1. Anti-TNF therapy in ankylosing spondylitis
- Clinical and structural outcomes -
Dr. X. Baraliakos
Rheumazentrum Ruhrgebiet, Herne
Ruhr-University Bochum
Germany 1

2. Ankylosing spondylitis: a chronic inflammatory rheumatic disease leading to high clinical impairment
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
24 years AS
49 years
Braun J, Sieper J. Lancet 2007

3. Inflammation driven by TNFa in AS
Detection of TNF α mRNA in the bone marrow of inflammed sacroiliac joints
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

4. NSAIDs are efficacious in AS
within 24 hours !
Amor B, et al. Rev Rheum Engl Ed 1995;62:10–5
Van der Heijde, et al. Arthritis Rheum 2005;52:1205–15 4

5. Many AS patients are refractory to NSAIDs
42%
29%
Clinical trials* n = 462
OASIS† n = 209
*Patients after 6 weeks of treatment with an active NSAID
†Epidemiological study = systematic recruitment of consecutive patients in daily practice 5

6. Sulfasalazine in early SpA
Disease activity in SpA patients with inflammatory back pain, with vs. without peripheral arthritis
BASDAI
BASDAI
IBP+, Peripheral arthritis -
IBP+, Peripheral arthritis +
IBP+, Peripheral arthritis -
p = 0.027
p = 0.3
IBP+, Peripheral arthritis +
at baseline
at 6 months
at baseline
at 6 months
Sulfasalazine (n = 112)
Placebo (n = 118)
Braun J, Baraliakos X et al. Ann Rheum Dis 2006 Sep;65(9):

7. ASAS/EULAR recommendations for the management of AS
Education, exercise, physical therapy, rehabilitation, patient
associations, self help groups
NSAIDs
Ana l
ges i cs
Axial
disease
Peripheral disease Su r ge y
Sulfasalazine
Local corticosteroids
TNF blockers
Zochling J et al. Ann Rheum Dis 2006 Apr;65(4):442-52

8. human/murine chimerik mAb
TNF Antagonists – a mile stone in the history of treatment of the (spondylo)arthritides
Physikalische und pharmakologische Eigenschaften
Infliximab
Etanercept
Adalimumab
Golimumab
Design
human/murine chimerik mAb
human TNF-Receptor/
Fc-Fusionsprotein
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

9. Anti-TNF therapy in AS - clinical data
Short-term data: Baseline - 6 months

10. The pilot study: infliximab in AS – open continuation phase
Infusions given according to disease activity (BASDAI)
Brandt J et al. Arthritis Rheum 2000; 43(6):1346

11. Anti-TNF therapy in AS: Most patients achieve at least a 50% reduction of disease activity
weeks 2 6 12
Braun J et al. Lancet 2002; 359:

12. Significant improvement of function and spinal mobility
Braun J et al. Lancet 2002; 359:

13. Early experiences with etanercept in AS
Improvement of disease activity (BASDAI)
n=30
ETN treatment in ETN group
ETN treatment in Placebo group
p = 0.003
Phase III
Brandt J et al. Arthritis Rheum 2003; 48: 1667

14. Approval of etanercept for AS
ASAS 20 Response Weeks 12 and 24
*P <
Patients Responding (%)
Davis JC, Arthritis Rheum 2003; 8:

15. Etanercept treatment in AS Reduction of acute phase reactants
BSG (mm/h)
Etanercept 2 x 25 mg/Wk (n=138)
Placebo (n=139)
Mittlere Änderung gegenüber dem Ausgangswert in %
CRP (mg/dl)
Mittlere Änderung gegenüber dem Ausgangswert in %
† p < 0,0001
† p < 0,0001
Hauptaussage:
Die Konzentrationen der Akute-Phase-Parameter hatten bei den Patienten der Enbrel® (Etanercept)-Gruppe nach zweiwöchiger Therapie signifikant abgenommen, verglichen mit einem deutlichen Anstieg unter Placebo. In der Grafik bedeuten Werte unter Null eine Besserung.1
Der mediane CRP-Wert der mit Etanercept behandelten Patienten hatte sich nach 6 Monaten von 1,1 mg/dl auf 0,3 mg/dl gebessert.1
Die mediane BSG der Patienten unter Etanercept war nach 6 Monaten von 23,0 mm/h auf 7,0 mm/h gefallen.1
In der Etanercept-Gruppe wiesen zu Beginn der Studie 46 % der Patienten und nach 6 Monaten 83 % der Patienten BSG-Werte innerhalb des Referenzbereichs auf.1
1 Davis JC, et al. Arthritis Rheum 2003; 48: † † † † † †
Week 2
Month 3
Month 6
Week 2
Month 3
Month 6
Davis JC, Arthritis Rheum 2003; 8:

16. Efficacy of Adalimumab in patients with AS – The ATLAS Trial –
Week 12
Week 24
***
***Statistically significant at p<0.001 level (ANCOVA)
van der Heijde D, Arthritis Rheum, (7): 16

17. ASAS 40 Response at Week 24 in Trials of Biologics for AS
Pbo n=107
Ada 40 mg eow n=208
Pbo n=139
Etan 25 mg BIW n=138
Adalimumab1
Etanercept2
Pbo n=78
Ifx 5 mg/kg n=201
Pbo n=75
Glm 50 mg n=130
Glm 100 mg n=138
Infliximab
Golimumab *
* P <.001 vs placebo
1van der Heijde D, et al. Arthritis Rheum. 2006;54: ;
2Davis JC, et al. Arthritis Rheum. 2003;48: ;
3van der Heijde D, et al. Arthritis Rheum. 2005;52:

18. Anti-TNF therapy in AS - clinical data
Long-term follow-up: 6 months – 8 years

19. Placebo-controlled phase
Patients with BASDAI 50% Response after 3 years of infliximab treatment
Placebo-controlled phase
Open phase
Braun J, Rheumatology (5):670-6

20. Continuous improvement of spinal mobility and function over 3 years
Placebo-controlled phase
Placebo controlled phase
Open phase
Open Phase
Mean BASMI
Mean BASFI
Braun J, Rheumatology (5):670-6

21. Anti-TNFα therapy in patients with AS Results after 8 years
Infliximab
Baraliakos X, EULAR 2009, Copenhagen 21

22. Anti-TNFα therapy in patients with AS Results after 6 years
Etanercept
Baraliakos X, EULAR 2009, Copenhagen

23. Anti-TNFα therapy in patients with AS Results after 6 years
Etanercept
35.1%
33.3%
Baraliakos X, EULAR 2009, Copenhagen

24. Efficacy of Adalimumab in patients with AS – long-term data from the ATLAS Trial
2 years
3 years
vd Heijde D et al, Ann Rheum Dis 2008
vd. Heijde D, Arthritis Res Ther 2009, 11:R124

25. Golimumab - ASAS Partial Remission after 104 weeks
GO-RAISE
Golimumab - ASAS Partial Remission after 104 weeks
Golimumab 100 mg (n = 140)
Placebo/ Golimumab 50mg (n = 78)
Golimumab 50 mg (n = 138)
Anteil Patienten (%)
Braun J. et al. ACR 2009, Abstract 1259
Braun J et al, ACR 2009, Abstract 1259

26. Golimumab – ASAS 40 Response after 104 weeks
GO-RAISE
Golimumab – ASAS 40 Response after 104 weeks
Golimumab 100 mg (n = 140)
Placebo/ Golimumab 50mg (n = 78)
Golimumab 50 mg (n = 138)
Anteil Patienten (%)
Braun J. et al. ACR 2009, Abstract 1259
Braun J et al, ACR 2009, Abstract 1259

27. Discontinuation of anti-TNF- treatment
Anti-TNF therapy in AS - clinical data
Discontinuation of anti-TNF- treatment

28. Design of studies 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
ETN: Brandt J et al. Arthritis Rheum 2003; 48: 1667
Baraliakos X et al, Arthritis Rheum 2005 (53):
INF: Baraliakos X et al, Arthritis Res Ther (3): R439-44

29. Clinically successful readministration of infliximab after withdrawal in all patients without infusion reactions
Infliximab withdrawal
Baraliakos X, Arthritis Res Ther (3): R439-44

30. Clinically successful readministration of infliximab after withdrawal in all patients without infusion reactions
Infliximab withdrawal
Baraliakos X, Arthritis Res Ther (3): R439-44

31. Clinically successful readministration of infliximab after withdrawal in all patients without infusion reactions
Infliximab withdrawal
Baraliakos X, Arthritis Res Ther (3): R439-44

32. BASDAI 50%, ASAS 40% response and partial remission after infliximab readministration
Infliximab withdrawal
after infliximab readministration
Baraliakos X, Arthritis Res Ther (3): R439-44

33. Duration of response after withdrawal
mean time to relapse: 17.5 ± 7.9 weeks
(range 7 – 45 wk, median 15 wk)

34. Correlation between disease activity (BASDAI) and response to withdrawal
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
(p=0.039) 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) 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
100%
(p=0.039)
80%
60%
40%
20% 0% 6 12 18 24 30 36 42 48
Kaplan-Meier Analysis
Log rank test
pts. with BASDAI < 3
pts. with BASDAI >= 3
Baraliakos X, Arthritis Res Ther (3): R439-44

35. 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) Mar;44(3):342-8.
Baraliakos X et al, Arthritis Rheum 2005 (53):
INF: Baraliakos X et al, Arthritis Res Ther (3): R439-44

36. Anti-TNF therapy in AS - clinical data
Additional data

37. Anti-TNFα in AS Patients with total spinal ankylosis – Data from the ATLAS Trial –
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.
vd Heijde et al, Ann Rheum Dis 2008;67:

38. Anti-TNFα in AS Patients with total spinal ankylosis – Data from the ATLAS Trial –
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 years
(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%
71%
vd Heijde et al, Ann Rheum Dis 2008;67:

39. Etanercept 25mg/week - effective in some patients with active AS
Berthelot J, Joint Bone Spine 74 (2007);

40. Improvement of key disease parameters by 3 mg/kg Infliximab
Maksymowych WP et al., J Rheumatol 2002; 29:959-65

41. Infliximab every 6 w. vs on demand therapy - response after 54 weeks: continuous treatment is superior %
75%
46%
27% 7%
Breban M et al, Arthritis Rheum 2008 (58):88-97

42. Addition of MTX to infliximab in patients with ankylosing spondylitis – response after 54 weeks: almost no difference %
51%
40%
10% 5%
Breban M et al, Arthritis Rheum 2008 (58):88-97

43. Evidence for different types of response to anti-TNF treatment in AS
Three groups of patients according to level and degree of
response 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

44. Switching anti-TNF therapy in SpA
infliximab to etanercept
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

45. Which AS patients should be treated with TNF-blockers?

46. ASAS-Consensus Statement TNF-Blockers in ankylosing spondylitis
Diagnosis of AS
2 NSAIDs within 3 m.
Non-responders to
NSAIDs
Increased disease activity
BASDAI > 4 +
Positive expert‘s opinion
Braun J, Ann Rheum Dis 2003, 62:
Braun J, Ann Rheum Dis 2006, 65: 201-8

47. Positive expert‘s opinion: based on objective signs of inflammation
Clinical examination/Patient‘s clinical history
Pos. CRP/ESR
Pos. MRI
Radiographic progression

48. ASAS-Consensus Statement TNF-Blockers in ankylosing spondylitis
Start of therapy with TNF-blockers
Improvement after 3 months
BASDAI-Improvement > 50% or
BASDAI-Improvement > 2 (0-10) +
Pos. expert´s opition
Braun J, Ann Rheum Dis 2003, 62:
Braun J, Ann Rheum Dis 2006, 65: 201-8

49. Safety data – Infliximab –
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
Nausea
Aphthen
Tachycardia
Swelling of the fingers
Paraesthesia in the forearm region
Total 26
Serious adverse events
(2 hospitalized injuries, 1 repeated local infection)
Braun J, Baraliakos X et al, Ann Rheum Dis March 1, 2008;67(3):340-5

50. Anti-TNF therapy in AS
Imaging

51. T- Cell infiltrates in Sacroiliitis
Good Correlation of MRI with histology of SIJ biopsies in AS patients
T- Cell infiltrates in Sacroiliitis
Bollow M, Ann Rheum Dis 2000; 59(2):135-40 51

52. Infliximab in AS – 2-year-MRI results
Sieper J, Baraliakos X et al. Rheumatology 2005

53. Spinal MRI during etanercept therapy
improvement
T2-FS MRI sequence
worsening
Baraliakos X, Arthritis Rheum Apr;52(4):

54. STIR MRI of the SIJ after 6 weeks and 24 weeks of etanercept treatment
at baseline
after 6 weeks
after 24 weeks
Rudwaleit M, Baraliakos X et al, Ann Rheum Dis Sep;64(9):

55. The challenge in ankylosing spondylitis: less radiographic progression in continuous vs. on demand users of NSAIDs
n = 214
p < 0.02
Wanders A, Arthritis Rheum Jun;52(6):

56. Radiographic spinal progression after 2 years of treatment with anti-TNF
Baseline characteristics TNF antagonists and OASIS (matched) are comparable
Etanercept1
OASIS (all)
OASIS (matched)
n.s.
Infliximab2
OASIS (all)
OASIS (matched)
n.s.
Adalimumab3
OASIS (all)
OASIS (matched)
n.s.
Title:
670 - Adalimumab (HUMIRA®) Therapy for Ankylosing Spondylitis Over 2 Years Does Not Demonstrate Inhibition of Radiographic Progression Compared With a Historical Control Group
Location:
Room 300
Category:
28. Spondylarthropathies and psoriatic arthritis: clinical aspects and treatment
Author(s):
Désirée van der Heijde1, Robert Landewe1, Walter Maksymowych2, Barbara Weissman 3, David Salonen4, Shaila Ballal5, Fred Holdbrook5, Robert Wong5, Hartmut Kupper6, John Medich5.
1Leiden University Medical Center, Leiden, Netherlands; 2University of Alberta, Edmonton, AB, Canada; 3Brigham and Women’s Hospital, Boston, MA; 4Mount Sinai Hospital, Toronto, ON, Canada; 5Abbott Laboratories, Parsippany, NJ; 6Abbott GmbH & Co. KG, Abbott GmbH & Co. KG, Germany
Abstract:
Purpose:
To evaluate the long-term effects of adalimumab on radiographic progression in patients with active AS.
Methods:
Radiographs of the lateral cervical and lumbar spine were obtained at baseline and Year 2 from patients in 2 Phase III clinical studies of adalimumab (M [N=82] and M [ATLAS, N=315]). Results were compared with baseline and 2-year radiographs of lateral cervical and lumbar spine from a natural history cohort (OASIS) of AS patients naïve to TNF-antagonist therapy. Patients with total spinal ankylosis at baseline were excluded. Radiographs from the OASIS cohort and the 2 adalimumab studies were combined and read in 1 batch by 2 independent assessors (both blinded to origin of cohort, treatment allocation and sequence) using the modified Stoke AS Spinal Score (mSASSS).
Results:
Findings for 307 adalimumab patients who had radiographs at baseline and Year 2 were compared with 169 controls from the OASIS cohort. Patients in this combined analysis were primarily male (76% for the adalimumab studies and 69% for OASIS), with a mean age of approximately 42 years for both groups. Baseline disease activity as measured by the Patient Global Assessment of Disease Activity and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was greater for adalimumab patients than for OASIS participants, but baseline mSASSS scores were comparable between groups. NSAID use was slightly greater (88%) for adalimumab patients than OASIS patients (77%). After 2 years of therapy, there was no statistically significant difference in the mean change in mSASSS for adalimumab patients vs. OASIS cohort control patients (0.8, standard error [SE]=0.16 vs. 0.9, SE=0.22, respectively; p=0.771). When only OASIS controls with baseline disease characteristics comparable to those enrolled in the adalimumab trials (n=77) were compared with the adalimumab -treated patients, the mean changes in mSASSS after 2 years for adalimumab-treated patients and OASIS cohort participants were 0.8, (SE=0.17) and 0.9 (SE=0.33), respectively (p = 0.744).
Conclusions:
Despite providing substantial and significant improvements in clinical efficacy, adalimumab therapy did not lead to inhibition of radiographic progression in AS patients treated for 2 years. These findings are comparable to what has been observed for both etanercept and infliximab in AS.1,2
1van der Heijde D, et al. Ann Rheum Dis. 2006;65(Suppl II):81. 2van der Heijde D, et al. Ann Rheum Dis
1van der Heijde et al. Arthritis Rheum 2008; 58:
2 van der Heijde et al. Arthritis Rheum 2008; 58:
3van der Heijde et al. ACR 2008 Abstract 670

57. Radiographic progression in AS after 4 years treatment with the anti-TNF-a antibody infliximab
Baraliakos X et al, Rheumatology, 2007;46(9):1450-3 57

58. 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): 58

59. No Syndesmophytes at baseline (n=59) Syndesmophytes at baseline (n=59)
Higher risk of radiographic progression with syndesmophytes at baseline
after 2 years
Change in scoring units (mSASSS)
p <0.05
No Syndesmophytes at baseline (n=59)
All patients (n=116)
Syndesmophytes at baseline (n=59)
Baraliakos X, Ann Rheum Dis 2007 Jul;66(7):910-5

60. Anti-TNF therapy in AS
Future perspectives

61. Efficacy of Infliximab in Patients with HLA-B27+ Very Early AS
Diagnosis: Inflammatory back pain RCT: 16 weeks (n=40)
Primary endpoints: change in MRI scores from baseline to week 16
Patients with spinal
lesions resolved 50
100
% of patients
60%
25% NS
3/5
1/4
n=9 pts with BL spinal lesions
IFX (n=20)
62.7%
29.4%
P=0.001 50
100
% of lesions resolving
47/75
20/68
Sacroiliac
MRI lesions resolving
PBO (n=20)
New
sacroiliac MRI lesions
100
P=0.004
% new lesions 50
12%
1.2%
Title:
A Randomised Controlled Trial of Infliximab shows clinical and MRI efficacy in patients with HLA B27 positive very early ankylosing spondylitis
Category: 28. Spondylarthropathies and psoriatic arthritis: clinical aspects and treatment
Presentation Number: L11
Author(s): Nick Barkham, Helen Keen, Laura Coates, Phil O'Connor, Elizabeth Hensor, Alexander Fraser, Lorna Cawkwell, Dennis McGonagle, Paul Emery. University of Leeds, Leeds, United Kingdom
PURPOSE: Untreated, patients with inflammatory back pain, HLA B27 and positive MRI would progress to ankylosing spondylitis in more than 90% of cases. Current diagnosis of AS relies on plain film sacroiliitis, which can take 10 years to develop. TNF alpha blocking agents have revolutionized the treatment of established ankylosing spondylitis. The benefits of treatment of AS in the preradiographic phase have not been established. The objective of this study was to assess the infliximab-induced changes of the spine and sacroiliac joints. METHOD: Patients with inflammatory back pain by Calin criteria who were HLA B27 positive underwent MRI scanning of the spine and sacroiliac joints. 40 patients within 3 years of onset of symptoms were recruited if oedema could be detected at the sacroiliac joints. In double-blinded, placebo-controlled fashion, patients were randomized equally to infusions of placebo or infliximab 5 mg/kg at 0, 2, 6 and 12 weeks. Concomitant NSAIDS at a stable dose was permitted for the duration of the study. MRI scans of the spine and sacroiliac joints (subdivided into 8 regions) were performed at baseline and at 16 weeks. Two assessors who were blinded to treatment and orderek read T1 and fat-suppressed T2 MRIs. Paired scoring was performed for each lesion using a semi-quantitative scale. The primary endpoint was change in MRI score from baseline to week 16. Clinical assessments were included as secondary endpoints. RESULTS: Forty of 49 patients with early inflammatory back pain and HLA B27 had bone oedema on MRI and were randomised. Twenty patients received infliximab, 20 placebo. The mean age was 28.8 years (SD 7.5), mean symptom duration was 15.3 months (SD 8.8), NSAID use was 90%, and 75% of patients were male. There were no statistically significant differences between the baseline characteristics of the 2 groups. Primary and secondary endpoints are described in the table. Compared to the placebo group, significant improvements in MRI and clinical endpoints were observed in the infliximab group. Overall, infliximab was well tolerated, and no patients discontinued due to adverse events. Table of Contents
Parameters All patients Infliximab Placebo P-value
(baseline) (change from baseline) (change from baseline)
Primary endpoints
Total MRI score of
sacroiliac joints, mean
(95% CI) ( ) 0( ) †
Patients with spinal
lesions, N (%) 9 (22.5%) 3/5 resolved (60%) 1/4 resolved (25%)
Sacro-iliac MRI lesions
resolving, N (%) (62.7) 20(29.4) †
New SI lesions on
MRI, N (%) (1.2) (12) †
Secondary endpoints
HAQ, median (IQR) 0.88 ( ) (-0.93 to -0.13) (-0.38 to 0.00)
ASQoL, median (IQR) 10.5 ( ) (-10.0 to -2.25) (-4.50 to 0.75) †
BASFI, mean (SD) (1.71) (2.36) (2.25) †
*BASDAI, mean (SD) 5.81 (1.46) (2.53) (2.42) †
*BASDAI50, N (%) (60.0) 3 (15) †
**ASAS partial
remission, N (%) (55.6) 2 (10) †
**ASAS20, N (%) (77.8) 5 (31.3) †
**ASAS50, N (%) (61.1) 3 (18.8) †
**ASAS70, N (%) (55.6) 2 (12.5) †
* N=38 (P=18, I=20), **N = 34 (P=16, I=18)
SUMMARY: Infliximab appears to be an effective therapy for very early inflammatory back pain by providing a rapid reduction in disease activity on MRI and measures of clinical efficacy. This is the first therapy to show suppression of the inflammatory lesions on MRI in very early ankylosing spondylitis. Further research should establish whether the effect of infliximab on bone oedema would also halt ankylosis.
Disclosures:  N. Barkham, Centocor; H. Keen, Centocor; L. Coates, Centocor; P. O'Connor, None; E. Hensor, None; A. Fraser, None; L. Cawkwell, None; D. McGonagle, None; P. Emery, Centocor.
Secondary endpoints 25 50 75
100
ASAS50
partial remission
PBO (n=16)
IFX (n=18)
% of patients
12.5
55.6
P=0.009
61.1
18.8
P=0.012
Baseline values
Age (yrs)*: 28.8
Symptom duration (months)*: 15.3
% male pts: 75
% HLA-B27+ pts: 100
Barkham N, Arthritis Rheum 2009 Apr;60(4):946-54 61 61

62. 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
RCT: 12 weeks (n=19)
OLE: 52 weeks (n=28)
p>0.05
p>0.05
p=0.003
p=0.004
Mean SI Joint Score (MRI)
SAT0266 ADALIMUMAB REDUCES INFLAMMATION IN THE SACROILIAC JOINTS OF PATIENTS
WITH ACTIVE SPONDYLOARTHRITIS WITHOUT RADIOGRAPHIC SACROILIITIS — RESULTS OF A
PLACEBO-CONTROLLED, DOUBLE-BLIND CLINICAL TRIAL THROUGH 52 WEEKS
H. Haibel1, X. Baraliakos2, M. Rudwaleit1, J. Listing3, R. Wong4, H. Kupper5, J. Braun2, J. Sieper*1
1Charité, University Medicine Berlin, Berlin, 2, Centre of Rheumatology, Herne, 3, German Rheumatism
Research Centre, Berlin, Germany, 4, Abbott Laboratories, Parsippany, NJ, United States, 5, Abbott GmbH &
Co KG, Ludwigshafen, Germany
Background: Adalimumab is very effective in improving the signs and symptoms of active axial
spondyloarthritis.1 No data are currently available on the course of the active inflammatory lesions in the
sacroiliac (SI) joints as detected by magnetic resonance imaging (MRI) in patients with active spondyloarthritis
without radiographic sacroiliitis.
Objectives: We investigated SI joint inflammation at baseline, Week 12, and Week 52 in patients with active
spondyloarthritis without radiographic sacroiliitis who were included in a placebo-controlled, double-blind trial
of adalimumab.
Methods: MRI investigations were conducted for patients at 2 centers in Germany enrolled in a 12-week,
placebo-controlled trial with a 40-week, open-label extension. Adult patients with active SpA (BASDAI ≥4) and
insufficient responses to ≥1 prior NSAIDs were included in this study. MRIs of the SI joints were performed at
baseline, Week 12 and Week 52. Active inflammation in the SI joints was scored according to Hermann et
al.,2 with each SI joint divided into quadrants and with modifications for additional points of intensity for each
SI joint (range: 0–34). MRIs were scored independently by 2 readers blinded to time points of the MRIs. Mean
scores of the 2 readings were included in the analysis.
Results: Of the 37 patients with complete MRI data for the SI joints at baseline, 84% had a SI joint score ≥1;
78% had ≥2, and 24% had a score ≥10 (reflecting extended SI joint inflammation). Of the 19 patients with
complete MRI data for baseline and week 12, mean SI joint score changed from 11.8 at baseline to 10.5
(median: 6.5 to 8.5) at Week 12 for the placebo group (n=9) and from 3.9 to 2.5 (median: 3.3 to 1.3) for the
adalimumab group (n=10), p>0.05 (not significant) for both groups.
Of 28 patients with complete MRI data for baseline and Week 52, the mean SI joint score changed from 10.1
to 4.3 (median: 6 to 2) for the initial placebo group (n=16), p=0.012, and from 4.8 to 3.0 (median: 3.25 to 3) for
the adalimumab group (n=12), p>0.05 (not significant). For the pooled group, there was also a significant
improvement from 7.9 at baseline to 3.8 (median: 5.3 to 3) at Week 52 (p=0.003). Of the pooled group of
patients, 18% had a score of 0 at Week 52, reflecting no inflammation of the SI joints, and 54% had an MRI
improvement of >50%. A score of ≥2 at Week 52 was found in 61% of patients. Inter-reader correlations were
substantial: 0.88 at baseline, 0.91 at Week 12, and 0.88 at Week 52.
Conclusion: Of patients with active axial spondyloarthritis without radiologic sacroiliits in this study, the
majority had inflammatory lesions as detected by MRI in the SI joints, and a substantial number of patients
also had extensive SI joint inflammation. Adalimumab therapy significantly improved inflammation as
observed by MRI for patients treated for 1 year.
References: 1Haibel H, et al. Arthritis Rheum. 2008;58:
2Hermann KG, et al. Radiologe. 2004;44:
Disclosure of Interest: H. Haibel, Abbott, Scherring Plough, Speakers fees
X. Baraliakos, Abbott, Consultant
M. Rudwaleit, Abbott, MSD, Schering-Plough, Pfizer, and Wyeth, Consultancies, speaking fees, honoraria
J. Listing, Abbott, Consultant
R. Wong, Abbott, Employee, stocks
H. Kupper, Abbott, Employee, stocks
J. Braun, Abbott, Schering-Plough, Wyeth, Centocor, Amgen, Reiumbursements, fees, grant
J. Sieper, Abbott, Schering-Plough, Wyeth, Research grants, Abbott, BMS, Roche, Schering-Plough, Wyeth,
Consulting fees or other remuneration, Abbott, Roche, Pfizer, Scheering-Plough, Wyeth, Speakers bureau
ADA therapy significantly improved inflammation as observed by MRI for patients treated for 1 year
Haibel H. EULAR 2009 SAT0266

63. Adalimumab reduces SIJ inflammation
in active pre-radiographic active axial SpA
Baseline
SAT0266 ADALIMUMAB REDUCES INFLAMMATION IN THE SACROILIAC JOINTS OF PATIENTS
WITH ACTIVE SPONDYLOARTHRITIS WITHOUT RADIOGRAPHIC SACROILIITIS — RESULTS OF A
PLACEBO-CONTROLLED, DOUBLE-BLIND CLINICAL TRIAL THROUGH 52 WEEKS
H. Haibel1, X. Baraliakos2, M. Rudwaleit1, J. Listing3, R. Wong4, H. Kupper5, J. Braun2, J. Sieper*1
1Charité, University Medicine Berlin, Berlin, 2, Centre of Rheumatology, Herne, 3, German Rheumatism
Research Centre, Berlin, Germany, 4, Abbott Laboratories, Parsippany, NJ, United States, 5, Abbott GmbH &
Co KG, Ludwigshafen, Germany
Background: Adalimumab is very effective in improving the signs and symptoms of active axial
spondyloarthritis.1 No data are currently available on the course of the active inflammatory lesions in the
sacroiliac (SI) joints as detected by magnetic resonance imaging (MRI) in patients with active spondyloarthritis
without radiographic sacroiliitis.
Objectives: We investigated SI joint inflammation at baseline, Week 12, and Week 52 in patients with active
spondyloarthritis without radiographic sacroiliitis who were included in a placebo-controlled, double-blind trial
of adalimumab.
Methods: MRI investigations were conducted for patients at 2 centers in Germany enrolled in a 12-week,
placebo-controlled trial with a 40-week, open-label extension. Adult patients with active SpA (BASDAI ≥4) and
insufficient responses to ≥1 prior NSAIDs were included in this study. MRIs of the SI joints were performed at
baseline, Week 12 and Week 52. Active inflammation in the SI joints was scored according to Hermann et
al.,2 with each SI joint divided into quadrants and with modifications for additional points of intensity for each
SI joint (range: 0–34). MRIs were scored independently by 2 readers blinded to time points of the MRIs. Mean
scores of the 2 readings were included in the analysis.
Results: Of the 37 patients with complete MRI data for the SI joints at baseline, 84% had a SI joint score ≥1;
78% had ≥2, and 24% had a score ≥10 (reflecting extended SI joint inflammation). Of the 19 patients with
complete MRI data for baseline and week 12, mean SI joint score changed from 11.8 at baseline to 10.5
(median: 6.5 to 8.5) at Week 12 for the placebo group (n=9) and from 3.9 to 2.5 (median: 3.3 to 1.3) for the
adalimumab group (n=10), p>0.05 (not significant) for both groups.
Of 28 patients with complete MRI data for baseline and Week 52, the mean SI joint score changed from 10.1
to 4.3 (median: 6 to 2) for the initial placebo group (n=16), p=0.012, and from 4.8 to 3.0 (median: 3.25 to 3) for
the adalimumab group (n=12), p>0.05 (not significant). For the pooled group, there was also a significant
improvement from 7.9 at baseline to 3.8 (median: 5.3 to 3) at Week 52 (p=0.003). Of the pooled group of
patients, 18% had a score of 0 at Week 52, reflecting no inflammation of the SI joints, and 54% had an MRI
improvement of >50%. A score of ≥2 at Week 52 was found in 61% of patients. Inter-reader correlations were
substantial: 0.88 at baseline, 0.91 at Week 12, and 0.88 at Week 52.
Conclusion: Of patients with active axial spondyloarthritis without radiologic sacroiliits in this study, the
majority had inflammatory lesions as detected by MRI in the SI joints, and a substantial number of patients
also had extensive SI joint inflammation. Adalimumab therapy significantly improved inflammation as
observed by MRI for patients treated for 1 year.
References: 1Haibel H, et al. Arthritis Rheum. 2008;58:
2Hermann KG, et al. Radiologe. 2004;44:
Disclosure of Interest: H. Haibel, Abbott, Scherring Plough, Speakers fees
X. Baraliakos, Abbott, Consultant
M. Rudwaleit, Abbott, MSD, Schering-Plough, Pfizer, and Wyeth, Consultancies, speaking fees, honoraria
J. Listing, Abbott, Consultant
R. Wong, Abbott, Employee, stocks
H. Kupper, Abbott, Employee, stocks
J. Braun, Abbott, Schering-Plough, Wyeth, Centocor, Amgen, Reiumbursements, fees, grant
J. Sieper, Abbott, Schering-Plough, Wyeth, Research grants, Abbott, BMS, Roche, Schering-Plough, Wyeth,
Consulting fees or other remuneration, Abbott, Roche, Pfizer, Scheering-Plough, Wyeth, Speakers bureau
Week 12
Week 52
Haibel H. EULAR 2009 SAT0266

64. Extraspinal manifestations
Anti-TNF therapy in AS
Extraspinal manifestations

65. Extra-articular Manifestations in AS Patients in Belgian Rheumatology Practices
58% AS
22%
Uveitis 2% 6%
Psoriasis ok 1% 2% 1%
IBD 7%
Vander Cruyssen et al. Ann Rheum. Dis 2007; 66(8):

66. Data collection Placebo-controlled studies Infliximab (2 studies)
Braun J et al, Lancet, (9313):
Van der Heijde et al, Arthritis Rheum, (2):
Etanercept (4 studies)
Gorman N et al, Engl J Med, (18):
Brandt J et al, Arthritis Rheum, (6):
Davis J et al, Arthritis Rheum, (11):
Calin A et al, Ann Rheum Dis, (12):
Adalimumab (2 studies)
van der Heijde D et al, . Arthritis Rheum 2006;54(7):
Haibel H, Arthritis Rheum 2006;54(2):
Open studies
Stone M et al, J Rheumatol, (7):
Braun J et al, Rheumatology (Oxford) (5): 670-6
Baraliakos X et al, Arthritis Rheum, (6):
Davis J et al, Ann Rheum Dis, (11):
Braun J et al, Rheumatology (Oxford) May;44(5):670-6

67. Acute anterior uveitis in ankylosing spondylitis
Prevalence: %
Incidence: /100 patient years
Clinical presentation: acute, unilateral
Prognosis: generally good, some severe
Conventional Therapy: corticosteroid eye drops

68. Incidence of acute anterior uveitis in AS patients on anti-TNF therapy
/100 patient years
pooled data
n = 717
Braun J, Baraliakos X et al, Arthritis Rheum, (8):

69. Incidence of anterior uveitis in AS - double-blinded and open-label phases
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
Braun J, Baraliakos X et al, Arthritis Rheum, (8):

70. Inflammatory bowel diseases (Crohn‘s disease and ulcerative colitis) in patients with AS
Prevalence: %
Incidence: 10/ / year
Clinical appearance: recurrences, flares, periphal symptoms
Prognosis: partly severe
Conventional Therapy: Corticosteroids, Azathioprine

71. Low but different incidence of acute inflammatory bowel disease (IBD) in patients on anti-TNF therapy
History of IBD in all patients 5.8 % n
2.3/100py (14 cases)
2.3/100py (3 cases)
1.3/100py (2 cases)
0.2/100py
(1 case)
9 trials pooled data
n = 1130
py = patient years
n = 366
n = 419
n = 295
n = 434
INF vs. ETN p < 0.001, INF vs. ADA p = 0.02, ETN vs. ADA p = 1.0
Braun J, Baraliakos X et al, Arthritis Rheum May 15;57(4):639-47

72. 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

73. Summary
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

74. Rheumazentrum Ruhrgebiet, Herne Ruhr-University Bochum
Thank you !
Dr. X. Baraliakos
Rheumazentrum Ruhrgebiet, Herne
Ruhr-University Bochum
Germany 74