That it seemed to be very much an untreated but treatable disease.

“There are now some papers showing that infliximab, used early in the disease, can put patients in remission and they can then come off the therapy.”

Because it was inflammatory, and inflammation is treatable. The question was finding mechanisms and using therapies that were less toxic than what we had available 20 years ago.

We had data from animal models suggesting that TNF was an important cytokine. It wasn’t clear it was going to be sufficient by itself. I think many of us it believed there was redundancy in cytokines, and so blocking a single one would only be partially effective. At the same time we were looking at blocking TNF, we were looking at interleukin-1, as well. But to everyone’s surprise, it seemed to be sufficient to block TNF. One or two animal models showed this and they proved to be prophetic in that sense.

We looked at the change on X-rays using a standardized score. We looked at two different aspects: one is called joint-space narrowing, which is indicative of the cartilage loss. The other one is erosion. And it pretty much halted both of those progressions.

I think everyone was. It was a landmark finding. Blocking TNF virtually halts structural progression. You stop damaging the joint.

Ideally you’d try to use it as soon as you know it’s necessary. If you can switch off inflammation and the knee is still normal, it can stay normal. There are now some papers showing that infliximab, used early in the disease, can put patients in remission and they can then come off the therapy.

There are now three agents that block TNF, all of which have been shown to be structurally beneficial. The biggest advance is in the early use of infliximab as a remission-induction regime. This was published by us in Arthritis and Rheumatism in 2005 (Quinn M.A., et al., "Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal," Arthritis Rheum. 52[1]:27-35, 2005).

The other advance is the development of alternatives to TNF-blocking, including two other NEJM papers. The first author on one is Edwards (Edwards J.C.W., et al., "Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis," NEJM 350[25]:2572-81, 2004) and that showed that a compound called rituximab, which kills B cells, is effective. And the other, the first author is Kremer (Kremer J.M., et al., "Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig," NEJM 349[20]:1907-15, 2003), is on a co-stimulatory blocker called abatacept. Both are about as effective as blocking TNF. Both have been shown to work in anti-TNF failures as well.

Well it depends. In clinical trials we do remission induction, get patients better and hopefully get them off treatment. Drug-free remission is our mission. If we do what the government pays us to do in the clinic, we do standard treatment. If that fails, then we give a blocker of TNF. IF those fail, then we can consider using one of the other agents. About 40% of our patients are on anti-TNF agents. At the moment there are three TNF blockers; two are monoclonal anti-TNF, the other is a soluble receptor that binds TNF. The data from our registry suggests there is little difference between them.

To earlier and earlier treatment. Better identification of the patient, through genetics, serology, and imaging. And the use of curative therapies, which are therapies that get you into remission.

It’s been extraordinary. I could never have predicted that we’d be this successful. And with the absence of side effects, as well, or at least the absence of non-manageable side effects.

It was actually the very early work, when we weren’t sure whether the patients would even get better in the short term. We worried about starting these patients on the therapy and then having to deal with potential long-term problems. The anxieties about long-term side effects. Even cancer. But this hasn’t been a problem. And the early patients on this therapy are still very pleased that they did it, even eight or nine years later.