dr. x. baraliakos rheumazentrum ruhrgebiet, herne ruhr-university bochum germany

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 !