New study disputes window-of-opportunity theory

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Rheumawire

Mar 3, 2004

New study disputes " window-of-opportunity " theory

Leiden, the Netherlands - New research from the Netherlands finds no

evidence for the " window-of-opportunity " theory of treatment in

rheumatoid arthritis (RA). Dr J van Aken (Leiden University Medical

Center, the Netherlands) and colleagues report their findings in the

March 2004 issue of the ls of the Rheumatic Diseases [1].

Clinicians have long debated whether there exists a period of timethe

so-called " window of opportunity " during early RA when some patients may

respond to intervention in a fundamentally different way than they would

if treatment were delayed and whether such therapy would reset the rate

of radiological progression.

Previous studies, such as the 5-year follow-up of the COBRA study, have

provided evidence that such a time window exists, van Aken et al say,

although they note that such data are " scarce. " In COBRA, a step-down

combination of prednisolone, methotrexate, and sulfasalazine was

superior to sulfasalazine alone for suppressing disease activity and

radiological progression of RA, and the 5-year results showed that the

benefit was maintained, as reported by rheumawire.

But now the Dutch researchers report evidence to the contrary. Using

patients recruited through a special early arthritis clinic, van Aken

and colleagues compared 2 cohorts: the delayed-treatment group, who were

treated initially with analgesics; and the early-treatment group, who

were given a disease-modifying antirheumatic drug (DMARD)either

chloroquine or sulfasalazineas well as nonsteroidal anti-inflammatory

drugs (NSAIDs) within 2 weeks of referral.

There was less radiographic progression from 0 to 4 years in the

early-treatment group, but the progression from 1 to 4 years did not

differ significantly between the groups.

Slope 0-1 year based upon radiographs at study entry, 6 months, and 1

year; slope 0-2 years based on radiographs at study entry, 6 months, 1

year, and 2 years; slope 0-4 years based on radiographs at study entry,

6 months, and 1, 2, 3, and 4 years; slope 1-4 based on radiographs at 1,

2, 3, and 4 years; slope 2-4 years based on radiographs at 2, 3, and 4

years.

" Except for the first year, the rate of joint destruction was found to

be equal in both the delayed- and the early-treatment group, " van Aken

et al observe. " In this specific study, no support for the

'window-of-opportunity' hypothesis was seen, " they add. " Thus, the fact

that early treatment is associated with less inflammation and cumulative

damage does not imply a 'window of opportunity' for the long-term

effect. "

The researchers also looked at HLA class II allelesit had been thought

that early treatment would abolish the association between HLA class II

alleles and the rate of joint destruction, they explain. However, this

" was not seen after 4 years " in their study. " This also indicates that

long-lasting modification of disease mechanisms was not achieved. "

" The question that arises from our results is whether the

'window-of-opportunity' hypothesis is incorrect or whether the timing

and type of early treatments, as in the current study, are not enough to

prevent acquirement of detrimental disease characteristics as measured

by the rate of joint destruction, " they state.

" Nowadays, RA is treated more aggressively than in the period during

which this study was performed (1993-1998). So far, it is unknown

whether the results of this study apply to present-day treatment. "

Dr Lipsky (National Institute of Arthritis and Musculoskeletal and

Skin Diseases, Bethesda, MD) commented to rheumawire: " Questions remain

about whether the length of arthritis before referral or the intensity

of treatment contributed to these results. "

" A considerable amount of unpublished data from a number of sources

support the 'window-of-opportunity' concept. The important issue is to

learn what was different about this study that might contribute to our

ability to design more effective therapeutic interventions and predict

outcome more accurately, " he says.

Lipsky is the chief investigator of the DINORA study, 1 of the most

ambitious studies ever to be attempted in RA. This will enroll patients

with very early RAonly those diagnosed in the past 2 to 6 weeks; the

cutoff is 14 weeksand the idea is that by intervening early with the TNF

inhibitor infliximab (Remicade®, Centocor), investigators can change the

natural course of the disease and, it is hoped, induce long-term

drug-free remissions.

Nainggolan

Source

1. Van Aken J, Lard LR, Le Cessie S, et al. Radiological outcome after

four years of early versus delayed treatment strategy in patients with

recent onset rheumatoid arthritis. Ann Rheum Dis 2004 Mar; 63(3):274-9.

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