I actually started investigating rheumatoid arthritis immediately after my medical school studies, which was quite a long time ago. I started working in the late 1970s as a post-doctoral fellow at the Institute of Immunology here at the University of Vienna, and rheumatoid arthritis and autoimmunity research were a major part of our investigations.

“...the earlier we can intervene with the disease process, the better off the patients are.”

In the late 1980s we were doing auto-antibody work and we described a new auto-antibody in rheumatoid arthritis, anti-RA33. From there we went onto cytokine research. That’s when I happened to meet Professor Maini from the Kennedy Institute. We shared common interests and attitudes toward research, so when his group embarked on the trials of infliximab they invited my group to be one of the four participating in the first controlled trial.

Well, that paper has several important aspects. Number one, it demonstrated the highly significant efficacy of the addition of a TNF-blocker to methotrexate in patients who failed methotrexate therapy, and this is not only in terms of clinical changes but also in terms of joint damage—something that had never before been appreciated.

Moreover, while it was known that other agents were are also active in terms of clinical improvement and radiographic changes, this showed the important difference of having a median of zero and a very, very low progression of joint destruction. To my recollection this was the first paper that ever showed that. Several papers later confirmed our findings.

Yes, it was probably a higher efficacy than we expected. I wouldn’t say I was surprised that it was effective, but it was more so than we expected.

If I recall correctly, that paper was actually held back for a long time in the review process, including the NEJM. Essentially that was the first study ever of a combination of a TNF-blocker on top of methotrexate in patients who had active disease despite prior methotrexate therapy. Moreover, we also set out to ask, a) what is the optimal dose (and we tested three doses), and b) what happens if we take away methotrexate and then have only the TNF-blocker.

It turned out that those patients who continued with methotrexate had much better and prolonged efficacy than those who stopped it. So this was the first paper that revealed that the combination of methotrexate plus a TNF-blocker not only works well, but is clinically superior to a TNF-blocker alone.

There are several options in that respect. The option we thought about in those days is that methotrexate reduces overall immunogenicity. But we really don’t know exactly what methotrexate does. It is likely that methotrexate has a different target than the TNF-blockers and may provide additive effects. There have always been contentions that methotrexate acts more on interleukin-1. Last but not least, methotrexate may alter the pharmacodynamics of the antibodies, and so increase the bioavailability of the biologics.

The field has gone in several directions. First, in the Lancet paper we published a year before the NEJM paper and in subsequent studies since then, a chemical compound, Leflunomide, was shown to also be effective clinically and in retarding joint damage; this is the latest addition to the traditional, non-biological disease-modifying drugs.

With respect to the biological agents, one direction was to show that the TNF-blockers have a particular effect on structural changes. We showed this quite clearly in a paper that came out last year. Even if patients did not change their disease activity at all, they had a significant reduction of joint damage if treated with a TNF-blocker plus methotrexate. We’ve known for many years that disease activity and joint damage correlate with each other. But this association is disrupted by TNF-blockers. So that’s one direction we’re still working on, which is to understand what’s going on with these therapies.

Another aspect relates to predicting response to therapy, which appears to be possible by virtue of baseline clinical and laboratory characteristics and, especially, by characteristics seen three months after onset of methotrexate therapy. And here again, the addition of a TNF-blocker to methotrexate disrupts this association.

Another direction comes from the recognition that TNF-blockers, as great as they are as therapeutics, still leave about half of all patients insufficiently responsive. Thirty to 50% of patients do not respond to the therapy. So new therapies are needed, and two new ones were just licensed a few months ago. Those are abatacept and rituximab.

Neither is. Abatacept is a so-called co-stimulation blocker and appears to interfere with activation of T cells. Rituximab depletes B lymphocytes.

To understand the pathogenesis of the disease in more detail and to find a cause. One of the interesting aspects of this research is that, almost regardless of which of the novel therapies you use, none of them give you 100% success. All of them get about 50-70% of patients with a clinically discernible response and 30-50% with a clinically meaningful response.

It’s interesting that we have all these different molecules and still very similar results with all of them—confirming not only the heterogeneity of rheumatoid arthritis, but also suggesting a genuine multiplicity and redundancy of pathogenetic events: in some patients, interfering with a particular molecule appears to be necessary and sufficient, while other molecules or more complex events drive disease in other individuals.

I think what we’ve experienced over the past decade has been an incredibly fast advance—literally from, say, 1993 or 1994. And this is one of the areas of research that has led to important insights in general for treatment of all inflammatory diseases, for understanding some pathogenetic aspects as well as reaching successful therapies. It’s important to remember that while TNF-blockers started with rheumatoid arthritis, they have also been used now in Crohn’s disease, for psoriatic arthritis, and for ankylosing spondylitis, which is an inflammatory spine disease. We had very little to offer these patients but now the TNF-blockers have been shown to be highly successful there, too.

I think there are three aspects to that. Number one is we’ve had novel insight into the immunology and pathogenesis of these diseases. Number two is the advancement in the pharmaceutical industry to produce bulk amounts of receptor constructs and monoclonal antibodies, which is very heavily linked to the molecular biology revolution that happened over the past 20-30 years. And finally, the third aspect is that clinical epidemiologic research, or maybe I should say outcomes research, has made highly significant advances in rheumatology. Questions, for instance, of how we measure disease activity and responsiveness to therapy. Which variables are best taken into consideration for assessing disease activity and improvement or deterioration?

The parallel development in these three areas, sort of serendipitously, led us to where we are today: innovative thinking, together with innovative production capacities by the industry and innovative clinical analysis have allowed for this sort of revolution.

I hope that 10 years from now we will have cured rheumatoid arthritis; that we will have found enough remedies to have something available for every patient. In fact, we already now aim for what we call "remission of disease activity." This is an important aspect in the context of therapeutic approaches. We have totally changed the paradigm. We go for tight control using established disease activity indices; we will switch therapies relatively rapidly if one is not sufficiently successful. And we aim for the lowest possible disease activity.

We hope to get patients effectively into a remission-like state. This may not be a cure. They may have to still continue therapy, just as diabetics have to continue taking insulin, but it is a cure-like situation. It normalizes life expectancy and quality of life and other aspects that are very important to the patient. This is what we now aim for.

Well, there is one additional aspect. What has developed in the past decade is the establishment of early arthritis clinics, so as to diagnose rheumatoid arthritis as early as possible. We know the disease progresses pretty fast, even early on. Within a few months we can see joint damage on radiographs. We can sometimes see this, even at presentation. So the earlier we can intervene with the disease process, the better off the patients are. We can retard the progression of the disease significantly if we start therapy earlier rather than later. And so early diagnosis is a critical aspect of the advances we’ve made.

Another point I would like to make is that when it comes to research like this, the kind of group collaborations that came together to do this infliximab-methotrexate trial cannot be spoken of highly enough. These international groups join forces to address different facets of the disease and try to test hypotheses. You could say we march together both within departments with my immediate co-workers as well as in cooperation with other centers, and I believe this is also key to the kind of remarkable success we’ve had over the past decade.