COMMENTARY

Say 'Guten Tag' to 8 Important Rheumatoid Arthritis Studies

Jonathan Kay, MD; Ronald F. van Vollenhoven, MD, PhD

Disclosures

June 20, 2012

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Jonathan Kay, MD: Hello, I am Jonathan Kay, Professor of Medicine at the University of Massachusetts Medical School and Director of Clinical Research in the Division of Rheumatology at UMass Memorial Medical Center, both in Worcester, Massachusetts. Welcome to Medscape. I am in Berlin at the EULAR (European League Against Rheumatism) 2012 meeting. Joining me is Ronald van Vollenhoven, who is Professor of Therapeutic Medicine at the Karolinska Institute and chief of the clinical trials unit in the Department of Rheumatology at Karolinska University Hospital in Stockholm, Sweden. Welcome, Ron.

Ronald F. van Vollenhoven, MD, PhD: Thank you, Jonathan.

Dr. Kay: I want to discuss 2 issues with you. One is the issue of induction therapy. Can we use shorter periods of time with potent biologic agents to induce remission that might be maintained with less expensive therapy such as methotrexate? The other is, what long-term, lasting benefits besides remission of disease activity might we be able to achieve with biologic agents?

Let's talk about induction therapy. A number of presentations have touched upon induction therapy. One study was the IDEA study[1] from Paul Emery's group in Leeds, United Kingdom. This study compared adjunctive infliximab vs adjunctive intravenous methylprednisolone given periodically to control disease activity in patients with an inadequate response to methotrexate. The long-term goal was to learn whether one option was better than the other at inducing remission, but the investigators presented preliminary data that described the response to each of these therapies.

Dr. van Vollenhoven: These investigators wanted to find out whether it makes a difference to give a very intensive treatment for a short period of time, and also what the long-term benefits are. This trial from the United Kingdom showed a very good effect for adjunctive infliximab, which was expected. The study also looked at intravenous methylprednisolone, which is not used as much in rheumatoid arthritis therapy, although it is certainly an established way of treating severe rheumatic disease, such as lupus vasculitis. Intravenous methylprednisolone also worked very well. In the follow-up there were no major differences, so I think both options could be considered in your patients.

The interesting question that comes up at this meeting, in very many presentations, is, if you do something for the patient that makes them better right now, does it have a carryover effect that you can maintain? One interesting trial was a study using certolizumab and presented by Professor Smolen,[2] who said that if you give the anti-TNF agent certolizumab to the patient who has moderate disease, the patient will improve, which is, of course, as expected. This conclusion is not trivial because patients with moderate disease are not always started on anti-TNF, as you know. Sometimes people say that this is not necessary for those patients. This trial showed a big improvement, but in this additional analysis, it turns out that if you stop it, patients will revert to their pretreatment status. In that setting with the established disease, this benefit is not sustained, which is a bit disappointing but what we have to accept.

When to Treat

Dr. Kay: Those are patients with moderate disease. In many countries where regulatory authorities govern who can receive anti-TNF agents, they require a Disease Activity Score (DAS28) of 5.1 or higher, indicating high disease activity. Might treating lesser disease activity, not only moderate disease activity but low to moderate disease activity, achieve better results? Could a short course of a biologic agent in someone with lesser disease activity allow you to avoid the need for a biologic agent further along?

Dr. van Vollenhoven: I think you are absolutely right. If you treat patients who have moderate disease with anti-TNF, which is a bit controversial in some countries and certainly not widely accepted, then you actually do see very good improvements. Sometimes these patients seem to be responding even better than the patients with high disease activity and achieve a better functional status and better quality of life. Of course, you can debate whether it is cost-effective to do that. The medical benefit is very clear. That was shown in the trial I just mentioned and also in other studies. In terms of maintaining a benefit after you have treated a patient intensively, that question comes up a lot in the context of early rheumatoid arthritis. As you know, such a trial has already been presented at other meetings, and additional analyses were presented at this EULAR Congress. This was the OPTIMA trial of adalimumab[3] in a complex design: an initial randomization to methotrexate alone vs methotrexate plus adalimumab vs placebo, and followed by an additional randomization for the patients who did well on the combination, which was also double-blinded and randomized. In the extension, patients either continued on the combination or continued on the methotrexate without adalimumab. One of the important findings of that trial is that many patients who do well initially with a combination of methotrexate plus the anti-TNF agent can actually maintain the good response with just methotrexate, which supports induction maintenance. However, another trial reported at the 2012 EULAR meeting, presented by Professor Burmester from Berlin, Germany, showed results that will [cause some controversy]. This trial was called Hit Hard,[4] so you know what they were thinking. Patients with early rheumatoid arthritis were hit hard with methotrexate plus adalimumab and did well. But when the adalimumab was stopped, the benefits were not maintained, and patients returned to their status with just methotrexate. There was a small benefit because during the time of more intensive treatment, some radiographic damage was prevented, and that is still very important, especially for the long term.

Improving Quality of Life

Dr. Kay: You mentioned quality of life and the use of biologic agents to improve quality of life. You and your colleagues in Sweden have done a wonderful job with the Swefot study, which used methotrexate to treat patients with at least moderate disease. Patients with an inadequate response to the methotrexate were randomly assigned to either infliximab plus methotrexate or triple therapy [with sulfasalazine, hydroxychloroquine, and methotrexate]. An analysis presented here looked at quality of life.[5]

Dr. van Vollenhoven: Johan Karlsson did a terrific job on these analyses. In this Swefot trial and in other trials, we see that if you give anti-TNF up front with methotrexate, or in Swefot, where you wait for 3 or 4 months to see if patients will respond to methotrexate (and if they do not, you give anti-TNF), you get a very good result with an anti-TNF agent. These are very good drugs. You can actually also get a good result by adding DMARDs (disease-modifying antirheumatic drugs). In Swefot, it turns out that after 2 years, the difference [in outcomes] was not statistically significant anymore. There was a radiographic benefit to giving anti-TNF, which is a strength of anti-TNF therapy; these treatments prevent almost all radiographic progression. The issue was, does anti-TNF therapy give a better quality of life to the patient? In the analysis presented here, it turns out that both treatments provide a good quality of life, much better than when patients started treatment and with no difference between the 2 options. That says that anti-TNF is a very good option, but adding conventional DMARDs is also a very good option for the patients. We may need longer-term [analyses] to see whether the radiographic difference will lead to a quality-of-life difference, but at this point we do not see it.

An Update on Comorbidities

Dr. Kay: The focus on comorbidities with rheumatoid arthritis is increasing -- cardiovascular comorbidities, malignancy, presenteeism/absenteeism from work. A couple of abstracts presented at this meeting have addressed the long-term benefit of treatment of rheumatoid arthritis [on several comorbid conditions].

Dr. van Vollenhoven: That is such an important area, because if you treat with something like an anti-TNF agent, you know that it will give a patient good symptomatic control but you always wonder what it is doing in the long run with this disease that, by itself, left on its own, is going to progress. There were several very important presentations at this EULAR Congress. One was from the United Kingdom and looked at surgeries.[6] If you give a good treatment to the patient [with rheumatoid arthritis], you would hope that you can prevent a need for surgeries, right? Surgeries always reflect how badly things are going. Indeed, a registry-based study compared patients who received anti-TNF therapies with those who received nonbiologics and DMARDs. It turned out that, especially surgeries of the small joints such as the hand surgeries, the wrists, the numbers of surgeries did come down with anti-TNF treatments after years of follow-up, showing a benefit for the biologics That is a clear indicator that we are achieving some long-term gains.

Two other very interesting findings were also presented at the EULAR meeting.[7,8]A group from Amsterdam looked at cardiovascular events -- heart attack, stroke -- events that you would like not to happen.[7] They compared these events in patients treated with anti-TNF agents vs patients treated with conventional DMARDs and found fewer events like that in the group that received the anti-TNFs. You might wonder whether that is because the anti-TNF group may have had fewer risks [to begin with], so the investigators said, let's look at the risks. They looked at all the known risk factors found in the Framingham study and elsewhere and could not find an explanation for the difference. One issue could be channeling bias, which is a term used for these registry studies, because you [the investigator] select the patients. But the results were quite convincing and may support the idea that with anti-TNF treatment or biologics in general, you actually can achieve a situation where the patient is less at risk for the cardiovascular events.

Another very interesting long-term result would be improved survival. Is that not the ultimate goal? We do know that patients with rheumatoid arthritis actually have a shorter survival, not because of the disease directly but from all the consequences of the disease. A German study based on the RABBIT registry and presented by Dr. Listing[8] here at this meeting showed that the patients who have a good response to the anti-TNF biologics do seem to have a better survival than the patients with rheumatoid arthritis who are not treated [or do not respond to treatment] with anti-TNF biologics.

Dr. Kay: That is an extension of data that have been published or presented elsewhere, which showed that cardiovascular events are lower in patients who are anti-TNF responders but not necessarily in all anti-TNF-treated patients; the nonresponders or inadequate responders did not have a reduction in cardiovascular risk.

Dr. van Vollenhoven: Correct, and that is totally logical. If you respond, you will have a benefit, but not if you do not respond.

Dr. Kay: Right. We have evidence that logic holds true.

Dr. van Vollenhoven: Every once in a while.

Dr. Kay: Every once in a while. Studies are now really beginning to investigate new treatment approaches to rheumatoid arthritis, such as induction therapy and looking at long-term outcomes. As the year progresses, I look forward to seeing these presentations published and to talking to you next year in Madrid about more studies. Thanks very much, Ron.

Dr. van Vollenhoven: Thank you.

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