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Rheumatoid Arthritis

We currently have a number of disease modifying drugs - methotrexate, gold, Plaquenil, sulfasalazine, and others - which were derived on empiric observations. We didn’t know how these drugs worked. It was just observed that they helped patients. They were then studied clinically and now they are used and they have shown to have disease-modifying properties. But now we know that most of these agents inhibit functions of cells in the rheumatoid synovium, particularly they inhibit T-lymphocyte and macrophage function which was a real clue that maybe T-cells and macrophages were important in this disease process. However, as I said, when these agents were first used we didn’t know that these cells were involved or how they were involved.

Next I want to emphasize a concept that is evolving regarding pathophysiology. That rheumatoid arthritis may represent a failure to maintain a balance between normal functions of immune and inflammatory cells and natural mechanisms to regulate or suppress these functions. Certainly these cells that are involved in pathophysiology are not there purely for that purpose. T-cells, B-cells, macrophages, fibroblasts, chondrocytes, they all have normal functions and these molecules that they are releasing.

IL-2 and gamma interferon. It has been difficult for investigators to find these staining the rheumatoid synovium, but I think people have not quite been looking with sensitive enough techniques and looking the right way. More recent studies have demonstrated that there are gamma interferon-producing cells and gamma interferon molecules present locally and that one does not need to have very many T-cells producing cytokines to drive a disease process, or to influence it. Less than 1 in 100 cells that may be the particular T-cell may be necessary. So I think that the absence of T-cell drive cytokines, that argument has been weakened.

Systemic effects of cytokines are also important. IL-1, IL-6 and TNF, predominantly IL-6, effects on the liver and leading to the release of acute phase proteins. These cytokines also react in the brain to cause fever. They travel to muscles where they enhance metabolism and breakdown of muscles, so the tissue breakdown that we see loss of muscle mass and patients with chronic disease is cytokine-driven, systemically. And lasting bone marrow effects. Some of the anemia in rheumatoid arthritis may also be due to cytokine effects on bone marrow cells. Then both local and systemically, TGF-beta may be a very important inducer or suppresser of T-cell functions. We know that in experimental animals systemic administration of TBG-beta is antiinflammatory. Injection of TGF-beta to the joint is pro-inflammatory, but separate from that consideration, I think that TGF-beta is a potent suppresser of T-cell function, which certainly characterizes active rheumatoid arthritis. So we have all these cytokines, and what I like to look upon this area is that this is a balance between pro-inflammatory mechanisms and antiinflammatory mechanisms. Now the figure in your handout I have revised in the last two months, based in part upon the abstracts from this meeting, that have given further details on additional cytokines. But I don’t want you to get upset with knowing what all these molecules are. The important conceptual point is that we have a balance going on and maybe during active inflammation the balance is in favor of pro-inflammatory molecules. Our therapeutic efforts and desires are to interfere with the cytokine balance, tipping it in favor of antiinflammatory. So we certainly know, enzymes that there are natural inhibitors of those enzymes that are made by fibroblasts and chondrocytes. So the enzyme/enzyme-inhibitor balance is important here. Then on the pro-inflammatory side, we talked already about the TNF, IL-1 and IL-6, we also have gamma interferon and GM-CSF potent up-regulators of MAC-class 2, particularly on dendritic cells. Then we have isolate and other chemokines, which are very important in calling cells into the joint. And now we have these new molecules, IL-15, 16, 17 and 18. And I am not going to go over their detailed functions. 

That is, the earlier ones that were discovered and studied, IL-1 and TNF for instance, may be downstream events and may be there are more proximal events of these additional cytokines. For instance, IL-18 is capable of … its major role is cause release of gamma interferon. IL-18 will also enhance production of IL-1 and TNF. So now the thought has come along that in addition to interfering with the traditional cytokines, maybe there are ways of interfering more upstream with some of these proximal driving mechanisms. So where do we stand now regarding cytokine inhibition? Well, certainly we have the inhibitors of IL-1, the type 2 receptor has yet to be studied clinically but the IL-1 RA molecule is being studied clinically and we have monoclonal antibodies to IL-6 receptor, which are being used in clinical trials. We are going to hear more today about the two very potent mechanisms for interfering with TNF affects. The CNF receptor, or Enbrel, and the monoclonal antibody to TNF. But then we have other cytokines that can function in the antiinflammatory fashion, IL-4,10,11 and 13. The most important one of these clinically has been IL-10, which is still in clinical trials for treating rheumatoid arthritis. Then IL-18, curiously enough, has its own inhibitor, IL-18 binding protein, which is a molecule which binds IL-18 in the fluid phase preventing it from binding to cells. Very much like a naturally occurring receptor, but it’s not. It is a separate molecule that’s made to bind IL-18. Many laboratories are interested in studying if this is a way of inhibiting the proximal events in the rheumatoid synovium.

Okay, to finish up, cytokine balance is important but an additional cell that we’ve now come to appreciate more about is the synovial fibroblast. So this illustrates macrophage/fibroblast interactions. Showing that there are molecules released by macrophages that activate fibroblasts, IL-1 and TNF among them, but in turn fibroblasts can produce additional cytokines that act back on macrophages. So we may have a circular mechanism set up here whereby maybe in some situations the macrophages can then be activated by released cytokines locally from fibroblasts and other cells. Macrophages may not need to be continually driven by T-cells. Maybe these circuits can be set up leading to so-called autocrine or paracrine mechanisms but keeping macrophage activation going. But for our interest here is fibroblasts, which can be activated - they can release their own cytokines, they can act back on the fibroblasts - and as I told you , fibroblasts themselves are an important releaser of enzymes as well as complement components. So a concept that has arisen, another interesting concept is that maybe these fibroblasts in the rheumatoid synovium, which certainly function as transformed cells, maybe they truly are transformed.

Okay, I just want to, in closing, emphasize a few conceptual points then and then emphasize where we may be going. So we’ve talked, and this presents the cell-cell interaction in a different fashion - this is in your handout. So here we have the endothelial cells. We know they have been activated. They expressed adhesion molecules, they have other functions which you know they are activated, enhancing the ability to remove cells or move cells from the circulation out into the tissue. We’ve talked about dendritic cells, T-cell interactions, I didn’t emphasize mast cells. They are present in the active synovium. We really don’t know what they are doing but that may be another area where new knowledge may lead to new approaches for treatment. We talked a little bit about B-cells, fibroblasts, macrophages, cytokines, synovial inflammation proliferation, cartilage and bone damage.