The rationale for the SEAM-RA study is intended to inform the question, for rheumatoid arthritis patients who have been doing exceedingly well, like are in remission and have been that way for quite some time, on combination therapy with methotrexate and a TNF, in this case, etanercept, whether one needs to continue both of those therapies indefinitely, or whether one might withdraw one of them, and if you're going to withdraw one of them, which should you withdraw? Should you withdraw etanercept, or should you withdraw methotrexate?
The reason that this is an important question is for somebody who, say, maybe in their 40s or 50s, they might need decades long therapy, and if they had to stay on both of those but didn't need to, then they're basically being over-treated, and one obviously wishes to avoid that. Patients certainly would like to be on whatever medicines are needed to keep them under good control, but not any more than that, and so the notion about whether therapy must be continued lifelong really has not been answered.
There have been some prior trials that have spoken to this question to some extent. The way in which though the SEAM-RA trial is really fundamentally different is that it starts with people in remission, and this isn't DAS28 remission. This is SDAI remission. This is arguably the most rigorous and, in my opinion, most reasonable level of disease activity that one might ask for, and frankly, those are the kinds of patients that are talking to me and that I'm approaching about possibly tapering or withdrawing one or more therapies for RA.
So patients that were eligible were those that were adults who in the investigator's judgment had very good RA disease control and importantly, had a low SDAI or Simplified Disease Activity Index of less or equal to 3.3. So this would be consistent with the ACR/EULAR criteria for remission, and again, it is a departure and a novel aspect of the study. Most prior trials looking at this question have not required that level of rigor for doing well and might only, for example, ask for DAS28 remission, which is not nearly as stringent.
So people had to be on both etanercept and methotrexate for at least six months, and then they were required to undergo a run-in period for 24 weeks. So the idea there is that there can be some natural oscillations in RA disease activity, but we really wanted to confirm that they were in remission, not just in the judgment of the clinician at the site, but that they had been observed for six or more months and were able to be stable and to maintain remission.
So those that were able to maintain remission over that 24 week run-in period were randomized 2 to 2 to 1 to receive either etanercept as monotherapy or methotrexate as monotherapy, or to continue both of them as basically the comparator arm, so as to have a benchmark for how well people might do if you don't perturb anything, you just let them continue the same treatments.
So this double blind treatment period was 48 weeks long, and the main comparisons were to compare etanercept as monotherapy where the patient had discontinued methotrexate versus methotrexate as monotherapy, where the patient had been discontinued etanercept. So it answers the very practical question, which one of these should you withdraw? Maybe they're both about the same, but the direct comparison was between the withdrawal of etanercept and the withdrawal of methotrexate.
So the main findings were that at week 48, the proportion of people on methotrexate monotherapy who remained in SDAI remission without disease worsening was approximately half the etanercept monotherapy arm. So it was 28.7% versus 49.5%. That was a statistically significant difference, and so the practical implications are of the trial that if you're going to take away one of those two therapies, methotrexate or etanercept, you're almost certainly better off to take away the methotrexate and keep etanercept in place, and that those people did the best.
Interestingly enough, the people who are on etanercept as monotherapy did numerically about the same in terms of maintaining SDAI remission as the people who have continued on combination therapy. So the proportion who stayed in SDAI remission on combo therapy was 52.9%, which numerically is quite comparable to the etanercept monotherapy arm. So those two arms were quite similar, but both of them were different and statistically significantly different than the methotrexate monotherapy arm.
The other important and very practical aspect of the trial was to look at what happens if people lose SDAI remission. They flare, they no longer have good disease control and need to be rescued. The rescue treatments are typical to an RA trial. You're allowed to use glucocorticoids or pain medicines for up to two weeks, but then one of the secondary outcomes of the study was to look at the amount of time that it might take to capture either remission or low disease activity, and very importantly, the vast majority of people were able to get back to remission or to low disease activity.
And so this is the very helpful second aspect of the trial that's quite practical, in that if you choose to take away one of the therapies, methotrexate or etanercept, and patients don't do well, the likelihood that you can recapture them back to good disease control, at least low disease activity if not remission, is nearly 100%. And that takes roughly about three to six months on average for patients that did have a temporary loss of disease control, but what it means in communicating with patients is that this is a relatively low risk thing to try, and if this doesn't seem to work out particularly well, that in most cases, you're going to get them back doing well by resuming combination therapy with both etanercept and methotrexate together.
Yeah, that's a great point, and it does imply the willingness to take away one or the other therapy, and patients may obviously have quite strong preferences in that regard. There is certainly a substantial literature as well as probably anecdotal experience, both from my practice and that of all practicing rheumatologists. There are certainly factors, particularly with methotrexate, that make people feel poorly, yet nevertheless are not true contraindications.
So for people that might have GI upset or nausea or just malaise or the blahs, if you will, they feel quite ill, particularly on the day or two after methotrexate. Sometimes those are things that might not rise to the level of complete discontinuation of methotrexate, but this notion that these are people that are grudgingly on methotrexate, they don't feel well on it, but they've been told, and they probably recognize, it's important to maintain their good disease control, and so they're willing to stay on it, they're just not terribly pleased about it.
I think asking about those kinds of questions and really putting it to the patient. If you have the choice or if all other things were equal, is one of these two treatments something that you would like to get rid of more quickly? And in my own practice, I find that there's a whole lot of nuisance aspects and side effects that people have with methotrexate that may make that the preferred option to discontinue, and to try to get rid of first. The SEAM-RA trial, of course, showed that if you take away methotrexate and leave etanercept in place, that the likelihood you'll continue to do well is significantly higher than if you tried to withdraw etanercept.
Some of those people still do well, but only about half as many. So if you are going to withdraw therapy, probably getting rid of methotrexate first is likely the important option. The other consideration that I would just make brief mention of, as an inclusion criteria for the trial and unlike many RA trials, prednisone was allowed but only at doses of up to 5 milligrams per day, and there were very few people actually who were even on any prednisone at all at any dose.
And so I would just make a point of the fact that if somebody is on combo therapy with methotrexate and etanercept and higher dose glucocorticoids, prednisone, prednisolone, 8 or 10 milligrams a day first, for example, probably that the steroids should be withdrawn or tapered first. And that would be consistent with the inclusion criteria of the SEAM-RA trial just because long term, higher dose glucocorticoids is probably the thing that you want to take away primarily, and then you can think about some of the other medications like methotrexate.
The only other thing that I would make a point of as next steps is, it would be ideal to know not just on average the likelihood that patients are going to do well if you withdraw methotrexate or etanercept, the SEAM-RA trial, of course, directly informed that, but which individual patients or patient characteristics are likely to do well and maintain good disease control off one or the other medications?
And so that's an ongoing aspect of the research agenda that will come out of this trial database, is to try to build predictors of what are those patient characteristics that are associated with doing well in the future if you stop one or the other medication, and given the large size of the trial, and the fact that there's an underlying biospecimen repository, I'm quite optimistic that we might be able to find individual predictors of those who can successfully discontinue one or the other therapy. So ongoing work in that regard directly from the SEAM-RA trial data.