really is the best time to be a doctor caring for patients with rheumatoid arthritis (RA) and no one would question that. There are so many treatment options available: drugs and biological products, etc. that were never dreamed of a few years ago. However, there are some clouds on the horizon. There are gaps in our ability to make the options available and really apply to patients in any scientific way. A good question to solve is what we need to do to get where we want to be within a decade.
Participants will be able to:
- State the importance of measurements.
- rethink the design flaws of the current trial.
- discuss the ethical concerns of current clinical trials.
During the past 20 years, thinking in RA and care of patients with RA has changed dramatically. We have a lot of tools now that we had twenty years ago.
Paradigm shifts of the last decade
Early treatment is critical . This was not so obvious until the last 10 years or so how really important this is.
The use of DMARD combinations. In one mid-90s used combinations of disease-modifying drugs for the treatment of RA. A patient is prescribed a drug; if it stopped working; lost its effectiveness, a new prescription. Rheumatologists are very shy. When we started our testing, we had a lot of trouble getting people to accept the concept of being more aggressive and we had to have IND and the FDA made using sulfasalazine smaller than we could even think doses today because people were afraid of combinations. Today FAME combinations are used in large majority of our patients.
Biological therapies. Biological therapies have obviously been a big change in the last decade
The critical role of comorbidities . One of the great things also has become very apparent over the last five years is the importance of comorbidities; Chief among them cardiovascular :. comorbidity of all our inflammatory diseases
Treatment of RA 😕 A remarkable success story
Here we have a 56-year-old has sero-positive, erosive RA. She has 17 tender and swollen joints. She is treated with methotrexate (MTX) and pushed the dose of MTX. They changed parents when he was not working completely, which is something that many rheumatologists forget to do and should remember. She still has many active joints. However, she is an ACR70. So is 70% better in a composite form in general and in any trial would be labeled as one of the successes. This highlights a huge problem we have in clinical trials and that is, we should really consider this patient is a success?
So what’s wrong with that picture? Although a lot of patients would be happy to only have five joints that are tender and swollen instead of 17, rheumatologists would not be happy with that. We are not happy when someone has five painful and swollen joints in the clinic. There is a big problem with what we measure success and as the question of what should be the objectives arises.
Where is the hemoglobin A1C; the level of LDL; the level of blood pressure that should be pointing in our disease?
Lord Kelvin ( left ) had some ideas about measuring things. “When you can measure what you are speaking about, and express it in numbers, you know something about it, but when you can not measure [and] express it in numbers, your knowledge is of a meager and unsatisfactory kind.”
He was not talking about measurements in rheumatoid arthritis, but it certainly applies. He also said, “if you can not measure you can not prove that.” That says a lot about the measures of success in rheumatoid arthritis. It lends itself to the way we define success in the clinics, which are rolling on.
What is the goal of therapy?
Clinical trials may be an ACR 20, 50, or 70 response, or a score of disease activity DAS 28, or any radiographic outcome. These are very different measurements. At the clinic it is likely to be only a gestalt for most of us. In particular, in this country, not many people do DAS 28s in clinics. There are other clinical-GAS measures, Rapid-CDAI that are evolving and the need to continue to evolve if we are to reach a uniform target for patients.
ACR Core Set
- Medical global estimate
- Functional status – Health Assessment Questionnaire (HAQ) multidimensional HAQ (MDHAQ)
ACR Basic and Disease Activity Score (DAS)
- tender joint count
- swollen joint count
- acute phase reactant – ESR, CRP
- overall estimate of the patient
Above 7 are measures that are the core set that forms the ACR 20, 50 and 70; and those used in the DAS. The problem with the set ACR is that it measures the percentage of improvement. DAS measuring an absolute level of disease activity, but has a lot of problems. There is nothing in the DAS on functional status; It is too sensitive to changes in sedimentation rates; joint pain are overemphasized compared with swollen joints.
DAS28 = 0.56 * sqrt (tender joint count 28) + 0.28 * sqrt (number of swollen joints 28) + 0.70 * e (ESR) 0.014 (patient assessment of global log status or activity)
The DAS is a complicated mathematical formula, but that’s not why it is not clinically useful to us. The reason it is not useful to us in the clinic is that most people do not make formal 28 joints and even if they do not have sedimentation rates or CRP in fact at the time they are seeing the patient. There is also a DAS that CRP can be calculated.
RA treatment: questions for the next decade
The ACR get an RFA in a new measure is capable of being used clinically and which would be measuring an absolute level of disease activity. The hybrid is not ACR, but is a better outcome measure in clinical trials and is an important point. In fact, it is good enough that if used as an outcome in clinical trials, the number of patients used can be reduced by half. It is an improvement in the tests, but it will be very useful in clinical because it can never be an objective for an individual patient, because, again, based on a percentage of improvement and that is a huge problem to get around.
To highlight some of the problems with the way we measure things, here is a study that analyzed a combination of methotrexate versus adalimumab versus methotrexate alone. In this case, one would have been much better to collect methotrexate compared with adalimumab. There is a statistically significant difference between methotrexate and adalimumab measuring the ACR 20. So to measure the signs and symptoms of RA, one is better with methotrexate for ACR 20, 50 and 70. However response, if the comparison of X-rays, one would be better off choosing adalimumab due to radiographic progression after two years it is better in the adalimumab group compared with methotrexate alone. So what we choose? Do we want the patient is clinically better and are less painful and swollen joints? Or we want them to have less radiographic damage? Again, we are questioning what we are measuring in clinical trials and how to define success.
This is a patient who has very crippling arthritis. You can recognize this patient ACR Collection. These are the X-rays in that particular patient. Sharp index 0. No erosions there. Because subluxation that can be called a little joint space narrowing, but there really is no joint space narrowing. So this patient has crippling arthritis, but Sharp progression-free rate.
One of the problems with the interpretation of clinical trials is not knowing what to do with radiographic results. Disability can and does occur without any change of radiography. So again, what should we really be measured in clinical trials? It is an SLE patient, but could be an RA patient having significant deformities because all synovitis. This is much more debilitating for the patient that the progression of some Sharp score points.
What is the goal of treatment for RA? Unfortunately, we can not cure RA at this time, but remission is a realistic goal and should be our goal with most patients. If we treat patients early, then we should be able to achieve remission in a significant percentage of our people. What is significant? Significant depends on how we measure remission.
The Ticora assay was done in Glasgow and the question was asked: what if we have a set of patients we treat one goal (intensive care) and another group of patients we treated with the best care (routine care)? The goal was the total DAS less than 2.4. They did not use biological therapies in this trial; therapy continued progression:
Patients had better results with a goal.
5 Tierno, 4 inflamed, ESR = 22
1 Tender, 0 inflamed, ESR = 7
What does this tell us? It tells us that if we had a target for our patients and made decisions to reach that goal of climbing too need therapy when all our patients could do better. Unfortunately DAS is cumbersome, so we need something in the clinic that is easier to follow.
Global Score arthritis. Overall score of arthritis (GAS) is based on measurements performed by the patient. This is a self-recorded count tender joints and is very easy to do. This can not be what we measure in the clinic, but we need to validate an outcome that is easy to use in the clinic. The gas has been shown to correlate well with changes in DAS most cases.
What should be the goal of our therapy? Or how to define success?
- absolute level of disease activity vs percent improvement
- vs Radiographic clinical
- vs cumbersome easy
- real-time vs tomorrow or next week
Back to the 56-year-old woman: ACR 20 response, but five five swollen joints tender. Rheumatologists are not happy with the result, but there is no test data that shows that we can do better in these patients with only five five swollen joints tender. All of our clinical trials have relied on people with more active disease. At the very least, be in cilincal trials sensitive patients have six six swollen joints. Most patients treated in clinics do not qualify for clinical trials. The main reason is not eligible to have very little disease activity. That makes it difficult to extrapolate knowledge from clinical trial data and apply it to the attention of an individual patient.
ATTRACT trial. The ATTRACT study was intended to study patients with aggressive disease who were inadequately responding to methotrexate. Patients with active rheumatoid arthritis despite treatment with methotrexate, defined as at least 6 swollen and tender joints and at least 2 of the following: morning stiffness of 45 minutes or more, the rate of erythrocyte sedimentation rate of a minimum of 28 mm / h, or C- reactive protein at least 2 mg / dl. All patients had to have been treated with methotrexate for at least 3 months at a minimum stable dose of 12.5 mg / week for at least 4 weeks before selection and no other concomitant DMARDs were allowed during the trial. Patients were, however, allowed to receive low doses of corticosteroids less stable than or equal to 10 mg / day and nonsteroidal anti-inflammatories.
The patient population ATTRACT was a reflection of a typical population of patients with active RA, which has an average age of 54 years, predominantly female and a majority of patients with positive rheumatoid factor. Patients had been in a median of 3 previous DMARDs, including methotrexate, ranging from 2 to 8 patients were in therapeutic doses of methotrexate prior to entry into the study, with a median dose of 15 mg / week . Despite being in therapeutic doses of methotrexate at baseline, patients had active disease. 20 had a median swollen and tender joints 31 and a median CRP 2.6 mg / dL. They also had substantial disability at baseline, indicated by a median HAQ score of 1.8.
Our patient started with 10 swollen and 10 tender joints, so you will qualify for all other trials. She remains an ACR 40 response and that is a success in most of our tests, but 10 tender and 10 swollen joints is bad. Clinical trials do not tell us how to treat this patient is; no trials comparing each other active therapies in patients with active disease despite treatment with methotrexate. There are plenty of options. All data that are available to us in the literature about which of these therapies work better than the other does not indicate when to use them. In other words, there is no data on the important issue in particular.
What is so soon soon enough?
Early treatment is important. How early we do not know the answer, but it is an important issue. If a patient says: “Doctor, no matter what, I have to be able to go to work tomorrow”, which of our therapies will work quickly?
This shows the first 14 patients who had never been treated with steroids in the world (Mayo Clinic, 1949):
|Start ESR||Final ESR||Response ESR|
They all had RA. RA was selected as the first disease to be treated, because it was thought that RA is a steroid deficiency disease. Some people still believe that and there is some evidence that would support that. Within a month, 100% of these patients had an ESR of 50. In other words, the sedimentation rate was approximately 50% better. Eighty percent of them had a VSG 70. A therapy that works quickly is steroids.
What about the latest data? Participants in the trial compared Cobra who received 60 mg of prednisolone daily for a week and then tapered fairly quickly with a group receiving sulfasalazine alone. The results showed that if steroids were administered at the front, the ESR is 75% better in two weeks. Sulfasalazine alone did the same but took six months. inhibition of TNF acts very quickly too. Those are the two options for a response within days or a week.
are current trial designs relevant to the current or future clinical practice?
What is the design of the current standard tests?
- The vast majority of trials especially the United States are pharmaceutical trials
- Most trials comparing active treatment to placebo
- Random selection of patients to A vs B in a rigid manner and ask the question who is better after 1 year? 2 years?
- Essentially, there is no significant data on profitability
- ethical issues: Placebos, duration of treatment failures, when knowledge about treatment assignment
First, the vast majority of trials, especially in the United States, are pharmaceutical trials. Because pharmaceutical trials, we have many options for patients who did not have a decade ago. However, pharmaceutical trials are designed to do a specific question by a group of people who have a vested interest in the outcome. They do not necessarily ask the questions that are most relevant for rheumatologists to care for patients at the clinic. pharmaceutical trials are necessary and important, but there is a need for further tests to do other important questions.
Most trials in patients with active disease despite methotrexate therapy comparing active placebos is ethically unacceptable. Why should we be doing another test that shows the work of that group therapy in 13 patients with suboptimal response to methotrexate when we know that there are 12 ways to make the patient better? Most trials randomized patients to therapy A therapy compared to B in a rigid manner and ask the question: who is better a year later or two years later? This is not how we deal with patients in the clinic. If a patient is not doing better in three to six months they will change to something else we have to do something different in the design of trials to solve this particular problem. There has been little or no attempt to look at the biological clinical parameters, or predicting responses.
In 2017 we will not be talking about the AR in the same way we speak of RA as a disease. We’ll be talking about subsets of RA and how they will be defined those subsets is the very important issue that we do not know the answer. Hopefully, we will have data from trials married to biological repositories that will address the question of how we can predict that you will have a success rate of 90% in therapy. Essentially there is no significant data on the profitability of our diseases. How can you make comparisons between something that is active against placebo rather than a precise performance data is given? trials comparing active therapies are needed each other. Until we have those, who have essentially no useful data profitability.
The use of placebos in trials is a major problem, which helps answer some questions, but it is not reasonable from the point of view of the patient. The duration of treatment failures – we need trial design that allows patients out of tests or allows them to change treatment in an appropriate clinical moment. If we do that, then the results of that test are not very useful for you to treat and care of a patient. We need time and knowledge of treatment allocation. Another thing is that it is inconceivable doctors and patients included in the trials did not learn of therapies administered until all participants have finished. That knowledge could have helped the doctor understand how to treat that patient. If a patient leaves the trial because of side effects, the code does not break until everyone is out of this trial unless there are extreme situations. That’s not the way it should be care of our patients. There are a lot of ethical issues involved in having patients participate in clinical trials.
Current study designs
ATTRACT Study design and methods. valuation criteria specified previously, primary and secondary in weeks 30, 54 and 102 in the ATTRACT study are shown here. The primary endpoint at week 30 was the proportion of patients who achieved an ACR 20 response level in each of the 5 treatment groups. The primary endpoint, week-54 was the degree of inhibition of progression of structural damage as measured by change from baseline in modified Sharp index. At week 102, the primary endpoint was improvement in physical function as assessed by HAQ change over time. Secondary endpoints included the change in modified Sharp index at weeks 30 and 102, ACR 20 response rates at weeks 54 and 102, and the change in HAQ over time through week 54.There is no reason that we should be following someone for 54 weeks or 102 weeks if they have not done well in therapy that we have selected. They must be out of this trial as a treatment failure much, much sooner than that. We should not put patients at risk.
TEAR (Treatment of early aggressive rheumatoid) trial. it is a lawsuit filed by the investigator. He started out an NIH trial, but not end that way. This is a trial in which we are looking at patients with early disease and are randomizing to either the strategy of triple therapy or strategy methotrexate plus TNF, inhibition, but only half of patients they are receiving therapy that front. The other half in both groups just is starting methotrexate and then only if they have stepped up to active disease, which is kind of how we do things at the clinic. The question then is what happens after two years.
RACAT (rheumatoid arthritis compared with active treatment) trial. This is a test performed on the VA with the collaboration of the Canadian Institute of Health, CIHR. It deals with the comparison of active therapies in suboptimal response to methotrexate by looking at a strategy. Whether based on methotrexate start, all of these patients are methotrexate, hydroxychloroquine or sulfasalazine etanercept in the beginning. Based on what you can start on what happens after a year in terms of achieving a DAS28 below 3.2 (low disease activity). The therapy used is not the main point; It is how the patient is doing. These patients at 24 weeks switch to the other therapy if they have not had a clinically significant improvement, defined as 1.2 in the DAS 28 in a blinded fashion. Everything is done in a blinded fashion. At the end of the day some of these patients who initially received sulfasalazine, hydroxychloroquine really be receiving etanercept. At the end of this day some of the patients may be in the triple therapy.
Strengths of judgment RACAT:
- First test to compare active therapies in suboptimal response methotrexate
- Evidence of a strategy is not fixed / rigid approach (comparison of one head to head despite sub-optimal results)
- No pharmaceutical funding, influence on the design or interpretation of the data or control data
- large concentration of men
- All study drugs supplied by the Veterans Administration
- robust economic analysis
- Serum bank and DNA
How can we profile patients effectively?
This is a big problem, and here is where we will make much progress in the next decade. If I am taking this decision for a new patient in my clinic, how to treat patients with RA? I have 6,683 options that I can do. We have 17 disease-modifying drugs, of which six are biological. Note that it is not unusual for us to use four-modifying drugs disease, so if you go through the mathematics in which, in the use of all drugs individually, with two at a time, three three, four at a time that is 6,683 options. I can not spin a wheel and pick, I need much better tools to help make that decision for our patients and when I have those tools will be much smarter. How can we get?
The shared epitope has been predicted in some models. CCP and the CCP isotypes could help us, serum cytokines could help, and other genetic markers could help us. There are many candidates out there, but not a lot of information at this time. But that’s one of the ways is to make quantum leaps forward
Ideal situation :. 2017:
- individual treatment profile AR
- Serum: IgA and IgG 4 CCP positive, -high MMP 3 sTNFR – low
- DNA: DRB1 -0401 / X heterozygote MTHFR C / T
- RNA: less negative shared epitope is required
- synovial Bx: Not required unless the active disease at 4 months
- LDL and HDL: 138 and 37