Agenda

• • • • Spondyloarthropathies Early Rheumatoid Arthritis Established Rheumatoid Arthritis Benefit - Risk

Dr. Jad OKAIS HDF 2009

Agenda

• • • • Spondyloarthropathies Early Rheumatoid Arthritis Established Rheumatoid Arthritis Benefit - Risk

Spondyloarthropathies

Early treatment By Anti-TNF Late treatment By Anti-TNF

Year 1 Year 10 Year 20

Inflammation Ankylosis

Arthritis & Enthesopathies

Anti-TNF treatment in AS

• • • • • In general, about half of the patients gain 50% improvement of disease activity as assessed by the Bath Ankylosing Spondylitis Activity Index (BASDAI).

30 –40% show an increase in function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). Applying the ASAS outcome criteria usually >60% reach ASAS 20, and >40% the ASAS 40 and ASAS 5/6 criteria, while 20 –30% even achieve ASAS partial remission. Furthermore, AS patients treated with TNF blockers report an improved quality of life and reach higher productivity scores.

There is very good efficacy on clinical disease activity, acute-phase reactants an inflammation visible on MRI.

1- Braun J,et al. Improvement in patientreported outcomes for patients with ankylosing spondylitis treated with etanercept 50mg once-weekly and 25mg twice-weekly. Rheumatology 2007;46:999–1004.

2- Davis JC et al. Health-related quality of life outcomes in patients with active ankylosing spondylitis treated with adalimumab: results from a randomized controlled study. Arthritis Rheum 2007;57:1050–7.

3- Van der Heide et al. Infliximab improves productivity and reduces workday loss in patients with ankylosing spondylitis: results from a randomized, placebo-controlled trial. Arthritis Rheum 2006;55:569–74.

4- Rudwaleit M et al. Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann Rheum Dis 2004;63:665–70.

90 70

Better response to TNF blockers with early treatment

Patients with AS treated with INFLIXIMAB

50 30 10

< 10 years N=37 11-20 years N=33

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

>20 years N=29

Anti-TNF and Syndesmophytes

• • Growing syndesmophytes and ankylosis seems not to be inhibited by anti TNF therapy some unresolved methodological issues : – historical cohorts are only included – the inability to assess the thoracic spine by standard radiography – the low sensitivity of the currently used modified Stokes AS spinal score scoring – the degree of damage: one (mean) new syndesmophyte developing in the whole spine over two years.

– continuous NSAID therapy may reduce radiographic progression in AS ( placebo group) Baraliakos X, Listing J, Rudwaleit M et al. Progression of radiographic damage in patients with ankylosing spondylitis: defining the central role of syndesmophytes.Ann Rheum Dis 2007;66:910–5.

Baraliakos X, Listing J, Brandt J et al. Radiographic progression in patients with ankylosing spondylitis after 4 yrs of treatment with the anti-TNF-alpha antibody infliximab. Rheumatology 2007;46:1450–3.

van der Heijde D, Landewe ´ R, Braun J et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with infliximab. Arthritis Rheum 2008.

Wanders A, van der Heijde D, Landewe ´ R, et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis.Arthritis Rheum 2005; 52:1756– 1765.

• • •

Link between the presence of inflammation at the vertebral corner on the MRI and sydesmophytes on plain rx

The presence of inflammation is associated with the development of new syndesmophytes The presence of inflammation is associated with the development of new syndesmophytes even when inflammation is suppressed with anti-TNF treatment A new syndesmophyte can occur even when initial RX and MRI are normal Walter P. et al. inflammatory lesions of the spine on MRI predict the development of new syndesmophytes in SA. A&R, 60;1; 2009 pp 93-102

Infliximab lessens cellular infiltration in bone marrow

RA SA

Wnt proteins and Dickkopf-1 (DKK-1)

Diarra D et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007;13:156–63.

DKK (

Dickkopf)

Level in RA and AS

35 30 25 20 15 10 5 0 Healthy * RA ** ** AS * Diarra D, et al. Nature Medicine 2007;13(2):156

Conclusion :

• • TNF blockers indeed do not inhibit syndesmophyte formation in AS.

Data with longer follow-up, with the antibodies against TNF in patients with early disease, will give us the final answer concerning the inhibition of syndesmophyte formation.

Ankylosing Spondylitis Early Pre-radiographic Axial SpA

The Inflixispine Study

Objective: To evaluate the efficacy of IFX in HLA-B27 + pts with MRI-determined early sacroiliitis Patients: HLA B27+, Inflammatory Back Pain (Calin criteria) and MRI determined sacroiliitis  40 pts included, mean age: 28.8 years, 75% male, mean symptom duration: 15.3 months. Protocol: Infliximab 5 mg/kg (n=20) or placebo (n=19/20) infusions at 0, 2, 6 and 12 weeks  FU every 4 wks from wk 16 to wk 40 or time to active disease (BASDAI>4) Pts with active disease  open label IFX infusions after wk 16

Barkham et al.

Arthritis Rheum.

2009; 60(4):946-954

Baseline characteristics Age, mean years % female HLA-B27 positive Disease duration, years mean (range)* or median (

±

SD) % MRI positive % Both HLA-B27 and MRI positive % with IBP BASDAI, mean (range)

InflixiSpine

(n=40) 28.8 (

± 7.6)

25 100

1.3 ( ± 0.73)

100 100 100 5.86 (

±

0.73)

Haibel et al.

Arthritis Rheum

. 2008; 58(7):1981-1991; Barkham et al. ACR 2007. Abstract L11.

HLA-B27

+

Very Early Pre-radiographic AS Treatment with IFX*

Primary endpoint: change in MRI scores from baseline to week 16 IFX (n=20) • All 3 criteria – IBP – HLA-B27 – MRI inflammation of spine or SI joints PBO (n=20) 100 5 0 New sacroiliac MRI lesions P=0.004

1.2% 12% 100 50 Patients with spinal lesions resolved n=9 (pts with spinal lesions at BL) P=0.016

60% 100 0 Sacroiliac MRI lesions resolved P=0.001

62.7% 0 3/5 25% 1/4 * IFX 5mg/kg w0, w2, w6, w12 50 0 47/75 29.4% 20/68 Barkham et al. EULAR 08 FRI0310 Barkham et al. Ghent SpA 08 poster .

Infliximab Therapy in Patients with HLA B27 Positive Very Early Ankylosing Spondylitis Pts treated with PBO or IFX 5 mg/kg at 0, 2, 6 and 12 weeks (RCT), FU from week 16-40. If pts developed active disease (BASDAI>4), they received OL IFX after week 16 Week 16 -0.75

-3.41

*

*p=0.002

Week 16 **p=0.009

56

**

13 Placebo (n=19) Infliximab (n=20) Barkham et al. EULAR 09 OP-0016

Remicade Therapy in Patients with HLA B27 Positive Very Early Ankylosing Spondylitis Pts treated with PBO or IFX 5 mg/kg at 0, 2, 6 and 12 weeks (RCT), FU from week 16-40. If pts developed active disease (BASDAI>4), they received OL IFX after week 16 Remission induction approach works in early AS, (8/20) 40% of the patients are biologic-free Week 16 Week 16 **p=0.009

Number of pts requiring OL IFX *p=0.035 vs PBO -0.75

56

**

Wk 16 Wk 40

*

17/19 -3.41

*

13 12/19 12/20 6/20 *p=0.002

Placebo (n=19) Infliximab (n=20) IFX IFX Short course of IFX



continued suppression of disease activity in early AS pts with sustained benefit in QoL, function and disease activity. 40% of the pts remained in a low disease activity state for 28 weeks off IFX after 4 IFX infusions. Barkham et al. EULAR 09 OP-0016

Clinical Efficacy of IFX in HLA-B27

+

Conclusions Very Early AS:

 Remicade appears to be an effective therapy for very early inflammatory back pain.  This is the first therapy to show suppression of the inflammatory lesions on MRI in very early Ankylosing Spondylitis .  Compared to studies of TNF blockers in established disease, the proportion of patients achieving ASAS partial remission was much higher suggesting a clear benefit for early treatment.

Barkham et al.

Arthritis Rheum.

2009; 60(4):946-954

Ankylosing Spondylitis Long-Term Efficacy

EASIC – C ohort E uropean A nkylosing S pondylitis I nfliximab

• Three abstracts submitted to EULAR 09: EASIC 5 years: – Outcomes (European Ankylosing Spondylitis Infliximab Cohort (EASIC): Outcome of patients who had discontinued infliximab after the end of ASSERT) – Long-Term efficacy (European Ankylosing Spondylitis Infliximab Cohort (EASIC): Long-Term (5 years) Efficacy of Remicade on disease activity and function – A real life experience after the end of ASSERT – Safety (European Ankylosing Spondylitis Infliximab Cohort (EASIC): Safety of long term therapy with Remicade in patients with ankylosing spondylitis (AS)

EASIC – C ohort E uropean A nkylosing S pondylitis I nfliximab

• • Background: insufficient knowledge of long term safety and efficacy of anti TNF therapy in AS EASIC-study: Open label extension of ASSERT

Brandt et al. EULAR 08 FRI0305, ClinicalTrials.gov identifier: NCT00237419

A Randomized, Double-blind Trial of the Efficacy of REMICADE ® (Infliximab) Compared with Placebo in Subjects with Ankylosing Spondylitis Receiving Standard Anti inflammatory Drug Therapy

ASSERT Study Design

Screening Patients (N=357) Assigned to treatment (N=279) Failed Screening (N=78)

3/8 ratio

R A N D O M I Z A I T O N Wk 0 Wk 2 Wk 6 Wk 12 Placebo (N=78) Infliximab 5 mg/kg (N=201) Wk 18 Wk 24 Endpoint Van der Heijde et al., Arthritis & Rheumatism 2005, 52: 582

EASIC – C ohort E uropean A nkylosing S pondylitis I nfliximab

• • • Background: insufficient knowledge of long term safety and efficacy of anti TNF therapy in AS EASIC-study: Open label extension of ASSERT Time course: 2 years ASSERT N=279 Mean: 1,3 + 0.9 yrs 15% did not receive IFX continuously between ASSERT and EASIC 5 years total

96 weeks

EASIC N=103

Brandt et al. EULAR 08 FRI0305, ClinicalTrials.gov identifier: NCT00237419

EASIC – C ohort E uropean A nkylosing S pondylitis I nfliximab Completers at 96 weeks n=4 n=5 n=76 ClinicalTrials.gov identifier: NCT00237419

EASIC – E uropean A nkylosing S pondylitis Outcomes at 96 weeks in Group 1 I nfliximab C ohort:

Group 1A: discontinuation and relapse (n=9)  44% (4/9) patients still on IFX  Mean BASDAI 6.7 + 2.4 start of EASIC  3.5 + 2.4

 Reasons for dropping: • 3/5 = infusions reactions 97 + 22 days after screening • 1/5 = lack of efficacy • 1/5 = lost to FU

Group 1B: discontinuation and remission (n=5)



1/5 remains on remission at week 96



4/5 relapses after 61+ 50 days



1 switched to ADA



3/4 treated with IFX 2/3 dropped out after 89 + 29 days of Tx (1 IR and 1 lack of efficacy) Overall 5 patients in Group 1 completed the study under therapy with IFX, mean BASDAI = 1.8 + 1.3 after 96 weeks. One pt remained in drug-free remission.

Heldmann et al. EULAR 09 SAT0259

EASIC – E uropean A nkylosing Term efficacy in Group 2 S pondylitis I nfliximab C ohort: Long-

Completers Group 2 (n=76/88)

100 10 80 8 BASDAI BASFI BASMI 6 60 4 40 2 20 0 End of ASSERT wk 0 wk 48 wk 96 ASAS 20 ASAS 40 ASAS Partial remission 0 B L A S S E ER nd T o f A S S ER T w k 0 w k 48 w k 96 At the end of EASIC: 78% pts had no arthritis and 85% no enthesitis Heldmann et al. EULAR 09 SAT0258

Long-term efficacy of aTNFs in patients with active Spondyloarthritis

ETN 1 IFX 2 IFX 3 3 yrs

62.3

77.8

Adherence (%) BASDAI 50 (%) ASAS 20 (%) PR (%) 81.0

35.0

63.0

ADA 4 4 yrs

67.3

ETN 1 6 yrs

65.4

IFX 2 8 yrs

53.6

58.0

67.5

81.8

39.4

35.5

67.6

81 35.1

Similar therapy adherence and efficacy data for the TNF blockers

1

Baraliakos et al. EULAR 09 AB0428,

2

Baraliakos et al. EULAR 09 SAT0284,

3

Devinck et al. EULAR 09 SAT0278,

4

van der Heijde et al. EULAR 09 SAT0254.

Belgian Cohort

Long-term efficacy/safety of IFX in patients with active Spondyloarthritis: Results of an 8-Year FU

SpA with active axial and/or peripheral disease were treated with 5 mg/kg IFX q8 (AS: 63 pts; PsA: 36 pts; und. SpA: 10 pts). Dec. 2008: 617 patient-yrs reached. 47 patients had peripheral arthritis at baseline (25 oligo-, 22 polyarticular), mostly were PsA and IBD related SpA

Nr pts Pt global Pt pain ESR CRP Nr AS pts BASDAI BASFI Baseline 107 66 61 20 2,00 63 51 58 Yr 1 101 20 22 10 0,60 59 21 39 Yr 2 90 17 16 10 0,40 53 16 27 Yr 3 90 12 11 8 0,30 49 9 27 Yr 4 77 20 20 9 0,25 41 10 23 Yr 5 61 20 20 7 0,20 30 13 27 Yr 6 49 20 20 7 0,30 23 12 21 Yr 7 32 30 25 9 0,20 11 22 39 Yr 8 11 20 25 6 8 5 0,20 20

All patients reached the 6 yrs evaluation A highly significant improvement in all disease manifestations was maintained over a FU period up to 8 years. No new safety signals.

Devinck et al. EULAR 09 SAT0278

Long-Term Sustained Clinical Response of Infliximab Therapy in AS

7 Completer analysis 6 5 BASDAI BASFI BASMI 4 3 2 1 0 0 12 24 54 IFX proved to be safe and efficacious over 8 years

Baraliakos et al. EULAR 09 SAT0284

78 102 weeks 132 156 182 206 230 254 Braun et al. Ann Rheum Dis. 2008;67(3):340-345

Patients in Partial Remission after 5 years of Treatment with Remicade

70 60 50 40 30 20 10 Completer analysis 0 0 12 24 54 78 102 132 156 182 206 230 254 weeks 35.1 % of patients in partial remission at 8 years!

Baraliakos et al. EULAR 09 SAT0284

Braun et al. Ann Rheum Dis. 2008;67(3):340-345

Psoriatic Arthritis Efficacy of Treatment in Early Polyarticular PsA

RE micade S tudy in P soriatic arthritis patients O f methotrexate N aïve D isease: The RESPOND Study Study design: Randomized, prospective, open-label, multi-center, multi-national study Inclusion criteria:

•

Patients >18 years of age

• • •

Diagnosis of Psoriatic Arthritis with peripheral polyarticular involvement Disease duration



Active PsA = ≥5 swollen and tender joints, + one of the following:



3 months prior to screening. ESR≥28 mm/hr, CRP≥15 mg/L or morning stiffness≥45 min

•

Pts naïve to MTX, anti-TNF agents, and could not be on DMARDS IFX 5 mg/kg; wk 0, 2, 6, 14 + MTX 15 mg/week n=57 PE: ACR 20 at wk 16 PsA pts, naïve to MTX and anti-TNFs n=115 Week 0 2 MTX 15 mg/week 6 n=58 14 16 Study visits Nasonov et al. EULAR 09 OP0196

RESPOND

IFX Plus MTX Significantly Improves Synovitis and Psoriatic Lesions in MTX-naïve PsA Patients

Randomized, prospective, open-label, 16 week (ITT analysis) 100 75 50 25 0 p<0.05

ACR20 p<0.01

ACR50 75 p<0.01

50 ACR70 100 25 0 p<0.0001

100 75 50 Good Response Moderate Response DAS28 Remission 25 0 p<0.01

PASI50* Outcomes at week 16: PE (ACR 20) is met and significant improvement in other endpoints, IFX + MTX vs. MTX alone p<0.0001

p<0.01

PASI75* PASI90* IFX + MTX MTX Early MTX naïve PsA patients with active disease achieved significantly greater ACR response rated and improvement in PASI scores when treated with IFX+MTX compared to MTX alone Nasonov et al. EULAR 09 OP0196

RESPOND

MTX-naïve PsA Patients Respond Rapidly to IFX+MTX Therapy

Randomized, prospective, open-label, 16 week (ITT analysis) 6 weeks p<0.0001

100 100 PASI 75* p<0.0001

75 50 p<0.0001

75 50 p=0.003

IFX + MTX MTX *Pts with BL PASI



2.5

25 p=0.0042

25 0 0 ACR50 ACR70 0 2 4 6 8 10 12 14 16 18 Weeks Outcomes at week 6: IFX + MTX treated pts attain a response significantly more rapid then MTX alone treated pts A significantly greater proportion of MTX naïve PsA patients – when treated with IFX+MTX – attain an early response to treatment in terms of arthritic and psoriatic signs and symptoms compared to MTX alone Nasonov et al. EULAR 09 SAT0353

Psoriatic Arthritis Efficacy

The Best Biologic for Pso and PsA - UST (

ustekinumab)

90 mg shows superior efficacy compared to all biologics except Remicade

Meta-analysis of 25 RCTs (n=9889 pts, mean age 44.1 yrs) 10 8 6 4 2 0 8.19

OR for PASI 75 vs UST 90 mg at wks 0 and 4 5.99

2.45

1.31

No superiority For PsARC Remicade better than ADA (OR 1.51) with no stat. difference between ADA, ETN, EFA, ALE EFA 1mg/kg QW ETA 50mg QW ADA 40mg EOW UST 45mg w 0, 4 IFX 5mg/kg Q8

•

PsO: UST 90mg is superior to all biologics except Remicade

•

PsA: Remicade is the best biologic

•

Toxicity and safety profiles of all biologics are comparable Mak et al. EULAR 09 SAT0345

Summary

Ankylosing Spondylitis •Short course IFX – Biologic-free remission induction in early axial AS • EASIC – long-term data • 8 years long-term data: q8 (Belgian cohort) • 8 years long-term data: q6 (Braun) Psoriatic Arthritis •2 abstracts on RESPOND - MTX-naïve PsA • Best biologic of choice

Agenda

• • • • Spondyloarthropathies Early Rheumatoid Arthritis Established Rheumatoid Arthritis Benefit - Risk

BeSt Comparison of Four Treatment Strategies

Initial MTX 1. Sequential monotherapy 2. Step-up combination therapy Initial Combo 3. Initial combination with high prednisone 4. Initial combination with infliximab

Treatment Strategies in the BeSt Study

Group 1

MTX

Group 2

MTX

Group 3

MTX + SSZ + PRED

Group 4

MTX + Infliximab SSZ LEF MTX + Infliximab MTX + SSZ MTX + SSZ + HCQ MTX + CSA + PRED MTX + Infliximab MTX + SSZ + HCQ + PRED SSZ LEF MTX + CSA + PRED MTX + Infliximab Goekoop-Ruiterman et al, 2005 Arthritis Rheum 52: 3381-90

Treatment Strategies in the BeSt Study

2 to 3-monthly treatment adjustments based on DAS 44 scores:

 DAS 44 >2.4  DAS 44 < 2.4  next step  continue therapy

Taper/Discontinuation



Restart:

 DAS 44 < 2.4 for ≥6 months medication  Taper to maintenance dose  DAS was ≤1.6 for ≥6 months after 2 yrs  Discontinuation last DMARD  DAS increased to ≥1.6  Restart with last DMARD

Goekoop-Ruiterman YPM et al., Arthritis Rheum 2005;52(11):3381-3390

BeSt 5 Year Results: Remission**

100% 80% 60% 40% *p<0.001 Gr 4 vs Gr 1&2 39% 46% 65% * 81% 20% 0% Group 1 Group 2 Group 3 Group 4 DAS<1.6** ** Includes ALL patients in remission (on drugs and off IFX and DMARDs) Achieved with initial treatment step “With DAS-steered, tight controlled treatment, 48% of all patients achieved biologic free remission”

100% Pts on IFX+ MTX after at least 3 DMARDS 50%

21% 5% 11%

0% Group 1 Group 2 Group 3 Klarenbeek et al. EULAR 08 THU0162

Sustained benefit of initial combination therapy in the amount of joint damage after 5 years Median Change in vdH-S Score after 5 years of FU 1 and 2 vs 4 p<0.01

16 14 12 10 14 11 8 6 4 2 7.6

6 0 Median change 3.5 2.5 1.0 1.0 Seq. Monotherapy Step-up Modified COBRA IFX + MTX Even a short period of early better suppression of disease activity still defines the amount of joint damage 5 yrs later Klarenbeek N. et al. EULAR 09 SAT0013

Agenda

• • • • Spondyloarthropathies Early Rheumatoid Arthritis Established Rheumatoid Arthritis Benefit - Risk

Remission induction with Remicade: First report on biologic-free remission in established RA

100 RA pts with DAS28<3.2 for 6 months discontinued Remicade 35 27 Relapsed after 7 mo, Back to IFX, Disease duration 6.3 years Off IFX for >1 year, Disease duration 2.5

years Off IFX for 7-12 mo 38

~40% pts could stop IFX therapy for > 1 year without progression of structural damage Y. Tanaka et al. EULAR 09 OP-0150

7 Year FU of Remicade in RA pts refractory to multiple DMARDs treatment: attrition and long-term effect 10 9 7 8

BL

6 5.7

45.5% achieved DAS28 remission 5 2 3 4 3.0

3.0

1.07

Pts treated with IFX for 7 yrs experienced sustained clinical benefit - maintenance of low DAS and HAQ scores. Long term treatment with IFX is safe as most safety issues occurred during the first 2 years of IFX treatment and reveals no unexpected safety risks.

1

DAS 28

0 Vander Cruyssen et al. Arthritis Res Ther. 2006;8(4):R112; Vander Cruyssen et al. EULAR 09 THU0181 DAS28 Mean HAQ

RAISE survey

Agenda

• • • • Spondyloarthropathies Early Rheumatoid Arthritis Established Rheumatoid Arthritis Benefit - Risk

TNF



Inhibitors: EU Summary of Product Characteristics

Contraindications , Warnings and Precautions of TNFα inhibitors Infusion / injection reactions 

/



Hypersensitivity/ allergy

Infections

, TB*, Sepsis Malignancies/ Lymphoma Congestive Heart failure* (NYHA class III/IV) Autoimmune processes/ auto-antibodies Neurological events Haematologic reactions † Hepatobiliary event

  Caution     

† * contraindicated for adalimumab and infliximab, special warning for etanercept special warning for adalimumab and etanercept EMEA Product specific SPCs 2008.

Registry

British Society of Rheumatology (BSR) Registry: Serious Infections with anti-TNF Agents Using Different Models

Treatment period Different models used, including varying lengths of follow up time Active treatment Follow-up period Model 1 st 90 days Receiving of Tx duration of Tx + 90 days Ever treated time Adjusted incidence rate of Serious infections of anti-TNFs vs. DMARDS using various models. OR (95% CI) 1 st 90 days of treatment ever treated Duration of treatment +90 days currently receiving treatment 0.1

1 DMARDS 10 100 Dixon WG, et al.

Arthritis Rheum

2007;56:2896-2904.

Algorithm for TB Testing: European-Based Recommendations

New patient office visit Administer appropriate TB screening test (PPD skin test + CXR + family history) Test negative Initiate therapy PPD test positive and normal CXR Initiate latent TB treatment PPD test positive and active TB Treat active TB to resolution Initiate therapy Initiate therapy Adapted from Arend SM et al. Netherlands J Med. 2003;61:111-119.

Remicade Benefit:Risk - Conclusions

• • • Remicade, with 7 approved indications, is the most widely used TNF  inhibitor – More than 15 years of safety data collected in clinical trials – Estimated exposure since commercial launch on 24 August 1998 • • >1.1 million patients >4.2 million patient-years since first exposure Remicade is effective in patients with inflammatory diseases who have failed conventional therapies in RA, AS, PsA, Pso, CD, Ped CD, and UC When given to appropriately selected patients, Remicade’s benefit-risk profile continues to be favorable

Data on file, Centocor (

PSUR 18

, October 2008).