TNFalpha antagonists on extra-articular manifestations
Reduction in the number of enthesetic regions- Infliximab- Etanercept - Adalimumab
Decreased incidence of anterior uveiitis- Infliximab- Adalimumab- Etanercept less effective
Braun et al., Lancet 2002; 359:1187-93
Marzo-Ortego et al., Arthritis Rheum 2001; 44:2112-17
Braun et al., Arthritis Rheum 2005; 52:2447-51
Lyndell LL et al, Arthritis & Rheumatism (2007)56:3248-3252
00
0
10
20
30
40
0 8 16 24 32 40 48
Placebo
Infliximab
Proportion of Patients with Enthesopathy
Weeks
Per
cen
t o
f P
atie
nts
Placebo cross-over to Infliximab
* p = 0.03
*
Phase II: All Patients Receive Infliximab;
Original Blind Maintained
16 500
00 16 50
The Impact Study
C. Antoni et al. Arth Rheum 2003
10
30
20
40
10
International ASAS Consensus Statement for the Use of anti-TNF in Patients with Ankylosing Spondylitis
•Indication Definitive ASActive disease - BASDAI ≥4
- expert opinion- acute phase response- imaging modalities
Failure of ≥2 NSAIDs In case of peripheral arthritis failure of intraarticular
corticosteroids/sulphasalazine Absence of contraindication
•Monitoring BASDAI ASAS core set Responder: improvement of ≥2 units on BASDAI
Baeten et al. Ann Rheum Dis 2003;62:829-34..
News from the ACR Meeting 2008
• Long-term efficacy for up to 7 years for all 3 TNF antagonists being licenzed for the treatment of AS. No new safety signals
• Re-Treatment of AS patients who flaired after ADA treatment was stopped is possible
• Early effective treatment of AS (as shown for ADA) might significantly improve the work productivity
Summary
• TNF antagonists proven in PsA, AS to have a long-term clinical efficacy and acceptable safety profile
• No new side effects reported in long-term clinical trials as compared to previous studies and registry data
• Identical recommendation for screening patients before TNFalpha antagonist should be started
• Psoriasis induced by TNFalpha antagonists– (Sfakis PP et al. Arthritis Rheum 2005)– (Kary S. Ann Rheum Dis 2006;65:405-407)– (Massara A et al. Rheumatology 2006;45:730-733)