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Slide 1 and 2 : Welcome to the Coalition of Rheumatology Educators program entitled “Getting to Remission, Measurements Versus Biomarkers Versus Better Drugs.” This activity is jointly sponsored by the American Academy of CME, Inc. and Princeton CME. The activity is supported by educational grants from Amgen Incorporated, Wyeth Pharmaceuticals, Bristol-Myers Squibb, Genentech Inc., Biogen IDEC Inc., and Abbott Laboratories.
I am Dr. Arthur Weaver, Clinical Professor of Medicine, Department of Medicine, Section of Rheumatology at the University of Nebraska Medical Center in Omaha, Nebraska. Please note that all faculty disclosures for this activity are included in the activity booklet. To receive continuing education credit following the conclusion of this activity, each participant must complete the post-test and evaluation form which can be easily completed online for immediate receipt of credit at www.princetoncme.com.
Slide 3: Let us start with a case and patient number 1, a 56-year-old white female with a 5-year history of zero positive rheumatoid arthritis comes into your office for a follow-up appointment. The patient is on a TNF inhibitor plus methotrexate 20 mg per week and celecoxib 200 mg twice daily for 42 months. She has no complaints of joint pain or morning stiffness for 18 months. No tender or swollen joints and her blood work, including the acute-phase reactants, is normal. Is this patient in remission? Would we order any additional tests or biomarkers? Would you change your therapy? We will try to answer these questions as we move forward. Certainly, she has had an excellent response but there may be some things that we would want to do later such as imaging techniques and so on.
Slide 4: What do you feel defines remission in rheumatoid arthritis? Lots of characteristics have been described. Number 1 might be no evidence of clinical activity, disability, or radiographic progression and the patient no longer using medication of any sort. A second definition might be no evidence of clinical activity, disability, or radiographic progression, but still taking scenario. And the third would be no evidence of clinical activity or disability, but evidence of radiographic progression. We will show some examples of each of these as we move forward.
Slide 5: Reaching the goal of remission in rheumatoid arthritis has been a topic that 10 to 15 years ago we did not talk about, but we have been able to do that with some of our recent clinical trials. The TICORA study shown on this slide, in your left upper quadrant, was an interesting study carried out by rheumatologists. A group of over 100 patients was split demographically into identical groups and 1 group was followed on a routine basis every 3 months—much as we see our patients—with the decision to change therapy based on the rheumatology and patient opinion. And the results were roughly 60, 40, 20 as far as the ACR20, 50, and 70 responses with a remission rate of 16%. This is not unlike what we have seen in some of the earlier trials with monotherapy using traditional DMARDs. There was another group, identical demographically, but followed on a once-a-month basis and the decision regarding therapy was based on a clinical measurement and dictated by that clinical measurement, not by physician judgment. The results were striking with 90, 80, 70, ACR20, 50, and 70 scores with a remission rate of 65%. Now bear in mind that this did not include biologic drugs. These are traditional DMARDs and these figures are significantly better than anything else that we have seen up to this point in time. So certainly, early, intensive, aggressive therapy based on measurement makes a difference as opposed to a measurement based on physician decision.
Another study widely quoted is the TEMPO trial in the left lower quadrant. This was a study looking at methotrexate versus etanercept versus combination methotrexate and etanercept, and as we have seen with all of the TNF inhibitors, the combination of methotrexate and etanercept had ACR scores that are much higher than monotherapy with either methotrexate or etanercept! 86, 71, 49, probably the best we have seen in any clinical trials and the remission rate was as high as 41%. We have seen the remission rates in this same range with adalimumab and other TNF inhibitors.
The third study is the BeSt study shown in the right lower quadrant, and this gives us another definition of remission. These are 2- and 3-year data using infliximab as induction therapy and stopping infliximab later and continuing on methotrexate. Roughly 55% of the patients were able to discontinue infliximab after a period of time. And if you look at the subnote down beneath that study, 14% of the patients were able to discontinue even the methotrexate. So the possibility of induction for the first time is now raised.
The right upper quadrant shows a typical difference that we have seen between TNF inhibitors and traditional DMARDs, and you will recall the TICORA study, with a remission rate of 65%, definitely had less radiographic progression in the group that was seen intensively but there still was radiographic progression. Whereas in the TEMPO trial, which included anti-TNF drugs did significantly better than methotrexate, but the combination actually showed complete halting of radiographic progression, which we have seen repeatedly with these drugs.
Slide 6: Are rheumatologists obtaining the types of results that we have seen in recent, clinical trials?
Slide 7: I think this just is a compilation of 3 of the major trials that have been done with all 3 of the available TNF inhibitors, and as you can see, the scores are quite good in all 3 of them. I would encourage you not to compare apples and oranges. None of these trials are identical and cannot be compared as far as the numbers in regard to response rates. All of these drugs are effective. We have infliximab on the left, etanercept in the center, and adalimumab on the right. The last 2 observed over 24 weeks, and the infliximab data over 54 weeks. But again, the ACR response rates are quite good with all of these studies. Again, I would ask that you not look at these figures and try to compare one versus the other. They are all very effective agents, particularly, as we pointed out, in combination with methotrexate. So are we achieving those kinds of results in our present day-to-day activities in dealing with rheumatoid arthritis patients?
Slide 8: Two studies out there would indicate somewhat sobering results in regard to 2 major trials that have been done. The SONORA trial carried out by Weisman and associates was after a 2-year follow-up and was a prospective 5-year multicenter inception cohort observational study carried out in North America with rheumatoid arthritis patients. Only 20% of these patients were on biologic DMARDs, although that was open to them. The ACR scores do not look very good, 41, 24 and 7. Now this is real world as compared to a clinical trial. A lot of people did not believe that, but then the RADIUS I and RADIUS II outcomes were presented at the American College in 2005. This was a rheumatoid arthritis DMARD intervention utilization study of over 10,000 patients. The BeSt results were in RADIUS II, 43, 24 and 11 as far as ACR 20, 50, and 70, and if you look across the left side of the slide, it is almost identical. This was also real world. Measurements were obtained in both of these studies but the treatment by physician was not necessarily changed according to assessment; it was done by physician recommendation. So what we are achieving in the real world is not as good as what we have seen in our recent clinical trials.
Slide 9: Now looking at the TNF inhibitors and their response rates, this is a study out of Denmark looking at the DANBIO open-label registry with large numbers of patients on TNF inhibitors. If you look at the EULAR response, which is basically based on a change in the DAS score from baseline to treatment levels, you can see that about 70% of patients on anti-TNF had a good to moderate response. But when you look at disease activity levels and remission versus low, moderate, and high activity, you have a remission rate of about 20% and low disease activity or remission of about 30%. Now that means that 70% of people on TNF inhibitors are still exhibiting moderate to high disease activity, something that perhaps we would be a little bit more aggressive in our approach today.
Slide 10: Looking at survival of anti-TNF and DMARDs in rheumatoid arthritis, this is a Norwegian study of over 2000 patients. It is very interesting because it looks like the survival is best, as we would expect with TNF plus methotrexate, but TNF monotherapy and methotrexate are certainly less, and the survival rate actually even with the best, which is anti-TNF plus methotrexate, is about 70% in 1 year. Not as good as probably what we would all estimate to have occurred.
Slide 11: Now we have questions. What is the best way to achieve remission? Is it early diagnosis and referral? Evaluating our prognostic indicators and biomarkers? Early aggressive combination therapy? Basing our treatment decisions on clinical measurements during each physician visit? The use of imaging modalities at a regular time interval? I think all of these are very, very important. Certainly, I think all of us have adopted early aggressive combination therapy, and we would all hope that the diagnosis is made early and these patients are referred. We all use prognostic indicators and have been for years. New biomarkers are being developed all the time, and I think the main key here is basing our treatment decision on a clinical measurement and not on a gestalt, if you will, or what we feel is best. Certainly the use of imaging at regular time intervals is important because there is a disconnect between controlling symptoms and signs and radiographic progression.
Slide 12: This next slide is interesting. It looks at the delay of DMARD therapy and what it does over a period of time. A large study was presented in 2001, patients were on either chloroquine or salazopyrine and they were very similar demographic groups, one group was started on the DMARD at the first visit, the other was delayed 6 months and then at the end of 2 years they looked at radiographic progression. The group that obtained—and these are the same medications—the DMARD 6 months earlier had significantly less radiographic progression than did the group that delayed therapy for 6 months. So early, aggressive treatment makes a difference.
The other trial shown on the bottom of the slide is the COBRA trial carried out by Martin Boers and his associates. This was an interesting trial done in the mid ’90s looking at sulfasalazine, which was the drug of choice in Europe at that time, versus sulfasalazine plus high doses of methotrexate for a few weeks, relatively moderate doses of methotrexate at 7.5 mg and then following these patients over time. Again, these were demographically similar groups, and when we saw that curve, most of us felt that this is probably the prednisone-related data because it was pooled index. But interestingly enough, the same group looked at radiographic progression 5 years later and just recall at this point in time, after 6 months, both groups were on nothing but sulfasalazine. Interestingly enough, the radiographic progression was significantly less in the group that obtained methotrexate and prednisone during that first 6-month period 5 years later. So again, what we do up-front, what we do aggressively, and what we do early makes a tremendous difference later on.
Slide 13: There are several things that we can look at as the best decision-making application we have in rheumatology. Is it the patient report? Is it the physician clinical judgment, which I think most of us have been using for years? Is it the ACR criteria or a DAS28? The simplified disease activity index or clinical disease activity index? Is it the swollen joints? Is it the HAQ or modified HAQ? And is it imaging? Well I think all of these have been used. I think I would comment that the ACR criteria are certainly better used in clinical trials and they do not really have the ability to measure a patient’s response from visit to visit. Certainly we learned in the TICORA trial, as we presented previously and I will show you here again in a minute, that a judgment based on a measurement is markedly superior to physician judgment. Certainly HAQ scores showed different things as far as disability over time and the imaging techniques. Again, as I pointed out, there is a discrepancy between clinical control and radiographic control.
Slide 14: The TICORA trial, which is important, aggressive therapy—intensive therapy, if you will—had markedly better scores and markedly higher remission rates than those patients who are seen on a 3-month basis and used physician judgment to treat as opposed to the aggressive group, which was based on a scoring system to determine changes in therapy. Radiographic progression was less, but again, as you will recall, the disconnect between anti-TNF and traditional DMARDs and TICORA is simply traditional DMARDs.
Slide 15: Now we mentioned the clinical measurements previously and this is just an outline of the outcome measures, all of which have been validated against one another and you can see the ACR at 20, not so good for measuring visit to visit but a very good tool in clinical trials. The DAS28, which is widely used in Europe, and also to a great extent in the United States, is a calculator-based number based on the physician global, tender, and swollen joint count and acute-phase reactants. It does require a calculator. The simplified disease activity index was basically developed so you did not need a calculator. You basically add up all the things that are outlined on this chart. The drawback of the DAS28 and the SDAI was that they required an acute-phase reactant or laboratory. Some physicians’ offices do not have laboratory available the same day that you are seeing that patient, so your decision would have to be delayed. So we, with a clinical disease activity index, eliminated the acute-phase reactant and, interestingly enough, the validation was over 90% without it. This is an additive score. Dr. Cush has recently presented a very simplified measurement that has also been validated in a small group of patients looking at the modified HAQ plus patient pain on the VAS scale, plus just a tender joint count and all of these have been validated against one another.
Slide 16: The next slide basically shows measurements and how we would use these various scoring systems to indicate remission, low disease activity, or moderate and high disease activity on the right side of the slide; obviously, we would want to get more aggressive.
Slide 17: Now functional limitation in RA, is it reversible in looking at HAQ scores? This is a very interesting study in 2006 by Aletaha and his people, and basically we looked at reversible HAQ and irreversible HAQ. Certainly the longer the disease duration, the greater chance that the HAQ is irreversible and that makes common sense. On the other hand, if your disease duration is less than 2 years, the HAQ is completely reversible in the vast majority of patients, as indicated on this slide. So this is very important data and I think that if you have a patient with significant disease duration, you might even be able to obtain clinical remission despite the fact that the HAQ is not zero.
Slide 18: Now if a patient is not in remission, I think we need to attribute that to the fact that the response is inadequate. There are some definitions that I think need to be understood. Primary inadequate response refers to those patients with poor or no response to an agent. This is somewhat unusual. Secondary inadequate response refers to those patients who demonstrated early response but subsequently experienced a lack of response to an agent or required increased frequency of administration or perhaps the higher dose. As I pointed out, an inadequate or incomplete response is certainly preferable to failure of response, as very few demonstrate the response to therapy. And again, I would ask you all to remember that there is a disconnect between controlling clinical symptoms and signs and controlling radiographic progression. I think we need both imaging and clinical measurements.
Slide 19: Now would it be possible, based on your findings, to determine a responder versus a nonresponder up-front at baseline? If that were the case, we would see bimodal curves. And this would be a bimodal curve for a swollen or tender joint count, an acute base reactant or a HAQ score and, you will notice on this slide, these are not bimodal. These are typical bell-shaped curves as occur in most things in medicine, and you cannot pick out a responder from a nonresponder up-front so, again, no bimodal curves, unfortunately.
Slide 20: The definition of remission according to the method used does vary to some extent. This is a study of over 600 patients with 2 consecutive visits determined to be in remission and they used modified ACR70 versus a DAS28 versus a simplified disease activity index and a clinical disease activity index. As you can see, the percentages are quite close actually, around 16% to 20% and the validation of these has been shown to be very, very close. This was a paper just published in Rheumatology in 2007.
Slide 21: Now what about imaging techniques? Plain radiography certainly continues to be the gold standard for assessment of joint damage in rheumatoid arthritis. We do know that radiographic progression certainly is more rapid in early disease. Particularly in the first 1 to 2 years of disease, radiographic progression is much more rapid. This is why comparing clinical trials sometimes is not possible from group to group. This particular study, presented in the Journal of Rheumatology in 2007, shows that 3 months may be sufficient to show group differences in radiographic scores of subjects on DMARDs. Not individual differences, but group differences.
So moving forward in clinical trials, we might be able to make a judgment early. We know that radiographic damage is critically important. Why is so much attention paid to that? Well, we have learned that radiographic damage and disability are very definitely linked and disability is associated with increasing costs. So, again, radiographic damage is important as far as periodic measurement.
Slide 22: The next slide does show radiographic damage occurring in patients in remission by DAS44 of less than 1.6. The DAS44 refers to a 44 joint count as opposed to the DAS28, which is a 28 joint count more simplified. But the bottom line of this particular slide says that the DAS remission at 1 or 2 points does not always mean there is no radiographic progression. As you can see, new erosions occurred in 53% of these patients with DAS remission. Controlling the clinical symptoms and signs as well as radiographic progression is important.
Slide 23: The second case is a 62-year-old man with zero positive RA, 10 years of disease duration, who comes in for a follow-up appointment. He is taking methotrexate 20 mg per week and 4 mg of prednisone on a daily basis. He feels well. Has no joint pain or stiffness. Physical examination reveals only very mild swelling of the wrist. His laboratory studies, including acute-phase reactants, are normal. And radiograph of his hands does show a slight increase in erosion in the wrist over 12 months. Do we have any biomarkers that would reflect ongoing disease activity, or looking at this gentleman in a different sense that we need a more aggressive approach?
Slide 24: I think taking a look at the nomenclature, biomarkers are disease-centered variables. Patient outcomes, which we have talked about, are patient-centered variables. The surrogates are validated biomarkers that have scored above a certain threshold to perform in a clinical context. Risk or prognostic factors, which we have had available to us for years, can identify subgroups that might respond to a medication but are not necessarily biomarkers, since they cannot substitute for the target outcome.
Slide 25: Looking at biomarkers of joint destruction and repair, there are several groups. The imaging techniques are MRI, traditional and 3D, and ultrasound with power Doppler. The inflammatory markers would include the acute-phase reactants; CRP and sedimentation rate plus individual cytokines such as TNF, IL-1, and IL-6. There are genetic and major histocompatibility markers, the HLA-DR and a generation and function and T-cells. Then there are biochemical markers of bone resorption and formation, which are not available to us yet but probably will be in the future and those are the ratio of RANK ligands and OPG, osteopontin, osteoclacin and bone morphogenic proteins. Again, not readily available, but possibly will be in the future.
Slide 26: Ultrasound assessment in rheumatoid arthritis. Our European colleagues use it a great deal more than we do in this country. It is low cost and it is easily available. Certainly you have the ability to scan multiple joints, you can detect early erosions, increased blood flow, synovitis, tenosynovitis and enthesitis. The results are dependent, however, on the experience and skill of the operator, and in controlled clinical trials, this technology is somewhat untested. Reliability and validity studies are in progress, but I think this is something that we very definitely need to pay close attention to in the future.
Slide 27: MRI assessment in rheumatoid arthritis. Looking at evaluation of bone marrow edema, bone erosions and synovitis, an MRI scoring system, RAMRIS, was developed in 2004, and has been recently updated in 2006. There is now an atlas of standard reference images published. MRI outcome measures are published in proof-of-concept trials, but I think more validation certainly is required before MRI can be considered an accurate and reliable instrument to measure outcomes in rheumatoid arthritis. The technology among the different available machines differs significantly, and I think validation probably still is a bit away.
Slide 28: Rheumatoid arthritis patients in remission can show synovitis in bone marrow edema on imaging studies, and there have been multiple studies in this regard. This was a study presented in 2006 looking at 107 patients in remission by DAS or ACR70 criteria on DMARDs that had MRI and ultrasound with a Doppler performed. Interestingly enough, in these patients on remission, 96% had synovitis and 46% bone marrow edema on MRI. On a gray scale, 73% had synovitis and 43% increased blood flow on Doppler studies irrespective of the remission criteria slide, and interestingly, 18% of the controlled subjects had synovitis but no bone marrow edema. Obviously, in summary, imaging may be required for accurate assessment of remission in rheumatoid arthritis.
Slide 29: Now looking at biomarkers that independently predict joint damage, some of these are not available to us at any great extent at the present time, but CTX or c-terminal crosslinking telopeptide, looks at bone and cartilage turnover, COMP or cartilage oligomeric matrix protein looks at cartilage degeneration, MMP-3, matrix metalloproteinases, synovial inflammation, the ratio of RANK ligands and OPG, looks at bone resorption, anti-CCP antibodies readily available to us, looks at radiographic damage in early rheumatoid arthritis as a biomarker, and MRI, the ability to predict joint damage at 1 year. So we are developing these biomarkers as we move forward that will help us make better decisions.
Slide 30: I think the next major breakthrough in rheumatology is going to be in pharmacogenomics. This is the genetic and postgenomic diagnostics that will significantly alter our approach to the treatment of rheumatoid arthritis. It will allow us to develop risk profile determination, disease prediction, and earlier diagnosis. We could make therapy decisions with regard to response and adverse events and toxicity. A predictable response to therapy for each individual patient will result in a tremendous savings of time and, importantly, a significant cost savings, rather than running through 5 or 6 medicines when you can determine one that would be the best for this particular patient.
Slide 31: Now looking at CRP as a predictor of response, interesting studies have been presented looking at changes of radiographic progression by quartiles of CRP levels. If you have a CRP of less than 0.5, you can predict that that patient is going to have very little change in radiographic progression, either treated with methotrexate or an anti-TNF drug. If the CRP is between 0.5 and 0.8, the anti-TNF drug will still work well. There will be some slight progression with methotrexate, but if that CRP is over 0.8 and this is baseline data, you can predict fairly well that the patient is going to progress radiographically on methotrexate but still be controlled with an anti-TNF inhibitor. So this is very important information regarding our initial determination of medications for individuals.
Slide 32: Do anti-CCP titers have any clinical meaning? There are pros and cons about this. A large study of about 40,000 cohorts from the Women’s Health Study showed that there was no relationship between anti-CCP titer and traditional measures of disease activity, suggestive that anti-CCP titer really had little clinical utility as a marker of disease activity in rheumatoid arthritis. On the other hand, another study of about 300 patients showed that an anti-CCP titer over 100 baseline showed significant prediction for radiographic progression from baseline to 24 months.
Slide 33: Anti-CCP antibodies look at predicted progression of undifferentiated arthritis, and this was out of Leiden, an early arthritic clinic cohort of 900 patients, 346 of which had undifferentiated arthritis. And then they looked at the patients that were CCP positive versus CCP negative, and after 1 year, of those that were CCP positive, 83% developed ACR criteria rheumatoid arthritis. After 3 years, it was 93%. On the other hand, those who were anti-CCP negative with undifferentiated arthritis, only 18% had RA after 1 year and only 25% after 3 years. So certainly, anti-CCP can predict undifferentiated arthritis moving forward to fulfill the ACR criteria.
Slide 34: Now this is an interesting study that was presented at the ACR in 2006, as most people over the age of 50 in the general population do not meet the ACR criteria for RA remission. This was a self-recorded questionnaire with an 80% response rate. Interestingly enough, less than 5% of the RA patients and 15% of the general population met ACR criteria for remission. The conclusion here being that RA remission criteria in populations over 50 years of age might require re-evaluation as to their sensitivity and specificity because we have problems after the age of 50 in other body systems that may impair our ability to meet the criteria that we are now utilizing for RA remission.
Slide 35: The next generation of RA therapy. We have excellent drugs available to us now, certainly, better than we did a decade ago. But moving forward, we are going to have more available to us. There are other TNF inhibitors in phase II and III trials, adalimumab, which is a long-acting anti-TNF, certolizumab, which is a pegylated anti-TNF and then the TACE inhibitors. There are other anti-IL-1 preparations in clinical trials. There is an IL-1 TRAP. There is fusion protein. There is a monoclonal antibody to IL-1 and also the ICE inhibitors. Anti-IL-6 or tocilizumab in phase III trials at the present time looks promising as well as anti-IL-15. Anti-RANKL is a drug that is being developed for osteoporosis but has shown in trials of rheumatoid arthritis patients to halt radiographic progression very effectively, this is denosumab. Alefacept, efalizumab, and natalizumab are antiadhesion preparations. B cell inhibitors in addition to rituximab are anti-BLYS therapy, ocrelizumab and ofatumab. And then interest has been peaking significantly in the small molecules. Why? Well, because these will probably be oral, and if they are oral, their cost may, indeed, come down. The JAK-3 inhibitor got a lot of press at the ACR and EULAR. CC-100004 and the P38 MAP kinase inhibitors are also generating significant enthusiasm at the present time.
Slide 36: Now summarizing our pathways to remission, I think certainly early diagnosis and referral are critically important. Assessing prognostic factors, clinical factors, and imaging prior to drug therapy, is very, very important so we have something to compare with. We have learned that early aggressive combination therapy with adjunctive medications, DMARDs and/or biologics, is critically important. We need to base our decision, therapy-wise, on sequential clinical measurements and imaging, and the goal of drug therapy, indeed, is remission now with no clinical evidence of disease and no radiographic progression. I think the role of our imaging modalities, particularly ultrasound and MRI, need to be better defined. And, certainly, I think all of us need a better understanding of the key pathogenic events, which lead to and sustain chronic inflammation and joint destruction.
Slide 37: A study just presented this summer at the EULAR annual meeting looked at disease activity in the early course of therapy. The conclusion of this study was that the best predictor of remission is low disease activity at 3 months. Baseline disease activity was important, but especially disease activity achieved at 3 months is significantly related to disease activity later in 1 year, so intensive strategy to evaluate responder status at 3 months is certainly the best approach at indicating early aggressive therapy.
Slide 38: Now just looking at a bunch of statements and true or false, I am just going to answer these because these are all things we have learned. TNF inhibitor monotherapy is superior to methotrexate in controlling symptoms and signs of rheumatoid arthritis. This is not true. We have learned that methotrexate controls symptoms and signs just as effectively statistically as TNF inhibitors. What it does not do is control radiographic progression as well.
Ultrasound is superior to clinical examination in rheumatoid arthritis. This is true. It is very definitely shown to be better than clinical examination.
Anti-CCP is more specific but less sensitive than rheumatoid factor in early RA. This is false. It is more specific and more sensitive in early rheumatoid arthritis.
Remission rates in excess of 60% can be achieved with nonbiologic DMARDs. I think most of you would say that this probably is not true. But we saw that in the TICORA trial, remember, 65% on traditional DMARDs obtained remission.
Radiographic progression may occur in patients with an excellent clinical response. We have learned that in multiple trials. We have seen it with the anti-TNF trials. We have seen it particularly with methotrexate.
Radiographic damage occurs more rapidly in early disease. This is very definitely true.
Elevated HAQ scores are more likely to improve in late disease as opposed to early disease. That is false. A reversible HAQ is usually present up-front, and the longer your disease duration, the less chance of reversing the HAQ.
