Treatment of Ankylosing Spondylitis

Enbrel RA MENA Speaker BureauDubai, United Arab Emirates

January 2009

Prof. Joachim R. KaldenDirector emeritus

Medical Department IIIDiv. for Molecular Immunology

University of Erlangen-Nuremberg

Ankylosing Spondylitis Overview

– A type of arthritis that causes inflammation and eventually fusion of the spine and the spinal joints. Involvement of peripheral joints and extraarticular manifestations.

– AS causes pain, stiffness, disability, decreased spinal mobility, and decreased quality of life

– The prevalence ranges from 0.1 to 1 percent of the population

– Men are affected three times more than women– Commonly develops between the ages of 15 and

40

– 95 percent of people with AS share the genetic marker HLA-B27

Treatment of Ankylosing SpondylitisOverview

• Treatment goals• Use of traditional therapies• Clinical results with TNFalpha antagonists• Guidelines for the management of TNFalpha antagonists

Treatment goals in Ankylosing Spondylitis

Reduce and or prevent deleterious effects of:• Inflammation• Ankylosis• Abnormal posture

Dougados et al. J.Rheumatol 2001;28-62:16-20.

Inhibition of osteoblastogenesis

Development of Ankylosis in Ankylosing Spondylitis

From: Cruickshank and Path, Pathology of Ankylosing Spondylitis

• The earliest change seen was a sub acute osteitis in the immediately adjacent bone.

• This was followed by extensive replacement of the fibrocartilage and adjacent bone by fibrous tissue in which there was often little remaining evidence of inflammation.

• The late stage of the disease in this joint consisted of assification.

Late Stage Reparation Mechanism - Dense Formation of

Osteoblasts

bone marrow

bone

Appel H, Loddenkemper C, Sieper J; unpublished

ASAS/EULAR Recommendations for the Management of AS

Education, exercise, physical therapy,

rehabilitation, patient

associations, self help groups

NSAIDs

Peripheral disease

Axial disease

Sulfasalazine

TNF blockers

Analgesics

Local corticosteroids

Surgery

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

Celecoxib Versus Naproxen in AS:Improvements in Primary Efficacy Measures

Barkhuizen et al. Ann Rheum Dis 2005;64(supplementIII);338(Abs).

Reduction of Radiographic Progression by NSAIDs in Ankylosing Spondylitis

Wanders et al. Arthritis Rheum 2005;52:1756-65.

Inhibition of proliferation and migration of

osteoblasts in a rat bone healing model by

diclofenac

GD Krischak et al. Arch Orthop Traum Surg 2007, 127:453-458

Sulphasalazine in the Treatment of Spondylarthropathy

20

40

60placebo

Sulphasalazine

% patients

43 40 42

59

Clegg et al. Arthritis Rheum 1999;42:2325-9.

Axialn=187

Periphraln=187

Placebo (n=39) Sulphasalazine (n=45)

Pain -17 -26

Swollen joints -1.6 -4.4

Tender joints -4.0 -8.8 Dougados et al. Arthritis Rheum 2005;38:618-27.

0

2

4

6

8

0 4 8 12 16Week

BA

SDA

I (m

ean)

All patients (n=20)

*Braun J, …, Sieper Jl. Ann Rheum Dis 2006 Apr 10; Epub **Haibel H, ..., Sieper J. Ann Rheum Dis 2005;64:124-6. †Haibel H, .... Sieper J. 2006; Aug 10; Epub.

0

2

4

6

8

0 4 8 12 16 20 24Week

BA

SDA

I (m

ean)

All patients (n=20)Peripheral arthritis (n=10)

Non-arthritis (n=10)

Leflunomide**20 mg/day

Methotrexate†

20 mg/week sc

012345678

0 4 8 12 16 20 24Week

BA

SDA

I (m

ean)

Placebo (n=60)Sulfasalzine (n=60)

Sulfasalazine*2 g/day

P=0.03

Conventional DMARDs in the Treatment of Ankylosing Spondylitis

Conclusions from treatment experiences in Ankylosing Spondylitis with traditional therapies

Traditional therapy options are not sufficient to treat active disease

• Physiotherapy important to maintain function • NSAIDs alleviate pain in some but not all patients• Steroids and immunomodulators have little/no effect• No drugs which impede disease progression

Unmet medical need in the treatment of severe AS

Infliximab Monotherapy Study In Active Ankylosing Spondylitis

54

BaselinePeriod

70 Patients

Placebo (N=35)

0,2,6

Infliximab 5 mg/kg Q 6 Wks (N=35)

LoadingPeriod

12

Infliximab 5mg/kg Q 6 Wks

Week

Double-Blind Open Label

Infliximab 5 mg/kgQ 6 Wks

Study Design

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

Reduction of Disease Activity Was Rapid and Durable Through 12 Weeks

Weeks

Percentage of Patients With Improvement of 50% in BASDAI

0

20

40

60

80

100

0 2 4 6 8 10 12

Patie

nts

resp

ondi

ng, %

PlaceboInfliximab 5 mg / kg

P<0.001

P<0.001 P<0.001

Intent-to-Treat Population

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

Maintenance of Efficacy of Infliximab in Ankylosing Spondylitis. Two year extension of a 3 months RCT

Braun et al. Ann. Rheum Dis 2005;64:229-34.

BASDAI 50% ASAS 40% ASAS 20% 5 out of 6

Radiographic Progression in Patients with Ankylosing Spondylitis treated for 2 years with Infliximab

Baraliakos et al. Ann Rheum Dis 2005;64:1462-6.

Control group Control group

Progression in total groupProgression in group with damage at baseline

Anti-TNF therapy in AS: Continuous improvement of spinal mobility and function over 2 years

-3

-2

-1

0

1

Weeks

Mea

n Cha

nge in B

ASF

I

Placebo-patientsCrossed-over

24 102

2

54

-2

-1

0

1

WeeksMea

n Cha

nge in

BASM

I

24 10254

Placebo-patientsCrossed-over

Braun J, et al. Arthritis Rheum 2008, in press

A randomized controlled clinical trial of infliximab shows clinical and MRI efficacy in patients with pos.

HLA B27 and very early AS

• 49 pat. with early inflammatory back pain, HLA B27 pos. and known oedema on MRI were randomized

• No demographic changes between the two groups

Result• Infliximab appears to be an effective therapy in very

early inflammatory back pain (significant change from baseline: MRI score of sacroiliac joints resolving of SI-joint lesions. Improvement of clinical parameters)

N. Barkham et al. ACR 2007. L11

Adalimumab in Ankylosing Spondylitis. The ATLAS trial: a RPCT on 315 patients treated for 24 weeks

25

50

75

100

21

58

14

41

19

51

14

39

Davis et al. Arthritis Rheum 2005;S208 (abs.483).

12 weeks 24 weeks

placebo

Adalimumab 40 mg eow

% patients

ASAS 20ASAS 40 ASAS 40ASAS 20

Adalimumab in Ankylosing Spondylitis. The ATLAS Trial: a RPCT on 315 patients Treated for 24 weeks

25

50

75

100

4

21

6

22

Davis et al. Arthritis Rheum 2005;S208 (abs.483).

12 weeks 24 weeks

placebo

Adalimumab 40 mg eow

Remission

% patients

Adalimumab in patients with total spine ankylosis

• Randomized, placebo-controlled trial (ratio 2:1)

• In patients with TSA adalimumab treatment resulted in rapid and clinically significant improvement in signs and symptoms of active disease– At week 12: 50% of adalimumab treated patients achieved

ASAS 20, 33% ASAS 40, ASAS 5/6 and BASDAI 50 as compared to non of placebo treated patients

– After 1 year: 8/11 adalimumab treated patients achieved ASAS 20

– After 2 years: 6/11 adalimumab treated patients achieved ASAS10

van der Heijde D et al, Ann Rheum Dis, Dec 2007

Etanercept for Ankylosing Spondylitis. Results of a 24-weeks RPCT on 277 patients

Davis et al. Arthritis Rheum 2003;48:3230-6.

Sustained Durability of Etanercept in Ankylosing Spondylitis for 96 weeks

Davis et al. Ann Rheum Dis 2006;64:1557-62.

Longterm anti-TNF therapy in AS - persistent low disease activity over 4 years

Mea

n B

ASD

AI

Weeks

0 24* 48 72 96 120 144 168 192

BASDAI (0–100)

0

10

20

30

40

50

60

70

Etanercept/EtanerceptPlacebo/Etanercept

*Week 24 represents the baseline of the OLE as well as the point of initial etanercept treatment for the patients switched from placebo to etanercept.

RCT

Davis J et al. Ann Rheum Dis 2008

0 24* 48 72 96 120 144 168 192

BASFI (0–100)

0

10

20

30

40

50

60

*Week 24 represents the baseline of the OLE as well as the point of initial etanercept treatment for the patients switched from placebo to etanercept.

Etanercept/EtanerceptPlacebo/Etanercept

Mea

n B

ASF

I

Weeks

Long-term anti-TNF therapy in AS - continuous improvement of function

Davis J et al. Ann Rheum Dis 2008

Assessment of Clinical Efficacy in a Randomized Double-Blind Study of Etanercept and Sulfasalazine in

Patients With Ankylosing Spondylitis

October 27, 2008American College of Rheumatology Annual Scientific MeetingACR 2008

J. Braun,1 F. Huang,2 R. Burgos-Vargas,3 I.E. van der Horst-Bruinsma,4

B. Freundlich,5 B. Vlahos,5 A.S. Koenig5

1Ruhr University, Bochum, Germany; 2Chinese PLA General Hospital, Beijing China; 3Hospital General de México and Universidad Nacional Autónoma de México, Mexico City, Mexico; 4VU University Medical Center, Department of Rheumatology, Amsterdam, Netherlands; 5Wyeth Research, Collegeville, PA, USA

Objective

To compare the efficacy and safety of etanercept 50 mg once weekly with sulfasalazine 1.5 to 3 g daily over 16 weeks in patients with active ankylosing spondylitis (AS)1

1van der Linden S. et al. Arthritis Rheum 1984;27:361–8.

Key Endpoints

• Primary– Proportion of patients achieving ASAS 20 (20% improvement by

Assessment of AS criteria) at 16 weeks • Select Secondary

– ASAS 20, ASAS 40, ASAS 5/6, partial remission1 – BASMI (Bath Ankylosing Spondylitis Metrology Index) – BASFI (Bath Ankylosing Spondylitis Functional Index) – BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) – C-Reactive Protein through 16 weeks – Back pain– Modified Schober’s test

1Anderson et al. Arthritis Rheum 2001; 441876-86

Proportion of Patients Who Achieved ASAS 20 (LOCF)

54.163.9

73.3 70.975.9

52.952.449.242.3

28.1

0102030405060708090

0 2 4 6 8 10 12 14 16Weeks

Patie

nts

(%)

Etanercept (n=378) Sulfasalazine (n=187)

*P<0.001, etanercept versus sulfasalazine

Primary Endpoint: Proportion of Patients Who Achieved ASAS 20 at week 16

**

* **

Proportion of Patients Who Achieved Partial Remission* (LOCF)

0

11.7

18.3

26.431.1

33.3

15.513.911.8

7.03.2

0

10

20

30

40

0 2 4 6 8 10 12 14 16Weeks

Patie

nts

(%)

Etanercept (n=379) Sulfasalazine (n=187)

*Anderson et al. Arthritis Rheum 2001; 441876-86; †P<0.001, etanercept versus sulfasalazine

†

†

†

†

†

Mean BASMI Scores (LOCF)

3.7

2.82.82.9

3.13.2

3.53.4

3.33.2 3.2

3.3

2.5

3

3.5

4

0 2 4 6 8 10 12 14 16Weeks

Mea

n Sc

ore

Etanercept (n=379) Sulfasalazine (n=187)

*P<0.001, etanercept versus sulfasalazine

**

* **

Conclusions

• In this 16-week study – Etanercept therapy was superior to sulfasalazine

therapy in the treatment of subjects with ankylosing spondylitis.

– There were no unexpected safety findings

Etanercept Shows Persistent clinical Efficacy over 5 Years

According to: Baraliakos X et al., FRI0291, EULAR 2008

No. Achieving at 12 weeks

No. Achieving at < 90% of all visits (%)

Clinical Remission 6 5 (83)

BASDAI < 3 11 8 (73)BASFI < 3 9 8 (89)BASFI < 4 11 11 (100)BASDAI + global physician‘s < 4 12 10 (83)

At 5 Years (n = 18): 33% were in partial remission according to ASAS criteria 38% achieved a BASDAI 50% response 62% achieved a ASAS 40% response 65% achieved a ‘5 out of 6’ response

Effectiveness of Adalimumab after failure of infliximab or etanercept in patients with PsA and AS

• Open-label phase IIb studies• PsA „STEREO“ 66 of 442 patients discontinued and

were switched to adalimumab• AS „RAPSODY“ 309 of 1186 patients discontinued

and were switched to adalimumab• PsA: Significant improvement in ACR 20, 50, 70 and

HAQ• AS: Significant improvement in ASAS 20, 50, 70 and

BASDAI

Burmester et al. Arthritis Rheum 2007; 56, 393

Rudwaleit et al. Ann Rheum Dis 2004;63:665-70.

Prediction of Response to TNF Antagonists in Ankylosing Spondylitis:

Infliximab n=69, Etanercept n=30

<4.5, 4.5-6.5, >6.5<10, 11-20 years, >20 years

Median percentage changefrom baseline

Interferon-γ Interleukin-6

CRPVEGF

Visvanathan Set al., Ann Rheum Dis, 2008

73

58

31

0

20

40

60

80

<10 years, N=37 11-20 years, N=33 >20 years, N=29

%

Patients with Ankylosing Spondylitis (n=99) treated with TNF-Blockers

Rudwaleit M, et al. Ann Rheum Dis. 2004; 63:665-70

Better Response if AS Patients Treated Early in the Disease Course (n=100)

(as judged by BASDAI 50 response)

Discontinuation of anti-TNF Therapy in Ankylosing Spondylitis

Baraliakos X et al., Arthritis Res Ther, 2005

Effects of TNFalpha antagonists on extra-articular manifestations

Reduction in the number of enthesetic regions- Infliximab- Etanercept - Adalimumab

Decreased incidence of anterior uveiitis- Infliximab- Adalimumab- Etanercept less effective

Braun et al., Lancet 2002; 359:1187-93Marzo-Ortego et al., Arthritis Rheum 2001; 44:2112-17

Braun et al., Arthritis Rheum 2005; 52:2447-51

Lyndell LL et al, Arthritis & Rheumatism (2007)56:3248-3252

00

0

10

20

30

40

0 8 16 24 32 40 48

PlaceboInfliximab

Proportion of Patients with Enthesopathy

Weeks

Perc

ent o

f Pat

ient

s

Placebo cross-over to Infliximab

* p = 0.03

*

Phase II: All Patients Receive Infliximab;

Original Blind Maintained

16 5000

0 16 50

The Impact Study

C. Antoni et al. Arth Rheum 2003

10

30

20

40

10

International ASAS Consensus Statement for the Use of anti-TNF in Patients with Ankylosing Spondylitis

•Indication Definitive ASActive disease - BASDAI ≥4

- expert opinion- acute phase response- imaging modalities

Failure of ≥2 NSAIDs In case of peripheral arthritis failure of intraarticular

corticosteroids/sulphasalazine Absence of contraindication

•Monitoring BASDAI ASAS core set Responder: improvement of ≥2 units on BASDAI

Baeten et al. Ann Rheum Dis 2003;62:829-34..

News from the ACR Meeting 2008

• Long-term efficacy for up to 7 years for all 3 TNF antagonists being licenzed for the treatment of AS. No new safety signals

• Re-Treatment of AS patients who flaired after ADA treatment was stopped is possible

• Early effective treatment of AS (as shown for ADA) might significantly improve the work productivity

Summary

• TNF antagonists proven in PsA, AS to have a long-term clinical efficacy and acceptable safety profile

• No new side effects reported in long-term clinical trials as compared to previous studies and registry data

• Identical recommendation for screening patients before TNFalpha antagonist should be started

• Psoriasis induced by TNFalpha antagonists– (Sfakis PP et al. Arthritis Rheum 2005)– (Kary S. Ann Rheum Dis 2006;65:405-407)– (Massara A et al. Rheumatology 2006;45:730-733)