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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.

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Dr. X. Baraliakos Rheumazentrum Ruhrgebiet, Herne Ruhr-University Bochum Germany

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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

  • 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

AS

49 years

Braun J, Sieper J. Lancet 2007


InflammationdrivenbyTNFa in AS

Detection of TNF α mRNA in thebonemarrow of inflammedsacroiliacjoints

  • mRNABraun J et al.Arthritis Rheum 1995; 38: 499

  • proteinBraun J et al.Ann Rheum Dis 2000; 59S: 85

  • bone marrowFrancois R et al.Ann Rheum Dis 2005


NSAIDs areefficaciousin 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


Many AS patients are refractory to NSAIDs

% Patients

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


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 6 months

at baseline

at 6 months

at baseline

Placebo (n = 118)

Sulfasalazine (n = 112)

Braun J, Baraliakos X et al. Ann Rheum Dis 2006 Sep;65(9):1147-53


ASAS/EULAR recommendations

for the management of AS

Education, exercise, physical therapy, rehabilitation, patient

associations, self help groups

NSAIDs

Ana

l

ges

i

cs

Peripheral disease

Axial

disease

Su

r

ge

r

y

Sulfasalazine

Local corticosteroids

TNF blockers

Zochling J et al. Ann Rheum Dis 2006 Apr;65(4):442-52


TNF Antagonists – a mile stone in the history of treatment of the (spondylo)arthritides

Physikalische und pharmakologische Eigenschaften


Anti-TNF therapy in AS- clinicaldata

Short-term data: Baseline - 6 months


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


Anti-TNF therapy in AS: Most patients achieve at least a 50% reduction of disease activity

2

6

12

weeks

Braun J et al. Lancet 2002; 359:1187-93


Significant improvement of function and spinal mobility

Braun J et al. Lancet 2002; 359:1187-93


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

Brandt J et al. Arthritis Rheum 2003; 48: 1667


Approval of etanercept for AS

ASAS 20 Response Weeks 12 and 24

*P < 0.0001

Patients Responding (%)

Davis JC, Arthritis Rheum 2003; 8: 3230-3236


Etanercept treatment in ASReduction of acute phase reactants

Etanercept 2 x 25 mg/Wk (n=138)

Placebo (n=139)

BSG (mm/h)

Mittlere Änderung gegenüber dem Ausgangswert in %

Mittlere Änderung gegenüber dem Ausgangswert in %

CRP (mg/dl)

† p < 0,0001

† p < 0,0001

Week 2

Month 6

Month 3

Week 2

Month 6

Month 3

Davis JC, Arthritis Rheum 2003; 8: 3230-3236


Efficacy of Adalimumab in patients with AS – The ATLAS Trial –

***

***

***

***

***

***

Week 24

Week 12

van der Heijde D, Arthritis Rheum, 2006. 54(7): 2136-2146

***Statistically significant at p<0.001 level (ANCOVA)


Adalimumab1

Etanercept2

*

Pbon=107

Ada 40 mg eown=208

Pbo n=139

Etan 25 mg BIWn=138

Infliximab

Golimumab

*

*

*

Pbon=78

Ifx 5 mg/kgn=201

Pbon=75

Glm 50 mgn=130

Glm 100 mgn=138

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.

* 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

Placebo-controlled phase

Open phase

Braun J, Rheumatology 2005. 44(5):670-6


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 2005. 44(5):670-6


Anti-TNFα therapy in patients with ASResults after 8 years

Infliximab

Baraliakos X, EULAR 2009, Copenhagen


Anti-TNFα therapy in patients with ASResults after 6 years

Etanercept

Baraliakos X, EULAR 2009, Copenhagen


Anti-TNFα therapy in patients with ASResults after 6 years

Etanercept

35.1%

33.3%

Baraliakos X, EULAR 2009, Copenhagen


Efficacy of Adalimumab in patientswith AS – long-termdatafromthe ATLAS Trial

2 years

3 years

vd Heijde D et al, Ann Rheum Dis2008

vd. Heijde D, Arthritis Res Ther 2009, 11:R124


Golimumab - ASAS Partial Remission after 104 weeks

Placebo/ Golimumab 50mg (n = 78)

Golimumab 50 mg(n = 138)

Golimumab 100 mg(n = 140)

GO-RAISE

Anteil Patienten (%)

Braun J. et al. ACR 2009, Abstract 1259

Braun J et al, ACR 2009, Abstract 1259


Placebo/ Golimumab 50mg (n = 78)

Golimumab 50 mg(n = 138)

Golimumab 100 mg(n = 140)

GO-RAISE

Golimumab – ASAS 40 Response after 104 weeks

Anteil Patienten (%)

Braun J. et al. ACR 2009, Abstract 1259

Braun J et al, ACR 2009, Abstract 1259


Discontinuationof anti-TNF- treatment

Anti-TNF therapy in AS- clinical data


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): 856-863

INF: 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

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

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

Infliximab withdrawal

Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44


BASDAI 50%, ASAS 40% response and partial remission after infliximab readministration

Infliximab withdrawal

after infliximab readministration

Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44


Duration of response after withdrawal

mean time to relapse: 17.5 ± 7.9 weeks

(range 7 – 45 wk, median 15 wk)


Correlation between disease activity (BASDAI) and response to withdrawal

100%

100%

(p=0.039)

(p=0.039)

80%

80%

60%

60%

40%

40%

20%

20%

0%

0%

0

0

6

6

12

12

18

18

24

24

30

30

36

36

42

42

48

48

time to relapse (weeks)

time to relapse (weeks)

pts. with BASDAI < 3

pts. with BASDAI < 3

pts. with BASDAI >= 3

pts. with BASDAI >= 3

100%

(p=0.039)

80%

60%

40%

20%

0%

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 2005. 7(3): R439-44


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): 856-863

INF: Baraliakos X et al, Arthritis Res Ther 2005. 7(3): R439-44


Anti-TNF therapy in AS- clinicaldata

Additional data


Anti-TNFα in AS Patientswithtotal spinal ankylosis– Data fromthe 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;67:1218-1221


Anti-TNFα in AS Patientswithtotal spinal ankylosis– Data fromthe 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;67:1218-1221


Etanercept25mg/week- effectivein somepatientswithactive AS

Berthelot J, Joint Bone Spine 74 (2007); 144-147

n = 21

n = 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

%

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

%

10%

40%

5%

51%

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 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


Switching anti-TNF therapy in SpA

infliximab toetanercept

  • 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


Which AS patientsshouldbetreatedwith TNF-blockers?


ASAS-Consensus Statement TNF-Blockers in ankylosing spondylitis

Diagnosis of AS

2 NSAIDs within3 m.

Non-respondersto

NSAIDs

Increaseddiseaseactivity

BASDAI > 4

+

Positive expert‘sopinion

Braun J, Ann Rheum Dis 2003, 62: 817-24

Braun J, Ann Rheum Dis 2006, 65: 201-8


Positive expert‘sopinion:based on objectivesigns of inflammation

  • Clinical examination/Patient‘sclinicalhistory

  • Pos. CRP/ESR

  • Pos. MRI

  • Radiographicprogression


ASAS-Consensus Statement TNF-Blockers in ankylosing spondylitis

Start of therapywith TNF-blockers

Improvement after 3 months

BASDAI-Improvement> 50%

or

BASDAI-Improvement> 2 (0-10)

+

Pos. expert´sopition

Braun J, Ann Rheum Dis 2003, 62: 817-24

Braun J, Ann Rheum Dis 2006, 65: 201-8


Safetydata– Infliximab –

Braun J, Baraliakos X et al, Ann Rheum Dis. 2008 March 1, 2008;67(3):340-5


Anti-TNF therapy in AS

Imaging


T- Cell infiltrates in Sacroiliitis

Good Correlation of MRI with histology of SIJ biopsies in AS patients

Bollow M, Ann Rheum Dis 2000; 59(2):135-40


Infliximab in AS – 2-year-MRI results

n=20

Sieper J, Baraliakos X et al. Rheumatology 2005


Spinal MRI during etanercept therapy

improvement

T2-FS MRI sequence

worsening

Baraliakos X, Arthritis Rheum. 2005 Apr;52(4):1216-23


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. 2005 Sep;64(9):1305-10


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. 2005 Jun;52(6):1756-65


n.s.

n.s.

Etanercept1

Infliximab2

OASIS (all)

OASIS (all)

OASIS (matched)

OASIS (matched)

Adalimumab3

n.s.

OASIS (all)

OASIS (matched)

Radiographic spinal progression after 2 years of treatment with anti-TNF

Baseline characteristics TNF antagonists and OASIS (matched) are comparable

1van der Heijde et al. Arthritis Rheum 2008; 58: 1324-1331

2 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

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


Higher risk of radiographicprogressionwithsyndesmophytesatbaseline

after 2 years

Change in scoring units (mSASSS)

p <0.05

All patients (n=116)

Syndesmophytes at baseline (n=59)

No Syndesmophytes at baseline (n=59)

Baraliakos X, Ann Rheum Dis 2007 Jul;66(7):910-5


Anti-TNF therapy in AS

Future perspectives


Patients with spinal

lesions resolved

Sacroiliac

MRI lesions resolving

n=9 pts with BL spinal lesions

100

100

P=0.001

62.7%

60%

PBO (n=16)

NS

% of lesions resolving

% of patients

IFX (n=18)

50

50

29.4%

47/75

3/5

25%

20/68

1/4

0

0

100

Secondary endpoints

P=0.012

P=0.009

75

61.1

55.6

% of patients

50

18.8

25

12.5

0

ASAS50

partial remission

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

IFX (n=20)

New

sacroiliac MRI lesions

PBO (n=20)

100

P=0.004

% new lesions

50

12%

1.2%

0

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


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=0.004

p>0.05

p>0.05

p=0.003

Mean SI Joint Score (MRI)

ADA therapy significantly improved inflammation as observed by MRI for patients treated for 1 year

Haibel H. EULAR 2009 SAT0266


Adalimumab reduces SIJ inflammation

in active pre-radiographic active axial SpA

Baseline

Week 12

Week 52

Haibel H. EULAR 2009 SAT0266


Anti-TNF therapy in AS

Extraspinal manifestations


Extra-articular Manifestations in AS Patients in Belgian Rheumatology Practices

A

S

P

E

C

T

n=847

58%

AS

22%

Uveitis

2%

6%

Psoriasis

1%

2%

1%

IBD

7%

Vander Cruyssen et al. Ann Rheum. Dis 2007; 66(8): 1072-7


Data collection

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


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

n

/100 patient years

pooled data

n = 717

Braun J, Baraliakos X et al, Arthritis Rheum, 2005. 52(8):2447-51


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, 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

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 = 434

n = 419

n = 295

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. 2007 May 15;57(4):639-47


Summary

  • Treatment withbiologicsisefficaciousandsafe in thelong-term in patientswithactive AS

  • Improvement of clinical, laboratoryandimagingassessments of inflammationcanbeseenevenin patientswith total spinal ankylosis

  • Discontinuationleadstoclinicalrelapse but retreatmentissafeandefficacious


Summary

  • DMARDs do not provideand additional benefit AS patientstreatedwithbiologics

  • Switchingbetweenbiologicsissafeandefficacious

  • Choice of biologiccompoundshouldbedonebased on individual needs of patient

  • Effect of biologictreatment on radiographicprogression of patientswith AS is still unclear


Thank you !

Dr. X. Baraliakos

Rheumazentrum Ruhrgebiet, Herne

Ruhr-University Bochum

Germany


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