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Anti-TNF therapy in ankylosing spondylitis - Clinical and structural outcomes -. Dr. X. Baraliakos Rheumazentrum Ruhrgebiet, Herne Ruhr-University Bochum Germany. Ankylosing spondylitis: a chronic inflammatory rheumatic disease leading to high clinical impairment. 24 years. - PowerPoint PPT Presentation
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Dr. X. BaraliakosRheumazentrum Ruhrgebiet, Herne
Ruhr-University BochumGermany
Anti-TNF therapy in ankylosing spondylitis
- Clinical and structural outcomes -
Ankylosing spondylitis: a chronic inflammatory rheumatic disease leading to high clinical impairment
Braun J, Sieper J. Lancet 2007
24 years
49 years
AS
• Involvement of axial skeleton, entheses,
perhipheral joints and other organs (e.g.
eyes)
• Main clinical symptom: inflammatory
back pain
• 1/3 of patients with severe clinical course
• High prevalence (0.5%)
• Strong association with HLA-B27
• Late delay of diagnosis (5-7 years)
• Decreased QoL
• High risk of sick leave
• Increased direct / indirect costs
• mRNA Braun J et al. Arthritis Rheum 1995; 38: 499 • protein Braun J et al. Ann Rheum Dis 2000; 59S: 85• bone marrow Francois R et al. Ann Rheum Dis 2005
Inflammation driven by TNFa in ASDetection of TNF α mRNA in the bone marrow of inflammed sacroiliac joints
NSAIDs are efficacious in AS
Amor B, et al. Rev Rheum Engl Ed 1995;62:10–5Van der Heijde, et al. Arthritis Rheum 2005;52:1205–15
0
10
20
30
40
50
60
70
80
90
AS (n=69) MechanicalBack Pain
(n=768)
% P
ati
en
ts w
ith
Go
od
Re
sp
on
se
*
0
10
20
30
40
50
60
70
80
Etoricoxib90/120mg(n=201)
Placebo(n=93)
% P
atie
nts
wit
h G
oo
d R
esp
on
se**within 24 hours !
0
20
40
60
Clinical trials*n = 462
OASIS†
n = 209
% P
atie
nts
*Patients after 6 weeks of treatment with an active NSAID†Epidemiological study = systematic recruitment of consecutive patients in daily practice
42%29%
Many AS patients are refractory to NSAIDs
Disease activity in SpA patients with inflammatory back pain, with vs. without peripheral arthritis
2,0
2,5
3,0
3,5
4,0
4,5
5,0
5,5
6,0
6,5
Screening Visit 5 Visit 8 Visit 10
p = 0.027
at 6 months
IBP+, Peripheral arthritis -
at baseline
IBP+, Peripheral arthritis +
BASDAI
2,0
2,5
3,0
3,5
4,0
4,5
5,0
5,5
6,0
Screening Visit 5 Visit 8 Visit 10
BASDAI
at 6 monthsat baseline
IBP+, Peripheral arthritis -
IBP+, Peripheral arthritis +
p = 0.3
Sulfasalazine (n = 112) Placebo (n = 118)
Sulfasalazine in early SpA
Braun J, Baraliakos X et al. Ann Rheum Dis 2006 Sep;65(9):1147-53
Education, exercise, physical therapy,
rehabilitation, patient
associations, self help groups
NSAIDs
Peripheral disease
Axial disease
Sulfasalazine
TNF blockers
Analgesics
Local corticosteroids
Surgery
ASAS/EULAR recommendations for the management of AS
Zochling J et al. Ann Rheum Dis 2006 Apr;65(4):442-52
Physikalische und pharmakologische Eigenschaften
Infliximab Etanercept Adalimumab Golimumab
Designhuman/murine chimerik mAb
human TNF-Receptor/
Fc-Fusionsprotein
recombinant human mAb
recombinant human mAb
Structure
Applic.-frequency 1 x / 6 weeks 1 -2 x / week 1 x / 2 weeks 1 x / month
Half-elimin. time
8–10 d ca. 3 d ca. 2 wks ca. 12 d
TNF Antagonists – a mile stone in the history of treatment of the (spondylo)arthritides
Anti-TNF therapy in AS- clinical data
Short-term data: Baseline - 6 months
The pilot study: infliximab in AS– open continuation phase
Infusions given according to disease activity (BASDAI)
0
2
4
6
8
10
0 4 8 12 16 20 24 28 32 36
weeks
BA
SD
AI
(med
ian
)
Brandt J et al. Arthritis Rheum 2000; 43(6):1346
Anti-TNF therapy in AS: Most patients achieve at least a 50% reduction of disease activity
Braun J et al. Lancet 2002; 359:1187-93
weeks 2 6 12
Significant improvement of function and spinal mobility
Braun J et al. Lancet 2002; 359:1187-93
Improvement of disease activity (BASDAI)
Early experiences with etanercept in AS
0
1
2
3
4
5
6
7
0 3 6 9 12 15 18 21 24 27 30
Weeks
BA
SD
AI (
mea
n)
Placebo/Etanercept
Etanercept
p = 0.003
Brandt J et al. Arthritis Rheum 2003; 48: 1667
n=30
ETN treatment in ETN group
ETN treatment in Placebo group
Approval of etanercept for AS
*P < 0.0001
27
60*
23
58*
0
20
40
60
80
100
Week 12 Week 24
Placebo (n = 139) Etanercept (n = 138)
Pat
ien
ts R
esp
on
din
g (
%)
ASAS 20 Response Weeks 12 and 24
Davis JC, Arthritis Rheum 2003; 8: 3230-3236
Etanercept treatment in AS Reduction of acute phase reactants
CRP (mg/dl)
Davis JC, Arthritis Rheum 2003; 8: 3230-3236
BSG (mm/h)
-80
-60
-40
-20
0
20
-80
-60
-40
-20
0
20
† p < 0,0001
Etanercept 2 x 25 mg/Wk (n=138)
Placebo (n=139)
Week 2 Month 3 Month 6
†
† †
††
†
Mit
tler
e Ä
nd
eru
ng
geg
en
üb
er d
em
A
usg
ang
swer
t in
%
Mit
tler
e Ä
nd
eru
ng
geg
en
üb
er d
em
A
usg
ang
swer
t in
%
† p < 0,0001
Week 2 Month 3 Month 6
***Statistically significant at p<0.001 level (ANCOVA)
20,614,0
18,714,0 12,1
58,2
40,9
48,6 50,5
39,444,7
13,1
0
10
20
30
40
50
60
70
ASAS20 ASAS40 ASAS 5/6 ASAS20 ASAS40 ASAS 5/6
Mea
n c
han
ge
fro
m B
asel
ine
Placebo Adalimumab
Week 12 Week 24
***
***
*** ***
******
van der Heijde D, Arthritis Rheum, 2006. 54(7): 2136-2146
Efficacy of Adalimumab in patients with AS – The ATLAS Trial –
ASAS 40 Response at Week 24 in Trials of Biologics for AS
1van der Heijde D, et al. Arthritis Rheum. 2006;54:2136-2146; 2Davis JC, et al. Arthritis Rheum. 2003;48:3230-3236; 3van der Heijde D, et al. Arthritis Rheum. 2005;52:582-591.
14
45
0
20
40
60
80
100
Per
cen
tag
e o
f P
atie
nts
15,4
43,554,3
0
20
40
60
80
100
Per
cen
tag
e o
f P
atie
nts
13,1
39,4
0
20
40
60
80
100
Per
cen
tag
e o
f P
atie
nts
Pbon=107
Ada 40 mg eown=208
Pbo n=139
Etan 25 mg BIWn=138
Adalimumab1 Etanercept2
12
47
0
20
40
60
80
100
Per
cen
tag
e o
f P
atie
nts
Pbon=78
Ifx 5 mg/kgn=201
Pbon=75
Glm 50 mgn=130
Glm 100 mgn=138
Infliximab Golimumab
* * *
*
* P <.001 vs placebo
Anti-TNF therapy in AS- clinical data
Long-term follow-up: 6 months – 8 years
Patients with BASDAI 50% Response after 3 years of infliximab treatment
0
20
40
60
80
0 6 12 24 36 48 54 66 78 90 102 114 132 144 156
Week
Pa
tie
nts
(%
)
Placebo / Infliximab
Infliximab
Placebo-controlled phase Open phase
Braun J, Rheumatology 2005. 44(5):670-6
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
0 12 24 36 48 66 78 90 102 114 132 144 156
Week
Placebo / Infliximab
Infliximab
0
1
2
3
4
5
6
0 12 24 36 48 54 66 78 90 102 120 132 144 156
Week
Placebo / Infliximab
Infliximab
Continuous improvement of spinal mobility and function over 3 years
Braun J, Rheumatology 2005. 44(5):670-6
Mea
n B
AS
MI
Placebo-controlled
phaseOpen phase
Mea
n B
AS
FI
Placebo controlled
phaseOpen Phase
0
10
20
30
40
50
60
70
80
90
100
0 6 12 24 36 48 54 108 114 120 124 132 144 150 156 204 224 312 364 416
Week
% P
atie
nts
BASDAI 50%
ASAS 40%
ASAS 5/6
Anti-TNFα therapy in patients with ASResults after 8 years
Infliximab
Baraliakos X, EULAR 2009, Copenhagen
0102030405060708090
100
0 12 24 54 102 216 258
weeks
% o
f p
ati
en
ts
ASAS 40% 5 out of 6 BASDAI 50%
Anti-TNFα therapy in patients with ASResults after 6 years
Etanercept
Baraliakos X, EULAR 2009, Copenhagen
0%
10%
20%
30%
40%
50%
60%
70%
0 12 24 54 102 216 258 312
weeks
% o
f p
ati
en
ts
35.1%
Baraliakos X, EULAR 2009, Copenhagen
Anti-TNFα therapy in patients with ASResults after 6 years
Etanercept
33.3%
Efficacy of Adalimumab in patients with AS – long-term data from the ATLAS Trial
vd Heijde D et al, Ann Rheum Dis 2008vd. Heijde D, Arthritis Res Ther 2009, 11:R124
2 years
3 years
Golimumab - ASAS Partial Remission after 104 weeks
21.8
31.9 30.7
0
20
40
60
Braun J. et al. ACR 2009, Abstract 1259
Golimumab 100 mg(n = 140)
Placebo/ Golimumab 50mg (n = 78)Golimumab 50 mg(n = 138)
An
teil
Pa
tie
nte
n (
%)
GO-RAISE
Braun J et al, ACR 2009, Abstract 1259
38.5
55.8 54.3
0
20
40
60
80
Braun J. et al. ACR 2009, Abstract 1259
An
teil
Pa
tie
nte
n (
%)
GO-RAISE
Golimumab – ASAS 40 Response after 104 weeks
Braun J et al, ACR 2009, Abstract 1259
Golimumab 100 mg(n = 140)
Placebo/ Golimumab 50mg (n = 78)Golimumab 50 mg(n = 138)
Discontinuation of anti-TNF- treatment
Anti-TNF therapy in AS- clinical data
• Withdrawal of biologic in all patients
• Regular visits to assess clinical relapse
(BASDAI > 4 and PhysGA > 4)
• Retreatment with same dosis• Assessment of clinical parameters
Design of studies
ETN: Brandt J et al. Arthritis Rheum 2003; 48: 1667 Baraliakos X et al, Arthritis Rheum 2005 (53): 856-863INF: Baraliakos X et al, Arthritis Res Ther 2005. 7(3): R439-44
Clinically successful readministration of infliximab after withdrawal in all patients without infusion reactions
0
1
2
3
4
5
6
7
baseline week 6 week 24 week 54 week 102 week 156 clinicalrelapse
24 weeks 48 weeks
BASDAI BASFI BASMI
Infliximab withdrawal
Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44
Clinically successful readministration of infliximab after withdrawal in all patients without infusion reactions
0
1
2
3
4
5
6
7
baseline week 6 week 24 week 54 week 102 week 156 clinicalrelapse
24 weeks 48 weeks
BASDAI BASFI BASMI
Infliximab withdrawal
Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44
Clinically successful readministration of infliximab after withdrawal in all patients without infusion reactions
0
1
2
3
4
5
6
7
baseline week 6 week 24 week 54 week 102 week 156 clinicalrelapse
24 weeks 48 weeks
BASDAI BASFI BASMI
Infliximab withdrawal
Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44
BASDAI 50%, ASAS 40% response and partial remission after infliximab readministration
0
10
20
30
40
50
60
70
80
0 week24
week102
clinicalrelapse
48weeks
% o
f p
ati
en
ts t
rea
ted
at
ea
ch
tim
e p
oin
t
partial remissionBASDAI 50%ASAS 40%
Infliximab withdrawal after infliximab readministration
Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44
Duration of response after withdrawal
97.6%(88-100%)90.5%
(78-96%)88.1%
(75-95%)
23.8%(13-39%)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
110%
12 weeks 24 weeks 36 weeks 48 weeks
cu
mu
lati
ve
pe
rce
nta
ge
of
pa
tie
nts
in
re
lap
se
mean time to relapse: 17.5 ± 7.9 weeks
(range 7 – 45 wk, median 15 wk)
TtR (weeks) 95 % CI (weeks)
Patients with low BASDAI (< 3) 18.9 15.4 – 18.9
Patients with high BASDAI (≥3) 14.8 10.0 – 19.6
Correlation between disease activity (BASDAI) and response to withdrawal
Kaplan-Meier Analysis Log rank test
(p=0.039)
0 6 12 18 24 30 36 42 48
time to relapse (weeks)
0%
20%
40%
60%
80%
100%
pts. with BASDAI < 3 pts. with BASDAI >= 3
Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44
(p=0.039)
0 6 12 18 24 30 36 42 48
time to relapse (weeks)
0%
20%
40%
60%
80%
100%
pts. with BASDAI < 3 pts. with BASDAI >= 3
(p=0.039)
0 6 12 18 24 30 36 42 480%
20%
40%
60%
80%
100%
pts. with BASDAI < 3 pts. with BASDAI >= 3
Response to retreatment
• Clear improvement of signs and symptoms
• Disease status similar to before withdrawal
• No adverse event, no other safety concern after resumption of etanercept and infliximab therapy
ETN: Brandt J et al. Rheumatology (Oxford). 2005 Mar;44(3):342-8. Baraliakos X et al, Arthritis Rheum 2005 (53): 856-863INF: Baraliakos X et al, Arthritis Res Ther 2005. 7(3): R439-44
Anti-TNF therapy in AS- clinical data
Additional data
• Total spinal ankylosis (TSA) represents end-stage fusion of the spine in patients (pts) with ankylosing spondylitis (AS)
• It is not uncommon for pts who already have TSA to still have symptoms of active disease.
Anti-TNFα in AS Patients with total spinal ankylosis– Data from the ATLAS Trial –
vd Heijde et al, Ann Rheum Dis 2008;67:1218-1221
• Total spinal ankylosis (TSA) represents end-stage fusion of the spine in patients (pts) with ankylosing spondylitis (AS)
• It is not uncommon for pts who already have TSA to still have symptoms of active disease.
1 year follow-up
(n=11 with TSA)
2 yearsfollow-up(n=8 with TSA)
Total ATLAS(2 years follow-up)
(n=304)
ASAS20 73% 75% 79%
ASAS40 36% 63% 67%
ASAS 5/6 55% 38% 49%
BASDAI50 45% 63% 71%
vd Heijde et al, Ann Rheum Dis 2008;67:1218-1221
Anti-TNFα in AS Patients with total spinal ankylosis– Data from the ATLAS Trial –
Etanercept 25mg/week- effective in some patients with active AS
Berthelot J, Joint Bone Spine 74 (2007); 144-147
n = 21n = 20
Improvement of key disease parameters by 3 mg/kg Infliximab
Maksymowych WP et al., J Rheumatol 2002; 29:959-65
Infliximab every 6 w. vs on demand therapy- response after 54 weeks:
continuous treatment is superior
0
20
40
60
80
ASAS 20 Part. Remission
Infliximab every 6w
Inflixmab on demand
%
75% 46% 27% 7%
Breban M et al, Arthritis Rheum 2008 (58):88-97
Addition of MTX to infliximab in patients with ankylosing spondylitis – response after 54 weeks:
almost no difference
0
10
20
30
40
50
60
ASAS 20 Part. Remission
MTXPlacebo
%
51% 40% 10% 5%
Breban M et al, Arthritis Rheum 2008 (58):88-97
Evidence for different types of response to anti-TNF treatment in AS
Three groups of patients according to level and degree ofresponse after 5 years of infliximab treatment:
Group A: remission at most time points (> 20/25 visits)
Group B: low disease activity (BASDAI < 3) (> 20/25 visits)
Group C: limited improvement, not fulfilling ASAS 20 at all
time points, BASDAI > 4 at some time points
Differences between groups:mean age (< / > 40 yrs, mean disease duration (< / > 10 yrs, mean BASFI at BL < / > 5)
Braun J, Baraliakos X et al, in press
Switching anti-TNF therapy in SpA
• patients with SpA n = 15 – 11 female, 4 male, mean age 43 – AS (n = 7)– uSpA (n = 6)– PsA (n = 2)– predominat axial involvement (n=13)– mean time of treatment with infliximab 11 months
• inadequate response or loss of response (n=11) • side effects (n=5)
• after 9 months 9/13 patients responded
Delaunay C et al. J Rheumatol 2005
infliximab to etanercept
Which AS patients should be
treated with TNF-blockers?
ASAS-Consensus Statement TNF-Blockers in ankylosing spondylitis
Non-responders toNSAIDs
Increased disease activityBASDAI > 4
Positive expert‘s opinion+
Diagnosis of AS
Braun J, Ann Rheum Dis 2003, 62: 817-24Braun J, Ann Rheum Dis 2006, 65: 201-8
2 NSAIDs within 3 m.
Positive expert‘s opinion:based on objective signs of inflammation
• Clinical examination/Patient‘s clinical history
• Pos. CRP/ESR
• Pos. MRI
• Radiographic progression
Improvement after 3 months
BASDAI-Improvement > 50%orBASDAI-Improvement > 2 (0-10)
Pos. expert´s opition+
Start of therapy with TNF-blockers
Braun J, Ann Rheum Dis 2003, 62: 817-24Braun J, Ann Rheum Dis 2006, 65: 201-8
ASAS-Consensus Statement TNF-Blockers in ankylosing spondylitis
Adverse event n=41 pat.
Upper respiratory tract infection 10
Infection at any site 6
Gum infection 4
Herpes simplex 3
Dry skin with pruritus 2
Infusion reactions 1
Elevation of liver enzymes 1
Nausea 1
Aphthen 1
Tachycardia 1
Swelling of the fingers 1
Paraesthesia in the forearm region 1
Total 26
Serious adverse events (2 hospitalized injuries, 1 repeated local infection)
3
Braun J, Baraliakos X et al, Ann Rheum Dis. 2008 March 1, 2008;67(3):340-5
Safety data – Infliximab –
Anti-TNF therapy in AS
Imaging
T- Cell infiltrates in Sacroiliitis
Bollow M, Ann Rheum Dis 2000; 59(2):135-40
Good Correlation of MRI with histology of SIJ biopsies in AS patients
-9,3%-14,4%
7,5%
-63,7%
-36,1%
4,5%
-74,3%
-65,2%
13,9%
-85%
-65%
-45%
-25%
-5%
15%
35%
STIR T1/Gd-DTPA T1
me
an
ch
an
ge
(%
) p
er
pa
tie
nt
Placebo after 12 weeks
Infliximab after 12 weeks
2y-Follow-up
Infliximab in AS – 2-year-MRI results
Sieper J, Baraliakos X et al. Rheumatology 2005
n=20
Spinal MRI during etanercept therapy
68%72.8%
53.7%
40.4%
4.3%
-12.8%-20%
0%
20%
40%
60%
80%
100%
after 12 weeks after 24 weeks after 48 weeks
chan
ge (%
) fro
m b
asel
ine
etanercept group placebo/etanercept group
improvement
worsening
T2-FS MRI sequence
Baraliakos X, Arthritis Rheum. 2005 Apr;52(4):1216-23
at baseline after 6 weeks after 24 weeks
STIR MRI of the SIJ after 6 weeks and 24 weeks of etanercept treatment
Rudwaleit M, Baraliakos X et al, Ann Rheum Dis. 2005 Sep;64(9):1305-10
The challenge in ankylosing spondylitis: less radiographic progression in continuous
vs. on demand users of NSAIDs
Wanders A, Arthritis Rheum. 2005 Jun;52(6):1756-65
p < 0.02
n = 214
Radiographic spinal progression after 2 years of treatment with anti-TNF
0,9
0,9
0,8
0 0,5 1 1,5
mSASSS change
Adalimumab3
OASIS (all)
OASIS (matched)
n.s.
1,27
0,95
0,91
0 0,5 1 1,5
mSASSS change
Etanercept1
OASIS (all)
OASIS (matched)
n.s.
1,2
1
0,9
0 0,5 1 1,5
mSASSS change
Infliximab2
OASIS (all)
OASIS (matched)
n.s.
Baseline characteristics TNF antagonists and OASIS (matched) are comparable
1van der Heijde et al. Arthritis Rheum 2008; 58: 1324-13312 van der Heijde et al. Arthritis Rheum 2008; 58: 3063-3070
3van der Heijde et al. ACR 2008 Abstract 670
Radiographic progression in AS after 4 years treatment with the anti-TNF-a antibody infliximab
13,2
12,7
17,1
11,6
12,5
15,5
10
11
12
13
14
15
16
17
18
baseline 2-year follow-up 4-year follow-up
Assessment time points
mS
AS
SS
uni
ts
Infliximab study
OASIS cohort
Baraliakos X et al, Rheumatology, 2007;46(9):1450-3
The long-term radiographic progression in AS
Linear mean radiographic progression
• Retrospective
evaluation
• FU = 13 years
• n = 146
Baraliakos X et al, J Rheumatol 2009 May;36(5):997-1002
10.0
0.5
1.0
1.5
2.0
2.5
3.0
0.8
1.3
2.6
All patients (n=116)
No Syndesmophytes at baseline (n=59)
p <0.05
Syndesmophytes at baseline (n=59)
Higher risk of radiographic progression with syndesmophytes at baseline
Baraliakos X, Ann Rheum Dis 2007 Jul;66(7):910-5
Ch
ang
e i
n s
co
rin
g u
nit
s (
mS
AS
SS
)
after 2 years
Anti-TNF therapy in AS
Future perspectives
Diagnosis: Inflammatory back pain RCT: 16 weeks (n=40)Primary endpoints: change in MRI scores from baseline to week 16
Baseline valuesAge (yrs)*: 28.8
Symptom duration (months)*: 15.3% male pts: 75
% HLA-B27+ pts: 100
62.7%
29.4%
P=0.001
0
50
100
% o
f le
sio
ns
reso
lvin
g
47/75
20/68
Sacroiliac MRI lesions resolving
New sacroiliac MRI lesions
1.2%12%
0
50
100
% n
ew l
esi
on
s P=0.004
Patients with spinal lesions resolved
0
50
100
% o
f p
atie
nts
60%
25%
NS
3/5
1/4
n=9 pts with BL spinal lesionsPBO (n=20)IFX (n=20)
Efficacy of Infliximab in Patients with HLA-B27+ Very Early AS
Secondary endpoints
0
25
50
75
100
ASAS50 partial remission
PBO (n=16)IFX (n=18)
% o
f p
atie
nts
12.5
55.6
P=0.009
61.1
18.8
P=0.012
Barkham N, Arthritis Rheum 2009 Apr;60(4):946-54
Adalimumab reduces SIJ inflammation in active pre-radiographic active axial SpA
Baseline: 84% of patients with active sacroiliitis in MRI but no sacroiliitis on x-rays
Mea
n S
I Jo
int
Sco
re (
MR
I) RCT: 12 weeks (n=19) OLE: 52 weeks (n=28)
p=0.003p>0.05 p>0.05
ADA therapy significantly improved inflammation as observed by MRI for patients treated for 1 year
Haibel H. EULAR 2009 SAT0266
p=0.004
Adalimumab reduces SIJ inflammation in active pre-radiographic active axial SpA
Haibel H. EULAR 2009 SAT0266
Baseline
Week 12
Week 52
Anti-TNF therapy in AS
Extraspinal manifestations
Extra-articular Manifestations in AS Patients in Belgian Rheumatology Practices
2%
1%
6%1%
7%
2%
22%
IBD
Psoriasis
58%AS
Uveitis
Vander Cruyssen et al. Ann Rheum. Dis 2007; 66(8): 1072-7
A
S
P
E
C
T
n=847
Placebo-controlled studies
Infliximab (2 studies)
• Braun J et al, Lancet, 2002 359 (9313): 1187-93
• Van der Heijde et al, Arthritis Rheum, 2005 52(2): 582-91
Etanercept (4 studies)
• Gorman N et al, Engl J Med, 2002 346 (18): 1349-56
• Brandt J et al, Arthritis Rheum, 2003 48 (6): 1667-75
• Davis J et al, Arthritis Rheum, 2003 48 (11): 3230-6
• Calin A et al, Ann Rheum Dis, 2004 63(12): 1594-600
Adalimumab (2 studies)
• van der Heijde D et al, . Arthritis Rheum 2006;54(7):2136-2146.
• Haibel H, Arthritis Rheum 2006;54(2):678-681
Open studies
• Stone M et al, J Rheumatol, 2001 28(7): 1605-14
• Gorman N et al, Engl J Med, 2002 346 (18): 1349-56
• Braun J et al, Rheumatology (Oxford) 2005 44(5): 670-6
• Baraliakos X et al, Arthritis Rheum, 2005 53(6): 856-63
• Davis J et al, Ann Rheum Dis, 2005. 64(11): 1557-62
• Braun J et al, Rheumatology (Oxford). 2005 May;44(5):670-6
Data collection
Acute anterior uveitis in ankylosing spondylitis
• Prevalence: 30 - 40%
• Incidence: 10 - 20/100 patient years
• Clinical presentation: acute, unilateral
• Prognosis: generally good, some severe
• Conventional Therapy: corticosteroid eye drops
Incidence of acute anterior uveitis in AS patients on anti-TNF therapy
Infliximab Etanercept Placebo Literature0
2
4
6
8
10
12
14
16
3.4
7.9
15.6
10.0
AU incidence
pooled datan = 717
/100 patient years
n
Braun J, Baraliakos X et al, Arthritis Rheum, 2005. 52(8):2447-51
• Infliximab: 3.4 flares / 100 patient years (CI: 1.1 – 8.0)
• Etanercept: 7.9 flares / 100 patient years (CI: 5.5 – 11.1)
• Placebo: 15.6 flares / 100 patient years (CI: 7.8 – 27.9)
• Statistical differences between incidences:
– Placebo vs. anti-TNFα : p = 0.01
– Placebo vs. Infliximab: p = 0.005
– Placebo vs. Etanercept: p = 0.05
– Infliximab vs. Etanercept: p = 0.08
Incidence of anterior uveitis in AS- double-blinded and open-label phases
Braun J, Baraliakos X et al, Arthritis Rheum, 2005. 52(8):2447-51
Inflammatory bowel diseases (Crohn‘s disease and ulcerative colitis) in patients with AS
• Prevalence: 0.3 %
• Incidence: 10/100.000 / year
• Clinical appearance: recurrences, flares, periphal symptoms
• Prognosis: partly severe
• Conventional Therapy: Corticosteroids, Azathioprine
Low but different incidence of acute inflammatory bowel disease (IBD) in patients on anti-TNF therapy
Infliximab Etanercept Adalimumab Placebo0
2
4
6
8
10
12
14
16
18
20
IBD cases
9 trials pooled datan = 1130
2.3/100py
(14 cases)
History of IBD in all patients 5.8 %
n = 366 n = 419 n = 434
n
2.3/100py (3 cases)
0.2/100py(1 case)
INF vs. ETN p < 0.001, INF vs. ADA p = 0.02, ETN vs. ADA p = 1.0
n = 295
1.3/100py (2 cases)
Braun J, Baraliakos X et al, Arthritis Rheum. 2007 May 15;57(4):639-47
py = patient years
Summary
• Treatment with biologics is efficacious and safe in the long-term in patients with active AS
• Improvement of clinical, laboratory and imaging assessments of inflammation can be seen even in patients with total spinal ankylosis
• Discontinuation leads to clinical relapse but retreatment is safe and efficacious
• DMARDs do not provide and additional benefit AS patients treated with biologics
• Switching between biologics is safe and efficacious
• Choice of biologic compound should be done based on individual needs of patient
• Effect of biologic treatment on radiographic progression of patients with AS is still unclear
Summary
Dr. X. BaraliakosRheumazentrum Ruhrgebiet, Herne
Ruhr-University BochumGermany
Thank you !