New study disputes window-of-opportunity theory

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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.

No support for hypothesis

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.

" 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. "

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

equal in both the delayed- and the early-treatment group. "

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. "

Is the hypothesis incorrect or the study outdated?

" 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. "

" 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.

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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.