Cohen: Well, hi to my listeners, this is Dr. Marc Cohen, and I am happy again to discuss with you advances in the efficacy and safety of TNF inhibitors. This is a subject of great interest to me and I’ve been able to share some information with you previously.

This time we are going to be again thinking about the concept of induction and maintenance with the treatment of rheumatoid arthritis. The concept is that we would treat patients as early as possible as aggressive as possible, and then perhaps to continue treatments with either different drugs or less drug or at least something less aggressive over an uncertain period of time to maintain clinical remission or a low disease activity state. This is a concept that I think we imagined maybe ten years ago for the last I would say two or three years there have been several studies just beginning to evaluate whether the concept is practical. And, I think there is now some data to discuss. We tried last time, and I will give you some new information this time.

So, with that in mind, if you look at the list of studies that I have in front of you, I’d like to talk about five separate studies all from 2012, and I think they represent different approaches to this concept and I hope you’ll find it interesting.

The first is the continuation of the evaluation of the so-called OPTIMA trial. This trial is very interesting to me, it has several purposes. It has a rather complicated set up, and I just want to remind you of that before we look at some data. So, the set up is that you’re taking patients who are treated with a combination of the TNF inhibitor, in this case Adalimumab, so TNF inhibitor plus Methotrexate, that’s one group. The other group is placebo plus Methotrexate. At 26 weeks, we’re going to evaluate who’s in low disease activity state or remission, and then we’re going to redefine the treatments. So, if in fact you’re a responder to the TNF inhibitor plus Methotrexate, at that point you are randomized to two different groups, one of which is placebo plus Methotrexate. So, we’ve taken away the TNF inhibitor after 26 weeks. The other is, again, continuation of the TNF inhibitor plus Methotrexate.

So, we have the opportunity at 26 weeks to compare maintenance therapy with Methotrexate compared to the aggressive initial treatment of the TNF inhibitor plus Methotrexate. If you don’t respond, both of those get shipped over to an open label extension, which I won’t discuss. The other group was placebo plus Methotrexate, that was the original group. And, if you were a responder to that, then you would continue to get placebo plus Methotrexate. If you don’t respond, then Adalimumab is added in an open label extension. So, I’m very interested in what’s happening to this concept of maintenance with Methotrexate to maintenance with a TNF inhibitor plus Methotrexate. And last year they reported the group responsible for OPTIMA reported some data that seemed some patients were able to hold their low disease or remission state on Methotrexate alone. We’re going to, at least with the slide I have in front of you we’re going to discuss the groups that didn’t respond, and then I’ll come back to make some conclusions about this.

So, at 26 weeks we’re going to look at the non responders, and we’re going to add the people who didn’t achieve low disease activity and we’re going to add Adalimumab and see what happens. And, in fact, the addition of Adalimumab to non responders resulted in improvement. I don’t think that’s necessarily a surprise, but the degree of improvement might be. You can look at how many patients achieved a very low disease activity state. How many patients were in remission, and then there’s the concept that adding the TNF inhibitor, also again allowed for radiographic improvement. All of this was statistically significant, and the conclusion is that in patients with disease that didn’t respond initially to Methotrexate or even with the combination, if you continue to treat them with a TNF inhibitor, they do better. And, the corollary is what I want to emphasize, and that is patients who have the Adalimumab withdrawn may lose that degree of control. So, there is the hint in this presentation that it’s very difficult to know which patient might respond to Methotrexate alone as maintenance. And, in fact there are patients who get that and they don’t do well. So, to me this is a follow up sort of evaluation of a subset of patients. Making a different point, I think. But, it also is a comment indirectly on whether maintenance is truly possible with Methotrexate alone. And, it might be for certain patients, but we’re having difficultly figuring out who those patients might be.

The next trial is the so called IDEA trial also presented in an only clinical form previously, this time we’ve got 54 patients randomized to Infliximab plus Methotrexate, or IV methylprednisolone and Methotrexate. Now, I’ve got the 50 week data in front of me and the radiographic data in front of me, and it’s fascinating. So, again if we use high dose corticosteroids initially, taper them quickly but use them initially, in fact you can’t tell the difference between the two groups. So, these are two different approaches, aggressive approaches to early treatment of rheumatoid arthritis, one with the TNF inhibitor, in this case Infliximab, the other with high dose corticosteroids. And, in fact, at 50 weeks you can’t tell them apart. You can’t tell them apart clinically, you can’t tell them apart radiographically. So, this is questioning whether or not in the induction phase, the use of immediate TNF inhibition is necessary. Whether it’s better or worse than IV prednisolone, methylprednisolone I’ll leave that to you, but at least here I think the conclusion is sustained response, remission rates, and radiographic control were achieved with two different strategies, and that’s again a little bit surprising. Just a little bit of a pull back from this need to treat aggressively, up front, with TNF inhibitors.

The next trial, it really sort of is the same concept, and this is the NEO-RACO group, the Finnish group that reported a different group of patients than previously sort of justifying sort of the aggressive treatments and early eval, reevaluation and changing treatment that we’ve seen before in RACO, well this is NEO-RACO. 99 patients just treated with triple therapy and a little pred. Then, so they get it up front, and then they’re randomized to up front they’re randomized to Infliximab or IV methylprednisolone. At two years, they can sort of be treated with whatever they want, and they have five year data. And they look at the comparisons and the remission rates, the total Van Der Heijde Sharp Scores; there isn’t any difference. In fact, the conclusion here is that the targeted treatments, aggressive repeat evaluation, change treatment as necessary, targeted treatment with combination DMARDS results in clinical remission and radiographic control regardless of whether or not the initial treatment includes a TNF antagonist. So, very similar concept to the last, again if we’re going to treat with induction, what should that be? Do, we need a TNF inhibitor up front?

So, questioning now induction therapy, the OPTIMA trial was looking at maintenance therapy,

and the next trial, just to even things out, is the CERTAIN trial, all caps there. This is longstanding RA, so a different group of patients there. So, we’ve got 96 patients that we’re going to give Certolizumab to, and we’re going to compare that to traditional DMARDS and we’re going to see what happens at 24 weeks. At 20 and 24 weeks, if they’re in remission, we’re going to stop the randomized therapy. The people who are on conventional DMARDS will continue. So, what happens at 24 weeks? Well, more patients who get the TNF inhibitor seem to have low disease activity, but then from 24 to 52 weeks, if they’re not on a TNF inhibitor, they really can’t sustain or retain that positive response. So, here the conclusion was if you, you know, stop the TNF inhibitor after you get to where you want to be, you’re unable to maintain remission. So now, again I’m questioning this concept of what are we going to do for maintenance.

Last slide, just to complete the cycle is the Japanese trial JESMR for which there was the radiographic piece added this time. So, this was a fascinating trial because 151 patients on Methotrexate who were considered incomplete responders. So, they stay on Methotrexate and they’re randomized to either Etanercept plus Methotrexate, or Etanercept alone. So, this time we’re going to take away the Methotrexate in one of the groups. And, what happens? Well, this is interesting. Here according to, and this is a follow up to previous reported trial, stopping the Methotrexate here led to more radiographic progression. So, in this situation it didn’t even seem like you could get rid of the Methotrexate. Previously, we looked at trials stopping the TNF inhibitor, it’s expensive, etc., but here you can’t even stop the Methotrexate and sustain the same kind of response, particularly radiographically.

So, to me, my summary of this, and these are my comments, maybe has to do with a little bit of pull back on the enthusiasm for discontinuation strategies, and also a little bit less enthusiasm I think this year as to whether or not initial aggressive treatment has to include a TNF antagonist. I think there are certain patients that can discontinue the biologic. But in those patients you have to watch them very carefully because a significant amount of them will not be able to sustain their low disease activity state.

Well, I’d like to sort of change topics a little bit and think about what else is out there. There was a nice report of what was called a TNF kinoid. So, this is given and you sort of self induce a polyclonal antibody response. So, you’re getting, you’re creating your own TNF inhibitor. And, in this early report, not that many patients, this was 40 patients. And, in a study from France three injections of this TNF kinoid gave you an appropriate immunologic response 100% of the time. In fact, two thirds with only two injections. And, most of the patients, at least half, who developed antibodies had the best EULAR response. So, I think that’s interesting. Inclusion quickly is active immunization with this product, was safe and immunogenic. You know, the question is how often are we going to have to give it, how long is this antibody response going to last, will it sort of decrease over time, what kind of responses are we going to get. So, all kinds of frequency duration, robustness, and that’s to be determined. But, interesting new comments, an approach to TNF antagonism.

The next slide I think was also interesting, and this may be the future. This was 200 patients in the Netherlands, and this group in the Netherlands does really excellent work. So, they’re on a TNF inhibitor in this case Adalimumaband were measuring trough levels and this was very interesting because trough levels had tremendous variation, between zero and 33 micrograms per mil. And, the patients who had very low levels did not respond clinically, and in those patients they all developed Adalimumab antibodies. So, a lot of consistency there. And then they defined the appropriate dose range between three and 12 micrograms, which I thought was quite narrow. And, in fact in that group the clinical response correlated with the serum levels. And, even more interesting, the higher levels didn’t get you anywhere. So, the conclusion here was fascinating, trough levels fluctuated widely to get max clinical effect. There was a narrow dose range, and the conclusion was that many patients, and you can see it in their graph, many patients are getting too much drug. Monitoring drug levels, in fact, might lead to really appropriate dosing, it would be a personalized approach. This really is an interesting comment on what we’re going to be able to do in the future. It’s going to be very interesting to see if it’s true for the other TNF antagonists or whether the other people could reproduce this work.

And now, I’m going to switch topics entirely and talk about safety issues. The slide that you’re looking at is really my approach. Over this last year, there has not been any new definitive studies looking at malignancy. I think that the conclusion this year still is the same. No increase in solid tumors. I think skin cancers including melanoma may be increased. We need more definitive information about melanoma. With regards to infection, really not much new. Obviously, I hope, bacterial, viral and opportunistic infections increased, you know that. The incidence of trouble on TNF inhibitors is probably between Methotrexate and corticosteroids, does not seem to be increasing over time. Comorbidities are critical; we need to control some of them. We need to be vigilant, we need to be aggressive with signs of infection. Now, cardiovascular disease has seemed to be the theme this year. There were several detailed reviews in the literature including one in Arthritis and Rheumatism. The feeling is in rheumatoid arthritis, as well you know, cardiovascular risk has increased in TNF antagonists, it’s probably decreased via myriad pathways. We still need to think about risk factor control. And then, which cardiovascular tests might help us is an ongoing discussion.

And really, I’ve just pulled two trials I’ve found interesting, one for different reasons.

The first is the TNF risk and infection, post op total knee and total hip arthroplasty from Canada. They looked at 236 patients who seriously had 347 procedures. They had seven infections at the surgical site, 4 at other sites. And, the comment was the risk of post op infections seemed to be related to steroids and/or Lefleunomide, they couldn’t associate a risk with TNF inhibitors, didn’t seem to matter what the comorbidities were. So, here the conclusion was post op infection was not related to biologics, comorbidities, DMARDS except lefleunomides and steroids, particularly high dose steroids, which was more than 10 mg.

I don’t understand why we don’t have a definitive trial about post op risk. We have several trials that are messy; this is not that many patients, with sort of dramatic conclusions I’m not sure they can make with 7 surgical site infections. So, a little call out trial for the definitive risk of TNF inhibition and surgery, particularly joint replacement surgery.

And lastly, a very nice trial looking at TNF inhibition and cardiovascular risk, and in this situation, acute coronary events. This is from the Swedish registry, which I think is one of the best out there. For each patient on a TNF, they had three patients not on a TNF and five general population referents. This group does really beautiful work. They had 85 acute coronary syndrome issues, and the conclusion was that the hazard ratio of having an event was not, was really not very dramatic, and they could not demonstrate a particular effect with TNF inhibition.

So, I think this is a group with a lot of patients in their registry doing very careful statistical analysis and could not come up with an association between TNF treatments and acute coronary syndromes. We’re hoping to demonstrate that aggressive treatment with TNF antagonists might improve the situation, but they could not make that conclusion. And, they discussed why not, maybe not enough events, etc. But, I’m presenting this to you because I think we’re all walking around now patting ourselves on the back that we’ve controlled risk, and we may have. But it’s been a little difficult to prove particularly by groups who do the best work. So, I’m a little concerned about whether we’ve justified the conclusion.

So, that’s what I’ve selected to present to you regarding TNF antagonists both with regards to efficacy and safety. I’ve had a very interesting year with regards to that. I’m looking forward to the future particularly with regards to the concept of induction maintenance and maybe clarifying the risk of infection and cardiovascularly. So, thanks so much for listening and I hope you’ll come hear me next time as well. Thanks.