Progression of radiological damage in patients with rheumatoid arthritis in remission: A prospective 2 year study:
Objectives: To examine the clinical and radiologic outcomes over 2 years in a cohort of 187 RA patients who met the ACR
criteria of complete clinical remission.
Methods: Patients were followed every 3 months. Radiographs of the hands and feet were obtained at baseline and after
2 years. Radiographs were scored for joint damage using the Sharp-Van der Heijde scoring (SHS) method (range score 0-448)
Results: Of 180 patients completeing the study,93 (52%) remained in complete remission (CR),87 had exacerbation of their
RA. If DMARDs were increased patients were classified as having an exacerbation. Patients who remained in CR over 2
years had significantly fewer tender joints,lower VAS (physician global assessment),lower HAQ scores,lower IgM-RF levels than
those suffering an exacerbation.
For the entire group the mean SHS at baseline after 2 years was 49 and 51 (p<.0.0010 respectively. For the subgroup
with persistent CR,mean SHS were 52 at baseline and 53 at 2 years (p<0.004). In the subgroup with exacerbations,mean SHS
were 46 and 51 (p<0.001). No significant correlations were seen between radiographic changes and baseline variables. Notably,there
were no correlations with DAS (Disease Activity Scale) and VAS.
The ability of DMARD agents to induce or maintain CR (clinical remission) is controversial. Although CR in
RA occurs,the frequency, duration and predictive factors are not accurately known.
The ACR criteria for CR is stringent and requires 5 of the 6 criterias for 2 months: no morning stiffness > 15 minutes,no
fatigue,no joint pain, no joint tenderness or pain on motion,no soft tissue swelling in joints,ESR < 30mm/hr (females)
< 20mm/hr (males).
It is no surprise that the patients with milder disease were more likely to remain in CR, However it is interesting that
patients with seemingly little to no clinically active disease continued to have radiographic progression.
The scatter plot of the data is even more impressive with some patients having marked-x-ray deterioration despite remaining
in CR. It would be interesting to see the SHS split into the component categories of joint space narrowing and erosions.
One might see how joint narrowing might proceed if the cartilage matrix were irreversibly damaged by inflammation.
These data highlight the need for markers of disease activity beyond clinical signs and symptoms.
Clinical significance of rapid radiographic progression in RA:--Patients were divided into two groups based on their
annual rate of radiographic progression (assessed by modified Sharp scores): rapid (>7.5) vs. non-rapid (<7.5) radiographic
progressors. The cutoffs were obtained from the Omeract definition of radiographic progression as smallest detectable difference
of 15 (SDO=15) which is based on the random measurement error calculated between observer variation in pairwise radiographic
Clinical parameters significantly associated with the rapid progressors included HLA-DR4+,higher Ritchie articular indices,higher
ESR,higher HAQ,higher DAS and older age.
Identifying rapid radiographic progressors in RA: This abstract attempted to use these clinical parameters in a prediction
model for identifying rapid progressors. In a model in which rapid progressors are predicted with 80% probability,36%
of the rapid progressors would be missed and 21% of the non-rapid progressors would be incorrectly identified as rapid progressors.
The other test showed that,over time,the rapid progressor group had higher HAQ scores and higher DAs scores than the non-rapid
Recent studies of the TNF inhibitors have shown these agents to slow or,in some cases,halt radiographic progression in
RA and have placed emphasis on radiographic changes as an important therapeutic outcome. However,the amount of of radiographic
progression that is significant is unclear.
From a practical view ,clinicians need to address whether slowing radiographic progression is worth the risk of more
aggressive therapy. One model addressed the question of whether the rate of progression seen early in the course of RA can
predict long term outcome. Not surprisingly,patients with more rapid radiographic changes have more disability and more disease
activity after several years of follow-up. thus it can be argued that radiographic progression should be an important criteria
for aggressive therapy.
The other model highlights the need for serial x-rays particularily in the early course of the disease to determine rates
of radiographic progression,as there are no clinical parameters to predict which patients will be rapid progressors. these
studies raise very important issues that will need to be further evaluated in further studies.
Highlights from the 2001 European Congress of Rheumatology--EULAR 2001.
Based on a analysis using several different approaches to evaluating potential definitions of improvement in RA, perhaps
suggestion that improvement for clinical trial patients be defined as 20% improvement in tender and swollen joint counts
and 20% improvement in at least 3 of the following 5 ACR core set measures: pain, patient and physician global assessments,
self-assessed physical disability, and acutephase reactant.
Researchers work suggests that this definition corresponds closely to clinicians' impression of patient improvement
since it emphasizes joint counts, and furthermore, it discriminates powerfully between active and placebo treatment, identifying
few placebo-treated patients as being improved.
This definition of improvement provides a single outcome measure that can be used in all RA trials. The definition of
improvement can characterize the response of individual patients to therapy, and using it, investigators can profile those
likely to respond to a therapy.
Analysis suggest that this definition of improvement increases the power of clinical trials since it draws on information
from multiple different outcome measures. Therefore, the sample size needed to demonstrate differences between therapies may
decrease, making it possible for some trials that previously would have been considered to be underpowered to have sufficient
patients to compare treatments.
For example, for the comparative trial analyzed , between 20 and 32 patients per treatment group would be required using
this improvement definition (80% power, a = 0.05, 2-sided), versus at least 80 patients per group if the trial were analyzed
in the current and traditional way, evaluating 1 of the 7 core set measures.
Ultimately, if the improvement criteria are widely used in a standard ized manner, it may be possible to rank the effcacy
of different therapies based on the percentage of patients who improve.
Since data analyses focused on defining improvement based on the differences between end of-trial and start-of-trial
scores, the recommendation is that patients be evaluated as improved or not improved based on their scores at trial's
end (or at the time they drop out) compared with entry scores.
Until now, improvement criteria have often relied on changes in joint count to determine whether a patient has improved.
Compared with more comprehensive measures, definitions that depend only onjoint count generally do not discriminate as well
between active drug-treated and placebo-treated patients, and usually identify more placebo-treated patients as being improved.
We hope that our definition of improvement satisfies a middle ground in that it relies heavily on joint count improvement
while incorporating data from other measures.
There are limitations both to our approach to defining improvement and to our definition. First, our analysis of how
well improvement definitions distinguished active drug-treated from placebo-treated patients was limited by the absence of
functional status data in our data sets. We had to rely on grip strength instead.
Analyses with smaller data sets that did contain functional status suggest that the results would have been similar.
Nonetheless, it is essential that these improvement criteria be validated with data sets that contain information on functional
status change. In general, validation in other prospectively measured data sets would be of great value.
In addition, the use of one single measure to evaluate the response to therapy in rheumatoid arthritis may be overly
simplistic. Some treatments affect joint count improvement more than improvement in acute-phase reactants, and others do the
opposite. To ignore the spectrum of improvement induced by a particular treatment would be a mistake, and that the change
in each outcome still be reported, but that the primary outcome for trials be improvement as reported.
In summary, a definition for improvement in rheumatoid arthritis that corresponds closely to rheumatologists' own impressions
of patient improvement and also discriminates between active drug- and placebo-treated patients, which suggests that its use
will enhance the statistical power of future trials.