Treatment of early RA cannot be early enough

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Treatment of early RA cannot be early enough

Rheumawire

Jul 15, 2004

Zosia Chustecka

Vienna, Austria - When it comes to the early treatment of rheumatoid

arthritis (RA) with disease-modifying antirheumatic drugs (DMARDs), a

new study " reveals that 'early' cannot be early enough, " say the

investigators, led by Prof f Smolen (Vienna University, Austria)

[1].

" This study extends all previous notions on the importance of early

DMARD therapy in RA by revealing the existence of a therapeutic window

of opportunity within the first few months of the disease, " they comment

in the July 2004 issue of Rheumatology. Preliminary results from this

study were first presented at the EULAR 2002 meeting and reported at the

time by rheumawire.

An accompanying editorial says this is an important study with important

results [2]. It " clearly points out the particularity of RA in its

initial phase and suggests that even a short delay of DMARD therapy will

have irreversible consequences for patients, " comment Dr Gerd Burmester

and colleagues (Free University of Berlin, Germany). It also suggests

that " very early treatment in patients with RA, or at high risk of RA,

can act as a kind of prevention. "

There has been a recent trend toward diagnosing and treating RA earlier

and earlier, but the term " early " hasn't really been defined, and some

trials have included patients with a duration of 1 to 5 years. " Even a

few years ago, a disease duration of up to 3 years was considered the

appropriate time span, " say the editorialists. Recent trial results have

focused attention on the first year of the disease, but here there is a

dilemma, they point out, " as the diagnosis of RA may not be definite

before at least a year has passed. " But now the focus has narrowed even

further, to very early RA (VERA), defined as having a maximum duration

of symptoms of 12 weeks.

This latest study shows that it is these very first few months of the

disease that are critical. The observations " demonstrate the urgent need

for early referral to rheumatologists and early aggressive treatment

with DMARDs, even in a phase when the diagnosis of RA is still

uncertain, " the editorialists conclude.

The latest trial compared a group of patients with VERA who had a mean

disease duration of 3 months (range 2 to 4 months) with a matched group

of patients who had RA with a mean duration of 12 months (range 9 months

to 3 years), referred to as the late-early RA (LERA) group.

Each group had 20 patients at baseline, and 20 in each group completed

the 1-year follow-up, but by the third year, some were lost to

follow-up, so the 3-year observations were made on 17 patients in each

group. The authors also repeated the VERA part of the study in a second

group of patients, to see whether the findings would be duplicated (they

were).

Both groups had similar disease activity scores (DAS) at baseline, with

a mean of about 9 swollen and tender joints, and 75% of both groups

tested positive for rheumatoid factor. They differed, however, in the

x-ray findingsnot surprisingly, comment the authors. At baseline, 25% of

the VERA group and 50% of the LERA group had radiologically visible

erosions.

All the patients were DMARD naïve and received routine treatment for RA

from a rheumatologist, consisting of traditional DMARDs (methotrexate,

sulfasalazine, chloroquine, cyclosporin A, or a combination) as well as

nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids,

all at the physician's discretion. (The biologics weren't licensed in

Europe at the time the study began). The initial distribution of DMARDs

between the 2 groups was similar, but as the study progressed, there was

3 times more switching due to inefficacy in the LERA group than the VERA

group (p<0.05), the researchers note.

Despite the fact that the 2 groups had similar disease and received

similar treatment, there was a big difference in the responses seen.

At baseline, both groups had DAS28 scores in the high range (more than

half in each group had DAS28 scores >5). After 3 months of DMARD

therapy, the DAS28 decreased by about 40% compared with baseline in the

VERA group but fell by an insignificant 12% in the LERA group, the

authors comment. At 1 year, there was a significant difference in the

response to treatment, with DAS28 scores falling by -2.72 in the VERA

group compared with -1.61 in the LERA group (p<0.05). For the VERA

group, the mean DAS28 score reached the low range, and it stayed there

for the next 2 years. Such low mean disease activity was never achieved

in the LERA group, they add.

The x-ray findings also show significant differences between the 2

groups, with the VERA group showing a greater retardation of

radiographic damage. During the 3-year observation period, changes from

baseline were significantly higher (more than 4-fold) in the LERA

patients when compared with the VERA group (p<0.05), the authors note.

The biggest increase in radiographic damage in the LERA group was seen

within the first year, but after that the increase paralleled that seen

in the VERA group. In contrast, the slope of radiographic progression in

VERA was linear throughout the observation period.

Both groups started with a similar disability score on the Stanford

Health Assessment Questionnaire (HAQ). A significant difference in this

score in favor of the VERA group was seen after only 3 months of DMARD

therapy, and this significant difference was maintained throughout the 3

years. So, while both groups started with a similar disability score

(0.9), this score was 150% higher in the LERA group than in the VERA

group after 3 years, the authors report.

A similar development was seen for pain assessment and for both the

physicians' as well as the patients' global assessments, with

significant differences between the VERA and the LERA groups, the

authors comment. However, the difference in swollen joint counts was not

significant, although numerically it favored the VERA group.

The acute-phase response, as measured by erythrocyte sedimentation rate

(ESR) and C-reactive protein (CRP), was decreased significantly in both

groups after only 3 months of DMARD therapy, and the decrease continued

throughout the study. At 3 years, the levels of both biochemical markers

were close to normal and not significantly different between the 2

groups.

" The major differences between the 2 groups occurred within the first

year and especially during the first 3 months of treatment, " the authors

point out. " This was particularly true for functional disability,

disease activity, and radiographic progression of joint disease. "

" Our observations provide evidence that there exists a critical

therapeutic window very early in the course of RA, " they conclude.

" This suggests that in very early arthritis, but not in arthritis

lasting for just a short time longer, disease progression can be halted

rapidly, " they comment. " Compared with very early RA, it is more

difficult to control RA ongoing for a prolonged period of time, even if

this 'prolonged' period is relatively short, ie, a few months. "

The data also suggest that, when treated very early, a large fraction of

patients respond very well to traditional DMARDs, with levels of

effectiveness that approach or even exceed those obtained with biologics

such as the TNF inhibitors, the authors comment. They propose that these

costly therapies be reserved for patients who do not respond well to

traditional approaches.

Observations from this study also support idea that inflammation and the

process of structural damage are somewhat independent of each other,

which has been discussed now for sometime. For instance, in the ATTRACT

trial with the TNF inhibitor infliximab (Remicade,

Centocor/Schering-Plough), it was noted that some patients who didn't

appear to respond well clinically and continued to have inflammation in

the joints still showed a retardation of radiographic joint progression.

Now, in this trial, although DMARD therapy suppressed inflammation in

both groups (as shown by the effect on ESR/CRP and swollen joints),

there was a significant difference in the effect on radiographic

progression, with a greater effect seen in the VERA group compared with

the LERA group.

This dissociation between inflammation and structural damage " appears to

be particularly present in very early disease when inflammation is

active but cartilage and bone structures have not yet been fully

attacked, " the authors comment. The data suggest that, although

inflammation may be halted to a similar degree in very early and later

RA, it appears that destructiononce initiated and progressingis partly

" autonomous, " they comment.

The dissociation is not complete, however. In the LERA group, once the

disease was under control with DMARDs (ie, after the first year), the

rate of radiographic progression slowed and paralleled that seen in the

VERA group, suggesting that rapid reduction of inflammation is key also

in established disease, the authors comment.

Sources

Nell VPK, Machold KP, Eberl G, et al. Benefit of early

referral and very early therapy with disease modifying anti-rheumatic

drugs in patients with early rheumatoid arthritis. Rheumatology 2004;

43:906-914

Kary S, Fritz J, Scherer HU, and Burmester GR. Do we

still miss the chance of effectively treating early rheumatoid

arthritis? New answers from a new study. Rheumatology 2004; 43:819-820

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org