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Sock's Toxicity And Drugs In RA:
Clinical Trials
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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.
 
Rheumatoligists's Comment:
 
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 scoring.
 
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 group.
 
Rheumatoligists's Comment:
 
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.
 

Etanercept And Infliximab:
 
Enbrel and Remicade have both been approved for the treatment of RA in Canada but most provincial health plans will not pay for treatment. The understanding is that in Ontario if one has failed traditional therapy then the biologic therapy will be covered. Some patients in the latter category have been covered by the provincial health plan but others have not (double standard) .
 
Those patients that have been approved say there is a lot of paper work and a long waiting list. I am a RA patient who have been on gold-predisone, methotrexate,(Arava did not work for me).  I can get treatment if I pay for the drugs but I can not afford the high cost.
 
In Ontario,at one time,Vioxx (NSAID)  was approved for Osteoarthritis treatment but not RA. I have OA and RA. I have a history of GI bleeding. Biologic drugs should be covered by the Ontario Health Plan. It is a essential medicine for RA therapy .
 
In clinical trial reports we often read about ACR  20(American College of Rheumatology),or an ACR 50 or an ACR 70. And what that means is,in rough terms,that's the degree of improvement. So,it's true that a high percentage of patients-will have a ACR 20,but lesser number of patients will have a ACR 50,which means that half the disease is controlled,small number of patients will have a ACR 70.
 
So,what that means for the patient is despite the fact that they're being treated with new therapies,there's still a lot of residual disease. This disease does not simply melt away,and everything is gone (in a lot of patients).

 
The Prosorba column has been in FDA-approved use for over ten years for idiopathic thrombocytic purpea (www.itppeople.com),an autoimmune blood disorder that affects 100,000 people in the U.S. In this disease the body's immune system attacks and destroys the blood patelets,tiny cell fragments that allow the blood to clot normally.
 
Among other problems,this can cause serious bleeding Some people with this disorder are helped by being treated with the Prosoba column,some people,over the years under treatment for ITP also experienced some relief from their RA symptoms.
 
If you were one of the sixteen out of forty-eight people with RA who showed a 20 % or greater improvement in their signs and symptoms after they participated in the 1998 tests of the Prosoba column,the intimate details of what protein A was doing in your blood was doing to your blood might not seem sp important.
 
It might fade in significance,particularily when the improvement after the Prosoba treatments last an average of thirty-seven weeks and up to seventy-five weeks in some cases . The treatment therapy cost is relatively high.
 
Each week for 12 weeks,one reports to a clinic or a doctor's office,where in the 2 hour procedure,one's blood flows,through tubing attached to an arm vein into a apheresis machine-a cell separator. this separates the liquid part of the blood (plasma) from the blood cells.
 
Then the blood flows pass through the Psorba column,about the size and shape of a soup can,out through another tube,where it is reunited with the blood cells and returned to you through a vein in the other arm.
 
Your blood cells wait while the blood plasma is "filtered",and then the plasma and cells are returned to you. the procedure filters about 4 to 8 cups of plasma over the 2 hour period. The term filter is not an accurate reflection of what goes on in the column.
 
The column is yet another example of RA treatment that can be effective for some patients,but for reasons that is not entirely clear.
 
The procedure has been done in Canada,but it was reported that the side effects may be of a nature that prevents wide useage,the cost and the lasting effects. Biologics should do a better job for most,but again it is a option for the rheumatologists "arsenal".