In deze video bespreekt Peter Taylor (University of Oxford, VK) hoe de resultaten van de SEAM-RA-studie de richtlijnen voor de behandeling van reumatoïde artritis kunnen beïnvloeden, en welke vragen voor toekomstig onderzoek hieruit naar voren komen.
One of the recommendations that crops up in both the current American College of Rheumatology recommendations for the management of rheumatoid arthritis and in the EULAR recommendations for the management of rheumatoid arthritis is that if our patients are on an advance therapy and are in remission that we might consider tapering down the dose. And this, of course, is very appealing when it comes to cost effectiveness of drugs. But on the other hand, there’s really relatively little evidence about how to do this in a way which ensures ongoing benefit for patients. And so the SEAM-RA study actually set out to address this problem. And it did it in a very interesting and robust way, because it was a study that was based on patients recruited who were on etanercept, the standard dose of 50 milligrams by subcutaneous injection once weekly, in combination with methotrexate at a varying dose between 10 and 25 milligrams orally once a week. And it asked the question, can you actually maintain a remission, if you’ve had remission for some time, by either withdrawing the etanercept or by withdrawing the methotrexate? But what was particularly pleasing about the design of this particular study is that the remission not only had to be maintained for up to six months, but it had to be a deep remission. So this was a remission by a metric called the SDAI, which is a fairly stringent measure of remission. And I think that’s important because had they chosen DAS28-CRP, which is a much less stringent measure of remission, then perhaps we would have had rather less confidence in the findings. What happened with this particular study was that after randomizing patients who had maintained remission by SDAI for some time, they were then randomized into one of three arms, either withdrawal of the methotrexate, withdrawal of the etanercept, or continuing on etanercept plus methotrexate, and it was a 2:2:1 randomization, with the smaller number on the combination therapy. And the patients were then followed for 48 weeks, and the primary endpoint was actually SDAI remission, which is a remission of 3.3 or less, and that’s what they were looking at. And then they looked for any time for loss of remission. And what the findings were were as follows, that firstly, and perhaps somewhat disappointingly, on the combination arm, only just over half the patients actually maintained this SDAI remission at 48 weeks. So in fact, 53%, more or less, maintained the remission if they were on the combination arm. But more pleasingly, the etanercept monotherapy patients had a very similar number, with 49 and 1/2% of patients maintaining remission. And this was statistically significantly higher than the proportion who maintained it on methotrexate, which was just under 29%. So one could say that what this study showed is that if you withdraw methotrexate that you’ve got a fairly similar chance of maintaining remission if you’re on etanercept monotherapy as if you’re on combination therapy. And given that one of the major problems of concomitant methotrexate is that it’s not always terribly well-tolerated– in fact, many patients stop taking their methotrexate because it’s not well-tolerated, and they may not even tell their physician that that’s the case. It’s estimated that a 1/3 or more of patients stop their methotrexate– then from that point of view, this is actually a very useful result to have. The other aspects of the results here were, as I say, rather disappointing, a large proportion of patients lost their remission state. And that happened gradually over time over a period of about six months or more. But for those patients who lost their remission state, it turned out that it could be regained fairly straightforwardly, and particularly if the patients went back on to combination therapy with etanercept and methotrexate, in which case about 80% of patients would eventually regain remission. And in fact, 100% of patients regained a low-disease activity state over the course of something like 24 to 44 weeks. So what impact might these results have on guidelines? Well, I think they’re very informative because what they might suggest is that firstly, if you’re going to consider tapering medication for patients that are doing relatively well on treatments, firstly, you want to know that they’re in a robust remission state. And I think that means that they have, at the very least, to be in a DAS28-CRP remission, but ideally in a deeper remission, so perhaps a DAS28-ESR, or an SDAI, or CDAI would be preferable. And most probably, you’d need to be in a remission state for at least six months. And then if you’re going to move to a single therapy rather than a combination, then it would be preferable to move to etanercept as a monotherapy is what this particular set of results would imply. But we can perhaps assume that similar findings might also be the case if one were to use other anti-TNFs, but of course, that’s yet to be proven. The other issue that I would very much like to see coming into guidelines is that for those patients who maintain their remission state on a lower dose, then that’s obviously a very good outcome. But for those patients who lose their remission state, which is a very high proportion of patients, that they should be able to go back onto the original therapy with a view to a rescue program to regain the remission state. And I’d like to see that creeping in because in some health care economies, such as, for example, in the United Kingdom where I work, it is not necessarily the case that you’ll get the original regime reimbursed if you’ve once stopped it. Well, there are several potential limitations. So for example, in this study recruitment was allowed for patients who were taking low-dose prednisolone. And you could potentially say that was a limitation, because idealistically, if you’re going to think about reducing an advance therapy or reducing the concomitant methotrexate, you’d like to see that patients were off steroid treatment first. But in actual fact, it turned out that across the randomization arms in this study, there were very few patients, indeed, on prednisolone, and so I think the investigators are to be commended for that. With respect to other limitations, of course, we only have results for one particular anti-TNF, namely, etanercept, and it’s not absolutely clear that these results would pertain with other anti-TNFs. And there are four other originators and, of course, many biosimilars now, but I don’t think it’s unreasonable to assume that there might be similar data if other anti-TNFs were involved in a trial design such as this. There are numerous opportunities for research that might emerge from this trial. I don’t believe the analyses have been done yet based on the presentation we heard at the American College of Rheumatology meeting. But one of the key questions is, are there predictors of those patients who will attain and maintain a remission status? And that’s really a very critical question. The other research question that I think is very important is for those patients who lose their remission status, in other words they flare to some extent, the data suggests that it may take quite a bit of time for them to regain remission status when they go back onto the original therapy or have reintroduction of etanercept as a monotherapy. And of course, this has implications, because it means the time-integrated inflammation that the patient’s exposed to could potentially result in structural damage or even functional loss. So we need to see the post hoc analysis data to understand whether there are any detrimental effects of allowing a patient to flare and then retreating with a view to gaining remission. And we need to know about predictors of either maintained remission or predictors of loss of remission. And of course, that would inform clinical practice.
Provided by Medicine Matters rheumatology; ©2020 Springer Healthcare Ltd, part of the Springer Nature Group.