casus

Casus

Vrouw, 43 jaar, gehuwd

huisvrouw en parttime werk buitenshuis

2 kinderen, 12 en 14 jaar oud

sedert 3 weken pijn in gewrichten

ochtendstijfheid maximaal 30 min.

geen doorgemaakte infecties

Casus




discreet artritis van MCP2 en 3 beiderzijds

artritis rechter pols

tangentiële drukpijn van voorvoeten

Casus




reumafactortest negatief

aCCPtest positief

röntgen van handen en voeten g.b.

stemkastjes

Zou u deze patiënte met een DMARD behandelen?

nee, de diagnose RA is nog niet zekerde diagnose RA is nog niet zeker, we kunnen wel enkele weken

wachten en gedurende die tijd volstaan met een NSAID

ja, want anders missen we de kans om het beloop van de ziekte

wezenlijk te beïnvloeden (missen we de “window of opportunity”)

ja, want therapie met NSAIDs alleen is ook in dit stadium

onvoldoende adequaat

Mieke Hazes

deze dia vervangen door eerste voordracht Hazes


nee, de diagnose RA is nog niet zekerde diagnose RA is nog niet zeker, we kunnen wel enkele weken






de diagnose is wel voldoende zeker


nee, de diagnose RA is nog niet zeker, we kunnen wel enkele weken






Hans Jacobs

Window of opportunity

““Window of opportunity”Window of opportunity”

A period of time (window) during early RA, during which patients A period of time (window) during early RA, during which patients

respond fundamentally different to therapy (opportunity) compared to respond fundamentally different to therapy (opportunity) compared to

other periods during the course of the diseaseother periods during the course of the disease

““Window of opportunity”: zou dit kunnen bestaan?Window of opportunity”: zou dit kunnen bestaan?

SYNOVIUM

Kraakbeen- en botdestructie

Synoviale vloeistof

Immuunglobulines

Metalloproteïnases

+

+

B-cel

IL-1, TNF

Th1

+

+

IL-15

IFN-IL-6

+

Mø

twee recente editorials overtwee recente editorials over “window of opportunity” “window of opportunity”

die verwezen naar:die verwezen naar:

Heide A van der, Jacobs JWG, Bijlsma JWJ, et al. The effectiveness ofHeide A van der, Jacobs JWG, Bijlsma JWJ, et al. The effectiveness ofearly treatment with “second-line” antirheumatic drugs:early treatment with “second-line” antirheumatic drugs:a randomized, controlled trial.a randomized, controlled trial.Ann Intern Med 1996; 124: 699-707Ann Intern Med 1996; 124: 699-707

Pyramid strategy versus early DMARD strategyPyramid strategy versus early DMARD strategy

DifferenceDifference95 % c.i.95 % c.i.

of differenceof difference

DisabilityDisability (HAQ, 0-3)(HAQ, 0-3)

PainPain (VAS,0-100 mm)(VAS,0-100 mm)

Joint score Joint score (0-534)(0-534)

ESRESR (Westergren, 0-140)(Westergren, 0-140)

0.30.3 (0.2 - 0.6)(0.2 - 0.6)

1010 (1 - 19)(1 - 19)

3939 (4 - 74)(4 - 74)

1111 (3 - 19)(3 - 19)

Heide A van der, Jacobs JWG, Bijlsma JWJ, et al, Heide A van der, Jacobs JWG, Bijlsma JWJ, et al, Ann Intern Med 1996; 124: 699-707Ann Intern Med 1996; 124: 699-707

% patients > 33% improvement; remission% patients > 33% improvement; remission

2525 5252

4747 6666

6060 8282

3737 6060

1313 2525Complete remissionComplete remission

PyramidPyramidstrategy n=57strategy n=57

Early DMARDEarly DMARDstrategy n=181strategy n=181

DisabilityDisability (HAQ, 0-3)(HAQ, 0-3)

PainPain (VAS,0-100 mm)(VAS,0-100 mm)

Joint score Joint score (0-534)(0-534)

ESRESR (Westergren, 0-140)(Westergren, 0-140)

Twee recente editorials over “Window of opportunity”Twee recente editorials over “Window of opportunity”


LandewLandewé RBM. The benefits of early treatment in RA. é RBM. The benefits of early treatment in RA. Arthritis Rheum 2003; 48: 1-5:Arthritis Rheum 2003; 48: 1-5:This investigation into window of opportinity has bias: confounding by indicationThis investigation into window of opportinity has bias: confounding by indication

O’dell JR. Treating RA early: window of opportunity? Arthritis Rheum 2002; O’dell JR. Treating RA early: window of opportunity? Arthritis Rheum 2002; 46: 283-5:46: 283-5:““A brief delay in starting DMARDs has a significant impact on disease A brief delay in starting DMARDs has a significant impact on disease parameters one year later”parameters one year later”

““Confounding by indication”Confounding by indication”

If in an If in an explanatoryexplanatory clinical trial, assignment to medication is not clinical trial, assignment to medication is not

completely random (= balanced between groups), but dependent e.g. completely random (= balanced between groups), but dependent e.g.

on disease activity (= not balanced between groups)on disease activity (= not balanced between groups)

Medication assignment in a Medication assignment in a pragmaticpragmatic clinical trial clinical trial

pragmaticpragmatic explanatoryexplanatory

setting daily practice experimental

research aim how to treat patients does this treatment work

context making a decision acquiring information

trial conditions equalized, “normal” optimal, “laboratory”

research aimed at patients pathophysiological mechanisms

patient selection according to daily practice strict criteria

Trial methodology

pragmaticpragmatic explanatoryexplanatory

blinding necessary no yes

intervention strategies (with drugs) one drug

analyses “intention to treat”“intention to treat” and “on treatment”

outcome effectiveness efficacy

applicable in daily practice yes no

- each design answers another research question

- neigther design is superior, both designs are complementary

has to be investigated in a pragmatic trial; its principle is that has to be investigated in a pragmatic trial; its principle is that assignment to medication is dependent on disease activityassignment to medication is dependent on disease activityof individual patients This is not bias by indicationof individual patients This is not bias by indication

““Pyramid strategy”Pyramid strategy”

is a completely different topic than ‘window of opportunity’ !!is a completely different topic than ‘window of opportunity’ !!

Twee recente editorials over “Window of opportunity”Twee recente editorials over “Window of opportunity”


LandewLandewé RBM. The benefits of early treatment in RA. é RBM. The benefits of early treatment in RA. Arthritis Rheum 2003; 48: 1-5:Arthritis Rheum 2003; 48: 1-5:““Bias: confounding by indication”Bias: confounding by indication”

O’dell JR. Treating RA early: window of opportunity? Arthritis Rheum 2002; O’dell JR. Treating RA early: window of opportunity? Arthritis Rheum 2002; 46: 283-5:46: 283-5:““A brief delay in starting DMARDs has a significant impact on disease A brief delay in starting DMARDs has a significant impact on disease parameters one year later”parameters one year later”

““Window of opportunity”Window of opportunity”

A period of time (window) during early RA, during which patients A period of time (window) during early RA, during which patients

respond fundamentally different to therapy (opportunity) compared to respond fundamentally different to therapy (opportunity) compared to

other periods during the course of the diseaseother periods during the course of the disease

An early start of therapy is better than a delayed startAn early start of therapy is better than a delayed start

4%4%

t=x t=y

7%7%

4%4%

4%4%

WoOWoO

WinstWinst

t=yt=x

a b

inflammation:ESR, swollen joint score

time

a: vroege Tx b: latere Tx

WoO

t=x t=y

cohort, n=335, early RA -> 5 years; X-ray at 1 and 5 y

variable: time from onset RA to start of first DMARD

<6m, 6-12m, >12 m

outcome: change in radiological score from 1 to 5 y

correction for disease severity at start = bias by indication

log.regress of base-line var-> model predicting prob of Tx; within groups of patientswith same prob, Tx independent of these var; fit of prediction about 75%

result: radiological change for start >12 m biggest, for start <6m smallest (= most favorable)

window of opportunity?

Bukhari MAS, et al. Arthritis Rheum 2003; 48: 46-53

Window of opportunity <---> radiological damage

a: vroege Tx

b: late Tx

joint damage

time

WoO

t=x

Effect of combination of SASP and MTX isnot superior to the effect of each drug separately

Haagsma CJ, et al. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol 1997; 36: 1082-88.

Dougados M, et al. Combination therapy in early rheumatoid arthritis: a randomized, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis 1999; 58: 220-5.

'Window of opportunity' effect?

dan bij deze patiënten met beginnende RA dankzij

hoge dosis glucocorticoïden?

moet nader onderzocht worden

conclusie

vroege start met adequate therapie: sneller effect van

therapie, minder cumulatieve schade

“Window of Opportunity”: (nog) niet bewezen,

(nog) geen argument voor vroege start








m.i. niet voldoende bewezen







onvoldoende adequaat Mieke Hazes

deze dia vervangen door tweede voordracht Hazes







onvoldoende adequaat inderdaad

stemkastjes

casus

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