New Treatments in Rheumatoid Arthritis

Jonathan Kay, MD; Stephen Paget, MD


January 19, 2011

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Jonathan Kay, MD: Hello, I'm Dr. Jonathan Kay, Professor of Medicine at the University of Massachusetts Medical School in Worcester and Director of Clinical Research in the Division of Rheumatology at UMass Memorial Medical Center, also in Worcester. Welcome to this Medscape Peer-to-Peer discussion from the American College of Rheumatology 2010 Annual Meeting in Atlanta, Georgia. Today I'm speaking with Dr. Steven Paget, Professor of Medicine at the Weill Cornell Medical College in New York and Physician Chief Emeritus in the Division of Rheumatology at the Hospital for Special Surgery in New York about new findings in rheumatoid arthritis (RA). Welcome, Steve.

Steven Paget, MD: Hi.

Small Molecules for RA

Dr. Kay: At this meeting 2 very interesting abstracts being presented about small molecules to treat RA: One is a p38 inhibitor and the other is the JAK-3 inhibitor. Now we have very effective biologic agents to treat RA that have revolutionized the treatment of our disease. How do these small molecules add to this armamentarium?

Dr. Paget: While the new biologic drugs that we use on a day-by-day basis are really amazing, and have totally transformed the care of patients with RA, at least in my practice 50% of patients either don't respond or stop responding, so there's still a large group of people that really need new drugs. Obviously, because we don't know the etiology of RA, often the disease takes a detour around the medicines, so we need an armamentarium that's broader. Also all of the current medications, these biologics, are parenteral medications. People in the United States, including those with RA, are very oral medication oriented, and there's no doubt that if we find medications that are oral, safe, and equally effective to the biologics -- 60:40:20 type of responses -- I think they'll take over the market.

Dr. Kay: The JAK-3 inhibitor tasocitinib is a twice-daily oral medication. The studies[1] have shown in phase 2 that the 5- and 10-mg doses taken twice daily are similar to the TNF [tumor necrosis factor] inhibitors with ACR20 (American College of Rheumatology criteria for 20% improvement in rheumatoid arthritis) responses of about 60%. At this meeting, there's a late-breaking abstract[1] that's presenting the data from a 6-month placebo-controlled, randomized, double-blind control trial that looks at 5 mg and 10 mg of tasocitinib compared with placebo, and the response is quite impressive: about 60% ACR20 for the 5-mg dose; about 65% ACR20 for the 10-mg dose, compared with a placebo response somewhere around 30%. This drug works quite rapidly as well; responses were seen within the first week or two. Is this kind of response going to overtake the TNF antagonist? Is the response more rapid than what we see with our patients?

Dr. Paget: Not only are the data equivalent as best as I can tell -- similar population, similar response -- but the side-effect profile is also impressive. When you're dealing with phosphorylation and transcription factors, which every cell in the body has, one might fear that suppressing these might cause increased risk for infections, and other problems. But this just doesn't seem to be the case. I think the combination of equal effectiveness and tolerability, at least in the short run, is important. The next thing obviously that has to be completed is disease modification.

Dr. Kay: The side-effect profile of tasocitinib includes some elevation of liver function studies; some elevation of lipids, which perhaps is due to a release of the suppression of lipid levels that's caused by inflammation; and maybe some leukopenia. These are very similar side effects to those of tocilizumab, so this drug may be working similarly to an IL-6 [interleukin-6] inhibitor. This medication looks very promising. Mark Genovese wrote an editorial in Arthritis & Rheumatism[2] a year or two ago where he said that for p38 inhibitors, the fat lady has sung. Now you work very closely to the Metropolitan Opera and there are many up and coming young singers, like Anna Netrebko, that may be Mark Genovese missed; he's presenting an abstract at this meeting on another p38 inhibitor that has modest effect but certainly shows statistically significant ACR20 responses compared with placebo. What are your thoughts about that?

Dr. Paget: I've looked at the JAK inhibitor and the p38 inhibitor side by side, and there's quite a big difference. They're both reasonably well tolerated, but the p38 inhibitor ACR20 response is not even twice what the control is, which reminds me of anakinra. So while it may be an option, when you see it compared with another small molecule that has a somewhat similar side-effect profile and is probably priced in a similar way, I just don't see it happening.

The Role of p38 and Syk Inhibitors

Dr. Kay: At the beginning of our conversation, you mentioned that one of the problems of TNF inhibitors and other biologic agents is that there are certain proportions of patients who just don't respond. We don't really have a good handle on the characteristics of that nonresponder population. Might a p38 inhibitor address some of those patients who don't respond to biologics or who might not respond to tasocitinib?

Dr. Paget: I think it's a possibility, but I'd first like to see longer studies. I didn't see all the data in the abstract with regard to other outcomes. The outcomes that I saw with regard to the ACR20 were kind of anemic in some way, and so it may not be ready for prime time, but maybe with more studies it will be. We may find it an important part of our armamentarium when all else has failed.

Dr. Kay: So we hear a faint voice from the wings -- another fat lady singing -- and Mark Genovese's editorial may have been a bit premature. What else is coming down the road? There was a paper in The New England Journal of Medicine recently by Mike Weinblatt and colleagues[3] about a Syk inhibitor, another oral agent. That agent seems to be quite rapidly effective; it has a bit of hypertension as a side effect, but it's not a limiting side effect.

Dr. Paget: I agree completely. I think all of these types of drugs still have to be proven, but that's what we do. Once the proof of concept has come through, when it's passed through the FDA [US Food and Drug Administration] with their very rigorous way of doing it, we'll then see. With anakinra, it wasn't going to work. It wasn't ready for prime time at all. Patients can become septic, but their RA doesn't change at all. Clearly, it's an immunosuppressive but not one that's related to the 24/7 illness that RA is. But still, I think these new drugs have tremendous promise not only because of their equal effectiveness, but also their general safety. Obviously, these drugs are not on/off switches but rheostats; otherwise we would probably be buying more potential side effects. I think the oral concept as well will free people who already have a burden from their RA and not make them feel so sickly.

Dr. Kay: It's amazing how far we've come from the days of injectable gold and aspirin, and nonsteroidal anti-inflammatory drugs really don't enter into the therapeutic algorithm for RA the way that they used to. We now have such potent drugs, and we have an embarrassment of riches where we can choose between very effective therapies. It will be very interesting to look at disease modification as you point out as to whether these agents give us the same structural benefit that the biologic agents give us.

Dr. Paget: Yeah, it's difficult to predict. I would imagine swelling begets erosions; no swelling means no erosions; and the swollen joint count is such an important thing in this assessment. However, I agree with you; if all things are equal, this is going to revolutionize what therapy might be given first. I think the other important thing is the new RA criteria -- the EULAR [The European League Against Rheumatism]/ACR criteria -- because they go hand in hand with new drugs that can be effective. The way I see the criteria being more useful now is that first of all, you don't want people to meet the old criteria. That's what we're trying to get away from. We now want to bring people in earlier and, using the 4 domains, get into the process before damages occur. Nobody has proven to me that when damage does occur that it's reversible by these drugs, so I think you have to stop the damage early on or stop it from forming. I think the world is a very different world, and we've always talked about the fact that when I was a fellow in 1975, our clinic was filled with wheelchairs, and 25% of all the joint replacements were done in people who had RA. Now it's 5%. Surgical residents and fellows don't even have enough problems to work with because it's so uncommon that people have hand surgery and problems like that. So I think we've really come so far, and it's an exponential type of thing. The problem is, of course, that we don't know the etiology, and so the immune system often takes this detour that I'd mentioned. But while and until we do find the etiology like we did in the last century with infectious agents, our progress is really profound. I think the new oral agents will add to the feeling of being more normal as opposed to having to inject.

Etiologies, Concluding Thoughts, and...Gingivitis?

Dr. Kay: Absolutely, and to the comment about infectious etiology, at the opening ACR lecture Gerald Weissman made some very interesting comments about the role of gingivitis in possibly setting up a process of citrullination and driving the inflammatory or autoimmune process in RA. Perhaps not only should patients stop smoking, but they should also brush their teeth, perhaps with a Sonicare toothbrush [Philips Electronics North America Corporation; Andover, Massachusetts]. We might even see less RA in the decades to come.

Dr. Paget: I think it's true. Although I thought that the lecture was extraordinary -- a typical Gerry Weissmann type of lecture -- the fact is he quoted minocycline as being an effective drug in RA, which it never has been shown to be. That doesn't take away from the issue of infectious triggers, both internal and from the outside; minocycline may not work because the trigger already occurred and no longer has to be there because the immune response is self-perpetuating. But certainly in studies with very potent tetracycline-type drugs, it has not been that effective. However, I think the concept is an important one; I think people do need to keep themselves healthy from an infectious point of view. I don't think any rheumatologist disbelieves that infectious agents might be connected with a trigger or the perpetuation of RA. Given the fact that periodontal disease is very similar pathologically, it kind of brings it to the forefront and makes us appreciate it.

Dr. Kay: Well, we have such tantalizing leads now toward understanding the etiology of RA; we have much better understanding of the bone biology that leads to bone destruction and now some insights into bone formation. With these new, powerful biologic agents and small molecules, we have a tremendous therapeutic armamentarium available at our hands. The next couple of years are going to be very exciting.

Dr. Paget: I agree completely. There's no doubt that we are controlling the inflammatory process to one degree or another better than we used to with gold, as you mentioned; penicillamine; and other drugs. The other side of the issue, the damage, reversing damage, or repairing damage, we don't focus on as much. We focus on it more in terms controlling the inflammation so you don't go to damage, but the people with the more severe disease have the overexuberant inflammatory process, and in terms of the underexuberant repair process, the question is how to rebalance those.

Dr. Kay: Ellen Gravallese at this meeting is presenting[4] some very interesting data showing that if inflammation is very well controlled, there can be some healing of bone erosions, so the better that we can treat RA and suppress inflammation, the better patients will do. Thank you very much for coming and discussing RA.

Dr. Paget: It's always great talking to you.

Dr. Kay: Great talking to you as well. Thank you for listening to this discussion today. I hope that you will come away with some information that will help you in your practice. I'm Dr. Jonathan Kay for Medscape.


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