RA Disease Management. Schematic Representation of the Course of RA Over 30 Years Inflammation Disability Radiographic Scores Kirwan J. J Rheumatol. 1999;26:720-5

RA Disease ManagementRA Disease Management

Schematic Representation of Schematic Representation of the the

Course of RA Over 30 YearsCourse of RA Over 30 Years

0 5 10 15 20 25 30

Disease duration (years)

Se

ve

rity

(A

rbit

rary

Un

its

)

Inflammation

Disability

Radiographic Scores

Kirwan J. J Rheumatol. 1999;26:720-5.

Current RA Treatment Strategy for 2009

DMARD (Step-up/triple therapy)MTX

SSZ

Biologic 1

Anti-TNFEtanercept

Infliximab

Adalimumab

Biologic 2Rituximab

Abatacept

DA

S28 d

riven

Goals of TherapyGoals of Therapy

ACR Goals of Therapy in RAACR Goals of Therapy in RA

Symptom relief

Improvement in physical function

Reduce physical disability

Slowing/arresting progression of structural damage

Guidelines for the Management of RA. Arthritis Rheum. 1996; 39:713-22.

Key Principles of RA Key Principles of RA ManagementManagement

Detect and refer early

Treat immediately

Tailor treatment to the individual

Control inflammation:

The fundamental concept of RA treatment

Progress in management of Progress in management of RA in recent yearsRA in recent years

DrugsDrugs ObjectivesObjectives ConceptsConcepts

19851985 MTX/SSZMTX/SSZ Signs & Signs & symptomssymptoms

19951995 CombinationCombination

LeflunomideLeflunomide joint damagejoint damage

20002000 TNF blockersTNF blockers Stop joint Stop joint damagedamage

Early treatmentEarly treatment

Prevent joint Prevent joint damagedamage

Tight controlTight control

Early intensive Early intensive tttttt

20082008 RemissionRemission

Traditional ApproachTraditional Approach

Traditional TherapiesTraditional Therapies

Wilske and Haeley. J Rheumatol 1989

Exp methods

MTX, axathioprine

Penicillamine, gold, hydroxychloroquine

Physcial medicine, rehabilitation

Salicylates, NSAIDs

Patient education, rest, application of heat or cold

Surgery

Glu

coco

rtic

oid

(sys

tem

ic o

r int

ra-a

rtic

ular

)

Treatment of RA With DMARDs

Traditional DMARDs1

• MTX• Hydroxychloroquine• Sulfasalazine• Leflunomide

“Biologics DMARDs”2-5

• Etanercept• Infliximab• Adalimumab• Anakinra• Abatacept• Rituximab

Combination Treatment2

1. 1. ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46:328-346. 2. Combe B, et al. Ann Rheum Dis. 2007;66:34-45. 3. Kineret® (anakinra) Prescribing Information, Amgen Corporation. Thousand Oaks, Calif. 4. Orencia® (abatacept) Prescribing Information, Bristol-Myers Squibb Company, Princeton, NJ. 5. Rituxan® (rituximab) Prescribing Information, Genentech, Inc., South San Francisco, Calif.

Methotrexate PersistenceMethotrexate Persistence

Kaplan-Meier survival estimates of DMARD usage

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8 10 12 Time (years)

Sulphasalazine Other

Hydroxychloroquine

Methotrexate Penicilamine

Gold

Pro

po

rtio

n o

n D

MA

RD

CJ Edwards et al, Rheumatology, 2005, 44 (11):1394-8

The Famous Combination The Famous Combination StudiesStudies

ARC low dose glucocorticoid study group trial

Methotrexate-Cyclosporin combination study

RAIN study of Methotrexate + SSP + HCQ: (triple therapy)

COBRA study: SSP + MTX + Prednisolone or SSP alone

Fin-RACo Trial: SSP+MTX+HCQ+Prednisolone vs single drug +/- Prednisolone

Best Use of MTXBest Use of MTX

Best Use of DMARDs: EarlyBest Use of DMARDs: Early

0

2

4

6

8

10

12

14

0 6 12 18 24

Time (months)

Med

ian

Sh

arp

Sco

re

Lard LR et al. Am J Med. 2001;111:446-451.

Delayed treatment(median treatment lag time, 123 days; n=109)

Early treatment(median treatment lag time, 15 days; n=97)

*

*P<0.05 vs delayed-treatment group.

Even Earlier: PROMPT Even Earlier: PROMPT StudyStudy

PROMPT study

Prospective, double-blind, n=110 with UA

MTX 15mg/wk vs placebo (if became ACR

positive changed to MTX)

Dose adjusted 3 monthly by DAS

12/12 study medication tapered to nil

Followed for 30/12

van Dongen et al, Arthritis Rheum. 2007 May;56(5):1424-32.

PROMPT– Results after 18 months

RemissionUndifferentiated

arthritis & other diagnosis

ACR-criteria

RA, treated with MTX

Placebo

21 259

MTX 15 mg/wk

2019 16

OR 0.38

P = 0.05

n=110

Best Use of DMARDs: Best Use of DMARDs: Protocol DrivenProtocol Driven

TICORA Study of Intensive vs TICORA Study of Intensive vs Routine Treatment: DAS ScoresRoutine Treatment: DAS Scores

*P < 0.001

** *

** *

0

1

2

3

4

5

6

0 3 6 9 12 15 18

Months

Mea

n D

AS

sco

re

Routine

Intensive

Grigor C, et al. Lancet. 2004;364:263-269

* P<0.02, ** P<0.002, Mann-Whitney

Radiographic Radiographic Progression:Progression:

0 and 18 Months0 and 18 Months

3

4.5

8.5

0.5

3.25

4.5

0

1

2

3

4

5

6

7

8

9

Erosion score Narrowing score Total Sharp score

Routine Intensive

**

*

Grigor C et al. Lancet 2004; 364: 263

Median change in erosion, joint space narrowing and total Sharp score

Key Anti-TNF TrialsKey Anti-TNF Trials

Late

ARMADA Adalimumab

ATTRACT Infliximab

TEMPO Etanercept

Early

ASPIRE Infliximab

ERA Etanercept

PREMIER Adalimumab

TEMPO TrialTEMPO Trial

Klareskog et al. Lancet 2004; 363: 675-81

ENBREL (n=223)

MTX (n=228)

Randomized(N=686)

ITT Population (N=682)

Failure on 1 DMARD

No recent MTX

ACR-N24 Weeks

Total Sharp Score52 Weeks

EndpointsBaseline

Enbrel® (etanercept) + MTX (n=231)

– Withdrawals: MTX, 30%; ENBREL, 24%; ENBREL + MTX, 16%

-1

0

1

2

3

4

5

6

7

Ch

an

ge f

rom

Baseli

ne (

mean

+ S

E)

MTX (n=210)

Etanercept (n=211)

MTX + Etanercept (n=213)

Primary Radiographic Endpoint: Primary Radiographic Endpoint: Change in TSS From Baseline - Change in TSS From Baseline -

Year 3Year 3

* * P P < 0.05, Etanercept vs MTX< 0.05, Etanercept vs MTX† † P P < 0.05, combination vs MTX < 0.05, combination vs MTX ‡ ‡ P P < 0.05, combination vs Etanercept< 0.05, combination vs Etanercept

5.95 5.95 (CI 2.96(CI 2.96, 8.94), 8.94)

1.61* 1.61* (CI 0.41, 2.81)(CI 0.41, 2.81)

-0.14-0.14†‡†‡ (CI –1.07, 0.78)(CI –1.07, 0.78)

van der Heijde D, et al. ACR 2005, Abstract L10.van der Heijde D, et al. ACR 2005, Abstract L10.

No Radiographic No Radiographic ProgressionProgression

50.5

61.1

76

40

50

60

70

80

90

100

TSS ≤ 0.5 at 156 Weeks

% o

f P

atie

nts

MTX

Etanercept

MTX + Etanercept

Long-term Safety & EfficacyLong-term Safety & EfficacyTEMPO Trial - Year 3 ResultsTEMPO Trial - Year 3 Results


When to use anti-TNF?When to use anti-TNF?

Straight away

After DMARD failure

• DAS28 >5.1 or less

Late

Macrophage or activated T-cell

Soluble TNF

Target Cell

TNFReceptor

Signal Induction

Synthesis and Function of TNF

TransmembraneTNF

Receptor-bound TNF

Predicting PrognosisPredicting Prognosis

Predicting prognosisPredicting prognosis

Severity marker Prognostic factor

Erosions Smoking, HLA DRB1, HAQ, XR damage, RF & anti-CCP, ESR & CRP

Disability HAQ, female, many joints, nodules, RF, >64yrs

Mortality HLA DRB1, HAQ, RF & anti-CCP

1. J Morel & B Combe, Best Pract Res Clin Rheumatol, 2005, 19:137-146

2. D Symmons & A Silman, Arthritis Res Therapy, 2006, 8: 214

Gene expression profiling of PBMCs from RA patients

PBMCs from RA

330 differentially expressed genes TNF receptor (p75)

RANTES

NFB

RAGE

Edwards CJ et al. Mol Med 2007 13:40-58

Gene expression predicting anti-TNF responders ?

Changes to gene expression profiles in infliximab responders vs non-responders 18 RA patients, infliximab 3mg/kg

PBMCs 0, 2, 14, 22 wks

Inflammatory genes decreased at 2 weeks and remained low in responders

Early gene expression changes predicting clinical response to etanercept 19 RA patients, etanercept 50mg/wk

PBMCs 0, 72 hrs

Early down-regulation predicted response at 3 months

– NFKBIA, CCL4, IL8, IL1B, TNFAIP3, PDE4B, PPP1R15A and ADM

1. Sekiguchi et al, Rheumatology, 2008, 47, 780-788; 2. Koczan et al, Arth Res & Ther, 2008, 10, R50

For early aggressive For early aggressive treatment we need the treatment we need the

followingfollowing

Early referal

Reliable diagnosis

Effective & safe therapies

Prognostic predictors

Disease activity measures

Decrease disease

activity & prevent

joint damage

Key MessagesKey Messages

Set clear disease activity targetsTICORA

TEAR

CAMERA

Earlier treatmentPROMPT

COMET

Therapeutic memoryBeST

B cell targeting

Key MessagesKey Messages

Predict prognosis

Collateral damage outcomes

Definition of RemissionDefinition of Remission

Clinical Remission

ACR/DAS criteria, or normal acute phase response, no clinical synovitis

Imaging Remission

No radiographic damage progression

No significant synovitis on sensitive imaging

True Remission

A state of low disease activity with no progression of structural damage

Clinical Remission by Clinical Remission by DAS28DAS28

Based on VAS of 100mmPrevoo MLL et al. Arthritis Rheum 1995;38:44-8. van Gestel AM et al. J Rheumatol 1999;26:705-11.

DAS28 Score

5.1

3.22.6

Severe

Moderate

Low

Remission

Disease Activity

DAS28 <2.6

Remission in RARemission in RA

Importance of Structural Damage

Determinants of Structural Damage

Interrelationship synovitis and damage

Remission Clinical and Imaging

Impact of DMARDs

Effect of TNF antagonists

Effect of anti-inflammatory Effect of anti-inflammatory therapy on BMDtherapy on BMD

Corticosteroids are associated with bone loss

RCT prednisolone 7.5 mg vs placebo in patients with early RA (< 2years disease duration) with a radiographic endpoint1

Examinations of the radiographs (95 patients) with DXR to study 2-year changes in hand bone density2

1. Kirwan et al N Engl J Med 1995;333:142-6.

2. Haugeberg et al. Arch Intern Med 2005;165:1293-1297.

Does anti-inflammatory Does anti-inflammatory treatment reduce treatment reduce

atherosclerosis / CVD?atherosclerosis / CVD?

Non-naproxen NSAIDs increase risk of thrombotic CV events

Anti-TNF drugs may reduce atherosclerosis

DMARDs and anti-TNF drugs seem to reduce CVD / CV mortality

McCarey DW et al. Lancet 2004;363:2015-2021

The effect of statin therapy in RAThe effect of statin therapy in RA

Atorvastatin Atorvastatin (n=58)(n=58)

Placebo (n=58)Placebo (n=58) PP

Primary outcome measurePrimary outcome measure

Disease activity scoreDisease activity score -0.50-0.50 0.030.03 0.0040.004

Secondary outcome measuresSecondary outcome measures

Erythrocyte sedimentation rate (mm/h)Erythrocyte sedimentation rate (mm/h) -5.03-5.03 1.911.91 0.0050.005

C-reactive protein (log mg/L)C-reactive protein (log mg/L) -0.46-0.46 0.120.12 <0.0001<0.0001

LDL-cholesterol (mmol/L)LDL-cholesterol (mmol/L) -1.40-1.40 0.070.07 <0.0001<0.0001

HDL-cholesterol (mmol/L)HDL-cholesterol (mmol/L) 0.030.03 -0.04-0.04 0.0970.097

Intercellualar adhesion molecule1 (ng/mL)Intercellualar adhesion molecule1 (ng/mL) -22.6-22.6 2.372.37 0.0760.076

Interleukin 6 (pg/mL)Interleukin 6 (pg/mL) -6.6-6.6 3.843.84 0.0280.028

Choi HY et al. Lancet 2002;359:1173-1177

ICD-9 codeICD-9 code DeathsDeaths Hazard ratio Hazard ratio (95% CI)(95% CI)

All-cause All-cause mortalitymortality

AllAll 191191 0.4 (0.2-0.8)0.4 (0.2-0.8)

CV mortalityCV mortality 390-449390-449 8484 0.3 (0.2-0.7)0.3 (0.2-0.7)

Non-CV mortalityNon-CV mortality <390 or >449<390 or >449 107107 0.6 (0.2-1.2)0.6 (0.2-1.2)

Effect of methotrexate on Effect of methotrexate on mortality in RAmortality in RA

Tools

Optimized MTX

Combination therapy

Anti-TNF therapy

Processes

Early treatment

– Avoid treatment delay

– Take advantage of “window of opportunity”

Patient monitoring

– DAS

New Therapeutic New Therapeutic Possibilities for RA – Possibilities for RA –

Remission is a Realistic GoalRemission is a Realistic Goal

Cumulative Probability Plot of Cumulative Probability Plot of Radiographic ProgressionRadiographic Progression

-10

0

10

20

30

40

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Cumulative Probability

Chan

ge in T

SS

Unchanged

Lower Score

Moderate Progression

Why Is Structural Damage Why Is Structural Damage Important?Important?

Cummulative measure, reflects disease control

Surrogate marker for long-term outcome (physical function, employment)

In cohorts ~ stable disease activity

– Very slow increase in HAQ score

– Constant progression in structural damage

Relationship Between X-ray Relationship Between X-ray Progression and Physical Progression and Physical Function - TEMPO TrialFunction - TEMPO Trial

X-ray progression and HAQ scores were determined at baseline, Year 1 and Year 2

After adjustment for co-variates, Sharp-score was a statistically significant determinant of HAQ-score (p<0.0001)

Progression of radiographic damage over a relatively short period of time leads to deterioration of physical function

van der Heijde D, et al. Abstract 1456, ACR 2005.

Negative Zero Mild Severe

Progression

Cumulative Probability Plot of Cumulative Probability Plot of Radiographic Outcome Radiographic Outcome

-10

0

10

20

30

40

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Cumulative Probability

Chan

ge in T

SS

Unchanged

Lower Score

Moderate Progressors

Rapid ProgressionRapid Progressors

TEMPO Trial - Year 3 Results

ACR ResponseACR Response

* * PP<0.05, etanercept vs. MTX<0.05, etanercept vs. MTX† † PP<0.05 combination vs. MTX<0.05 combination vs. MTX

‡ ‡ PP<0.05 combination vs. etanercept<0.05 combination vs. etanercept

71

42

21

75

54*

27

86 † ‡

71 † ‡

49† ‡

0

10

20

30

40

50

60

70

80

90

ACR20 ACR50 ACR70

Per

cent

of

Pat

ient

s

MTX (n=228)Etanercept (n=223)Etanercept + MTX (n=231)


Radiological Damage in RA Radiological Damage in RA Patients on Sustained Remission Patients on Sustained Remission

GrGréégory Cgory C, et al. Abstract 346, ACR 2006., et al. Abstract 346, ACR 2006.

? is their radiological progression over 5-years in recent RA patients with persistent remission (Between Y3 and Y5)

191 RA patients <1 year on SSZ, MTX or Both

Available patients: 134

30 (22.4%) Remission with DAS44 <1.6 at 3 and 5 years

6 (20%) patients had radiographic progression or new erosions between Y3 and Y5

-2

0

2

4

6

Cumulative Probability (%)

Ch

ang

e In

To

tal X

R S

core

AllAsymptomatic

20 40 60 80 100

X-ray X-ray ProgressionProgression in in Symptomatic and Symptomatic and

Asymptomatic JointsAsymptomatic Joints

Brown A et al. Arthritis Rheum 2008; in press.

Welsing et al. Arthritis Rheum 2004;50:2082-93

* RF Positive Patients

Const. Low DAS Fluct. Low DAS Fluct. High DAS Const. High DAS

Baseline TSS = 20

0

20

40

60

80

100

120

140

160

0 3 6 9

Time (Yrs)

Sh

arp

Sco

re

Baseline TSS = 0

0

20

40

60

80

100

120

140

0 3 6 9

Time (Yrs)

Sh

arp

Sco

re

Control of Structural Damage is Greatest Control of Structural Damage is Greatest with Continuous Control of Disease with Continuous Control of Disease

Activity*Activity*

Landewé R et al. Abstract 867, ACR 2005.Landewé R et al. Abstract 867, ACR 2005.

TEMPO trial - Disconnect between TEMPO trial - Disconnect between Disease Activity Radiographic Disease Activity Radiographic

ProgressionProgression

Change in Sharp Score by Treatment Group StratifiedFor Subcategories of ta-CRP*

* Time-averaged CRP

Disconnect Between Disease Disconnect Between Disease Activity and Radiographic Activity and Radiographic


Change in Sharp Score by Treatment Group Stratified for Subcategories of ta-DAS*

* Time-averaged DAS

Landewé R et al. Abstract 867, ACR 2005.Landewé R et al. Abstract 867, ACR 2005.

Remission on DMARDsRemission on DMARDs

DMARDs frequently produce clinical remission

DMARDs rarely produce imaging remission

Hence DMARDs rarely produce true remission

Explains progression of damage in patients in clinical remission on DMARDs?

What happens with TNF antagonists?

BeSt Trial - BeSt Trial - Disposition of Disposition of patients in the anti-TNF arm:patients in the anti-TNF arm:

120 enrolled

8 stopped for side effects

22 did not achieve response

13 continued

77 stopped because they achieved a DAS44 <2.4

– 46 were on 3mg/kg

– 22 on 6 mg/kg

– 6 on 7.5 mg/kg

– 3 on 10 mg/kgVan der Bijl AE, et al. ACR 2005, Abstract 876.

Induction of remission in Induction of remission in patients with ERA treated with patients with ERA treated with

anti-TNF – BeSt Trialanti-TNF – BeSt Trial

Outcome at 3 Years

67 MTX mono

23 combination

30 next steps

18 no DMARD

46 MTX mono

21 combination

31 next steps

4 lost to FU

Van der Kooij. Abstract 1306, ACR 2006.

QUEST – RA studyQUEST – RA studyMarch 2008March 2008

4,363 pts from 48 sites in 15 countries

Clinical assessment by rheumatologist and self reported questionnaire by patients

Co-morbidites recorded

MI, angina, coronary disease, coronary bypass surgery, stroke

Risk factors recorded

Hypertension, hyperlipidemia, DM, smoking, physical activity, BMI

Naranjo A, et al. Arthritis Res Ther 2008; 10: R30

Quest RA Study – effects of Quest RA Study – effects of therapy on risk of CV therapy on risk of CV

morbiditymorbidity

Agent H.R. 95% CI

Methotrexate 0.85 0.81 to 0.89

Leflunomide 0.59 0.43 to 0.79

Sulfasalasine 0.92 0.87 to 0.98

Glucocorticoids 0.95 0.92 to 0.98

Biologic agents 0.42 0.21 to 0.81 (P<0.05)

Naranjo A, et al. Arthritis Res Ther 2008; 10: R30

Does good clinical Does good clinical control translate control translate

into NO into NO radiographic radiographic progression?progression?

Predictors of Predictors of radiographic radiographic

progression in early progression in early RA patients treated RA patients treated

with MTXwith MTX

CRP Change And Radiographic CRP Change And Radiographic Progression - PREMIER TrialProgression - PREMIER Trial

55%

35%

84%

0%

20%

40%

60%

80%

100%

All Patients

Always NormalAbnormal to NormalAlways Abnormal

CRP Levels:

% w

ith

No

Rad

iog

rap

hic

Pro

gre

ssio

n

van der Heijde DF, et al. Ann Rheum Dis 2005;64(Suppl III):436-7 (SAT0085)

86%

68%

53%

33%

54%

31% 33%

75%

91%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Combination Adalimumab MTX

Always Normal

Abnormal to Normal

Always Abnormal

CRP Levels:

% w

ith

No

Rad

iog

rap

hic

Pro

gre

ssio

n

van der Heijde DF, et al. Ann Rheum Dis 2005;64(Suppl III):436-7 (SAT0085)

CRP Change And Radiographic CRP Change And Radiographic Progression - PREMIER TrialProgression - PREMIER Trial

TICORA Study of Intensive vs TICORA Study of Intensive vs Routine Treatment: DAS ScoresRoutine Treatment: DAS Scores

*P < 0.001

** *

** *

0

1

2

3

4

5

6

0 3 6 9 12 15 18

Months

Mea

n D

AS

sco

re

Routine

Intensive


Clinical Results at 18 MonthsClinical Results at 18 Months

P<0.0001-3.5-1.9Mean Fall in DAS

P<0.000184%40%ACR50

9.3

-0.97

-30

71%

65%

82%

Intensive Care (n=50)

P=0.021

P=0.0025

P=0.09

P<0.0001

P<0.0001

P<0.0001

P-value

4.0SF12 Physical Summary Score

-0.47Change in HAQ

-14Change in CRP (mg/dL)

18%ACR70

16%EULAR Remission

44%EULAR Good Response (DAS ≤2.4 and fall of 1.2 from baseline)

Routine Care(n=53)

Aim for a Target –TICORA Trial


* P<0.02, ** P<0.002, Mann-Whitney

Radiographic Radiographic Progression: 0 and 18 Progression: 0 and 18

MonthsMonths

3

4.5

8.5

0.5

3.25

4.5

0

1

2

3

4

5

6

7

8

9

Erosion score Narrowing score Total Sharp score

Routine Intensive

**

*

Median change in erosion, joint space narrowing and total Sharp score

Grigor C, et al. Lancet. 2004;364:263

Early RA:

Early DMARD therapy

MTX dose 15-20 mg/week

(within 1-2 months)

+ glucocorticoid

Cobra?

Long-standing RA:

If previosuly inadequate dose:

Optimize DMARD (MTX) dose

+ glucocorticoid

DAS28 improvement >1.2 or

HAQ improvement >0.5

within 3-4 months

Smolen, Sokka, Pincus, Breedveld, Clin Exp Rheumatol 2003

Switch to another DMARD

+ glucocorticoid

Add a biologic agent (eg, TNF- antagonist)

or

NO

Add another DMARD

+ glucocorticoid

Add a biologic agent (eg,TNF- antagonist)

or

NO

SDAI <3.3 or

DAS28 < 2.4 or

HAQ <0.5

within 4 months by adjusting dosages

X-rays

YES Continue

DMARD therapy, lower corticosteroids

YES

Algorithm for Achieving Therapeutic Success in RA

Predictors of radiographic progression Predictors of radiographic progression of patients treated with MTX in the of patients treated with MTX in the

ASPIRE trial ASPIRE trial

Baseline CRP

Baseline ESR

Week 14 DAS

Mean CRP over 52 weeks

Mean ESR over 52 weeks

Smolen J et al. Arthritis Rheum 2006;54:702

Treatment Goals for RA Treatment Goals for RA TodayToday

TREAT EARLY

Any delay impacts on outcomes

TREAT OPTIMALLY

Combination of traditional DMARDS

TARGET CLINICAL REMISSION

Targeted outcomes / Tight control

EARLY USE OF BIOLOGICS

DAS28 after 14wks of MTX Tx DAS28 after 14wks of MTX Tx Predicts Rapid Radiographic Predicts Rapid Radiographic


2.02.5

6.0

-

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

Sh

arp

Sco

re P

rog

ress

ion

at

Wee

k 52

DAS <2.84

DAS > 2.84 and < 4.02

DAS >4.02

If a ERA subject continues to have a DAS28 score > 4 after 14 weeks of MTX 20mg the subject can expect to experience rapid radiographic

progression.Smolen J et al. Arthritis Rheum 2006;54:702

What Factors Will Predict What Factors Will Predict Persitemt and Erosive RA?Persitemt and Erosive RA?

Visser et al, Arth Rheum, Feb 2002

Patients were startified according to:

CRP levels: < 5 mg/L ; 5-15; > 15

DAS44:

– <1.6 (remission) /1.6-2.4 (Low disease activity)

– 2.4-3.7 (moderate diseaseactivity)

– >3.7 (high disease activity)

Results:

In the MTX group only the High CRP and High DAS progress

In the MTX + ETN no progresson regardless of CRP level and disease activity

Landewé R et al. ACR 2005, Abstract 867.

TEMPO trial - Disconnect between Disease TEMPO trial - Disconnect between Disease Activity / Inflammation and Radiographic Activity / Inflammation and Radiographic

Progression (2 year data)Progression (2 year data)

34

7

12

8

0

43

0

41

3

5

7

6

5

3

3

0

2

4

6

8

10

12

14

16

18

0 1 2 3 4 5 6 7 8Total no. of joints with US synovitis

Brown, Arthritis Rheum 2006; 54: 3761

Pat

ien

ts (

n)

Patients NOTsatisfying ACRRemission Criteria (n)Patientssatisfying ACRRemission Criteria (n)

Clinical Remission on DMARDs in 100 RA Clinical Remission on DMARDs in 100 RA patients: patients:

# of Patients with US Synovitis # of Patients with US Synovitis (ACR Remission (ACR Remission vsvs non ACR Remission) non ACR Remission)

Combe B, et al: Arthritis Rheum. 2001;44:1736-1743.

• Conclusion: early destruction, high ESR, IgM RF positivity and DR type predict destruction during 3 years of disease

Odds ratio 95% CI

Erosion score 5.12 2.17–12.1

IgM RF positivity 3.88 1.41–10.6

ESR >33 3.44 1.39-8.5

DRB1*04+ 2.88 1.18–7.0

Stepwise Logistic Regression Analysis of Stepwise Logistic Regression Analysis of Predictive Factors of Radiographic Predictive Factors of Radiographic


Treatment Strategies in Treatment Strategies in Early RAEarly RA

SequentialMONO-Therapy

STEP-UPTherapy

Initial COMBOTherapy

Initial BIOLOGICTherapy

MTX MTX MTX+ SSZ + PRED

MTX+ Biologic

1.

SSZ MTX+ SSZ

MTX+ CSA + PRED

SSZ2.

LEF MTX+ SSZ + HCQ

MTX+ Biologic

LEF3.

MTX+ Biologic

MTX + SSZ+ HCQ + PRED

MTX + CSA + PRED

4.

MTX + Biologic

5.

BeSt

Radiographic ProgressionRadiographic Progression28 27

16

11

0

5

10

15

20

25

30

Mono Tx Step Up Combo + Pred Combo + INF

Pro

po

rtio

n o

f P

atie

nts

w

ith

TS

S-p

rog

ress

ion

> S

DD

(%

)

PP = 0.003* = 0.003*

Goekoop-Ruiterman YPM, et al. Abstract L4 ACR 2004.

* Overall * Overall PP-value, SDD = smallest detectable difference-value, SDD = smallest detectable difference

Early DMARD Intervention - BeST Trial Year 2 OutcomesEarly DMARD Intervention - BeST Trial Year 2 Outcomes

Documents

RA Disease Management. Schematic Representation of the Course of RA Over 30 Years Inflammation Disability Radiographic Scores Kirwan J. J Rheumatol. 1999;26:720-5