Stephen Paget, MD: My name is Dr. Stephen Paget and I'm the chief of rheumatology at the Hospital for Special Surgery and I'm pleased to introduce Dr. Lionel Ivashkiv who is an associate professor of medicine at the Weill College of Medicine of Cornell University. Dr. Ivashkiv is an internally recognized scientist who focuses his research in the are of cytokines or chemicals that actually either suppress or stimulate inflammation.
Stephen Paget, MD: First of all, what is a cytokine and what do they do in disease?
Lionel Ivashkiv, MD: Cytokines are proteins that are made by cells of the immune system and they are very important in regulating cell activation and differentiation and also effect functions. So they basically are regulating responses and can drive inflammatory response. In terms of diseases, I think cytokines have been identified to have an important pathogenic roll in several diseases and probably the best example is rheumatoid arthritis where the pathogenic rolls of TNF or tumor necrosis factor, and interleukin 1 or IL-1 are well known.
In addition to driving basic pathogenic mechanisms, for example destroying joints or driving the inflammatory process. Very recent exciting developments have been identification of cytokines as a good therapeutic target. So one of the more exciting therapies for rheumatoid arthritis has actually be cytokine blockade which has been quite successful and can be achieved in several different ways.
Stephen Paget, MD: How do you define what the best target is and thus how do you define the balance that has to be struck to put people back to equilibrium?
Lionel Ivashkiv, MD: I think defining the best target is a tricky business and in RA it took about 20 years to figure that out and there were many people who were involved in those efforts. The idea is for one, the target needs to be a cytokine that is a key player in the pathogenic process but at the same time that its blockade will not predispose the patient to too many side effects or infections.
The approaches that we are taking were a number including studies with tissues and cells from patient's joints. Similar to the kinds of experiments that we are doing here which identify TNF as a key player in in-vitro. In addition there were important experiments validating the rolls of some of these cytokines in animal models. For example, collagen induced arthritis, where the various approaches included neutralizing antibody's origin and that kind of studies.
Stephen Paget, MD: There are many cytokines. Can you tell us how many there are and which ones you are specifically focused on?
Lionel Ivashkiv, MD: It's an ever-expanding family of factors within the human genome. As the sequences are being completed it's clear that there are several hundred cytokines and several hundred receptors and it's a very complicated system. Actually it is interesting because in the 1980s that cytokines would be good therapeutic targets was first brought up there was a lot of skepticism and the idea being there are so many that they tend to have redundant rolls meaning that the cytokines can do the same thing and that this is not a good approach.
But I think what has turned out that there are cytokine networks and the cytokines are interrelated in very intricate sort of regulatory and homeostatic networks, meaning that every time there is something that drive in formation, there is also a balance and it triggers a feedback in addition. It has become clear that the cytokine networks can be perturbed at different levels and have very significant and strong effects on the overall autoimmune process.
In terms of the cytokines that we are studying in our laboratory, it is actually a different family from the TNF and IL-1 and its cytokines which activate a major signal transduction pathway that has been called Jak-STAT signaling pathway. This is an important signaling pathway that involves the Jak's which are kinases and also STAT's which were discovered just across the street at Rockefeller and these are transcription factors. The word STAT actually stands for 'signal transducer and activator of transcription'. What these proteins do is they turn on these cascades of gene regulation in response to cytokine stimulation itself. So the cytokines of specific to my lab would be interleukin-6 and interleukin-10 and more recently the interferons-alpha and interferon-gamma are the type 2 and type 1 interferons as they are also known. These are cytokines which actually help in immunosuppressive anti-inflammatory effect.
The ideas that we were developing in the laboratory is that some of the defects in our area and more recently, we have been working a little bit on lupus as well, are not suggesting a positive effect, meaning that there is too much inflammation but there is a problem with the ability of the patients to turn off the inflammatory process and what we propose and we have evidence for now is that some of these anti-inflammatory cytokines, for example, IL-10 which is a very potent control of inflammatory, don't work properly in rheumatoid arthritis and we started to get some evidence that it might not work properly in lupus as well.
Stephen Paget, MD: When you perturb a finely tuned system sometimes that leads to problems. What are the potential problems in working with nature's equilibrium?
Lionel Ivashkiv, MD: Yes, it's tricky and I think it's hard to anticipate. I think there are some clues from animal models where many of these things can be tested but I think the TNF story is a good example, that TNF is a very strong pro-inflammatory cytokine and TNF blockade has been very successful in treating the inflammatory aspect of rheumatoid arthritis and also inflammatory involved disease. However it has become apparent that TNF also has potent immunosuppressive properties especially in terms of long term possible through the formation of suppressive results.
The data with animal models and more recently some case reports with patients as well, suggest that if you block TNF you can get unanticipated side effects meaning certain autoimmune phenomenon in patients. For example, autoantibody production which might be similar to that seen in lupus also there have been some hints of possible development of the demyelinating syndromes which again might be a consequence of sort of missing this immunosuppressive effect of TNF.
Stephen Paget, MD: Tumor necrosis factor plays a sentinel role in skin and in preventing infection. Have people developed increased propensity for infections when you block TNF.
Lionel Ivashkiv, MD: Yes that is really the other major problem. Again it was only partially anticipated on the basis of clinical trials where there was just a small incidence of what were mostly mild infections. However I think once these drugs got out of the clinical practice, there have been reports of severe infections especially in patients who have pre-existing immune compromise. For example, diabetic people with ulcers and other sources of sort of chronic indwelling infection. So there is always a risk and a benefit and so far, at least in the short term, the benefits I think have far outweighed the risk but its something that we really need to keep in mind and especially in terms of the long term evaluation of the benefits of these medications they haven't really been tested long term and the other issue would be tumor suppression. So that would there be increased incidence of tumor formation in people who would be treated with these medications long term. I think we are optimistic that that wont happen but the studies have not been completed yet.
Stephen Paget, MD: Scientists and companies have conceptualized using combinations of cytokine blockade including TNF blockers along with IL-1 receptor antagonists which blocks IL-1. They fear that possibly the combination will be even more effective in blocking both the inflammatory process and its attendant downstream problems and also the joint damage. What are your thoughts about that?
Lionel Ivashkiv, MD: I think it's an interesting approach but one where we need to be even more cautious about which combinations are chosen. I think the TNF IL-1 combination is in part chosen because some people feel that TNF would work better on the inflammatory symptoms and IL-1 would have a better effect on preserving or preventing tissue damage. My concern about that approach is that if we were to block both simultaneously I would worry that we might really predispose people to greater infections. An approach that I would favor instead would be to choose other cytokines which by themselves might not be as important for preventing infection. An example would be Osteoprotegrin which is a soluble factor which blocks bone destruction. In animal models it has been shown to be extremely effective at preventing the destruction of bone even though it seems to have really very minimal effect on the inflammatory process. I think its such an approach, we really combined something like TNF which would work on the inflammation and something like osteoprotegrin in which would work on preventing the bone destruction which is a very important part of morbidity in RA. But the potential side effects and complications would be different so we would not be subjecting patients to a potentially increased possibility of severe infection.
I think the other idea which is a good idea that we are working on in the laboratory is that a lot of these cytokines utilize similar signal transduction pathways and these can actually be targeted by small molecules and the types that more traditional medications made by the pharmaceutical industry. I think would be another approach that may be to key in on key signal transduction pathways which might be more important in driving the inflammatory process in RA but less important in sort of a sentinel roll of preventing infections.
Stephen Paget, MD: So far the cytokine blockers have all been given either subcutaneous or intravenous therapies. Using small molecules would allow you to use oral medications, that are not proteins and not broken down by the gut?
Lionel Ivashkiv, MD: Yes I think for both patient convenience, acceptability by patients and also from expense, this would be a great step forward. I think the issues with all of these is as specificity. I think even with the biological, where the idea has been that you can maybe achieve exclusive specificity for that particular protein, in practice it hasn't necessarily held up. The example being the TNF soluble receptor can also block the signaling by related cytokines. So I think the issue with the oral agents is going to be how specific can you make it and how much you can avoid getting side effects at other tissue sites. The potential approach to deal with that type of problem would be the evolution of gene therapy approaches trying to deliver either biologics or to manipulate signal transduction systems at joints. So basically at the site of inflammation and not systemically and that's again something we are starting to get into in the laboratory.
Stephen Paget, MD: Thank-you very much Dr. Ivashkiv.
Dr. Ivashkiv was interviewed by Dr. Stephen A. Paget, Physician-in-Chief, Hospital for Special Surgery.