RHEUMATOID ARTHRITIS: SLIDES & ANIMATIONS
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When two IgG antibodies combine with antigen (immune complex formation) the complement cascade can be initiated.
In most situations, the formation of immune complexes is a good thing, but immune complexes are often the cause of tissue injury in autoimmune disease, such as RA and systemic lupus erythematosus (SLE). The power of combining an immune complex with the destructive force of complement is shown in animation 10. Two antibodies have combined with the cell surface of a bacterium. The complement component, C1Q reacts with the Fc portion of the two antibody molecules, initiating the complement cascade. The inflammatory response is enhanced by the formation of small complement fragments, which will direct white cells to the site, in a process called chemotaxis. The membrane attack complex (MAC) is formed, instills itself into the bacterium's membrane, leading to osmotic destruction of the cell. Here, this immune response is beneficial to the body, but imagine such destructive force misdirected at human organs and tissue. The inflamed skin of a patient with SLE is shown in slide 41. A lupus rash is most frequently caused by immune complex deposition in vessels.
Animation10: Complement activation by an immune complex : Immune complex formation leads to complement activation and the destruction of a bacterium.
Animation 11: Promotion for "Monkey Juice" : A cartoon promoting a chimeric consisting of monkey and human protein.
Animation 13: Enbrel sops up TNF :This cartoon depicts a macrophage secreting TNF, which is then sopped up by enbrel (etanercept).
Animation 14: IL-1 induces cell activation : IL-1 is shown first combining with its receptor which then induces an intracellular signal.
Animation 15: IL-1ra blocks cell activation : IL-1ra, a natural inhibitor of IL-1, blocks activation of the cell.
The first monoclonal agent tried in the treatment of RA, to my knowledge, was a monoclonal antibody targeted against the CD5 antigen (1)(the study was done in the late 1980's It took a few years to get it written up and published). This agent was very special because it was conjugated with a toxin, i.e. ricin. The idea was that after binding to the appropriate cell, a T-Cell, the ricin toxin would enter the cell and kill it. Early studies were very exciting and encouraging. However, because of toxicity, appropriate doses could not be used. One major source of problems stemmed from the fact the the antibody was entirely mouse protein. When given to humans, this lead to an immune response to the drug, causing allergic reactions and inactivation of the drug. Scientists attempted to circumvent this problem with subsequent monoclonals, by making antibodies consisting of a higher percentage of human protein. These constructs are called chimeric antibodies.
Animation 10: Complement activation by an immune complex Immune complex formation leads to complement activation and the destruction of a bacterium.
Animation 11: A Promotion for "Monkey Juice" : A cartoon promoting a chimeric consisting of monkey and human protein.
Animation 12: TNF induces cell activation : TNF activates a cell via the TNF receptor which then produces IL-1.
Animation 13: Enbrel sops up TNF : This cartoon depicts a macrophage secreting TNF, which is then sopped up by enbrel (etanercept).
Animation 14: IL-1 induces cell activation : IL-1 is shown first combining with its receptor which then induces an intracellular signal.
Animation 15: IL-1ra blocks cell activation : IL-1ra, a natural inhibitor of IL-1, blocks activation of the cell.
Immune complex formation leads to complement activation and the destruction of a bacterium.
A cartoon promoting a chimeric consisting of monkey and human protein.
TNF activates a cell via the TNF receptor which then produces IL-1.
This cartoon depicts a macrophage secreting TNF, which is then sopped up by enbrel (etanercept).
IL-1 is shown first combining with its receptor which then induces an intracellular signal.
IL-1ra, a natural inhibitor of IL-1, blocks activation of the cell.
Animation 10: Complement activation by an immune complex Immune complex formation leads to complement activation and the destruction of a bacterium.
Animation 11: Promotion for "Monkey Juice" : A cartoon promoting a chimeric consisting of monkey and human protein.
Animation 12: TNF induces cell activation : TNF activates a cell via the TNF receptor which then produces IL-1.
Animation 13: Enbrel sops up TNF This cartoon depicts a macrophage secreting TNF, which is then sopped up by enbrel (etanercept).
Animation 14: IL-1 induces cell activation : IL-1 is shown first combining with its receptor which then induces an intracellular signal.
Animation 15: IL-1ra blocks cell activation : IL-1ra, a natural inhibitor of IL-1, blocks activation of the cell
(My patients could never remember the drug's technical name, so we all called it "Monkey Juice". Neither Idec nor SKB ever really liked that name very much. )
TNF is felt to play a prominent role in the pathophysiology of RA. A model for TNF and its effects on a cell is shown in animation 12. TNF reacts with its receptor producing a intracellular signal. The signal ultimately results in the cell producing the cytokine IL1. There are three biologics nearing approval for use in RA (author's note: this was written in 1998). One agent is a humanized monoclonal to TNF called cA2 (which will be called infliximab (remicade)). When used with low dose methotrexate, 60-70% responses were obtained in RA(3). Another agent targeting TNF is a fusion product in which the fc portion of an antibody is genetically fused to two TNF receptors (Enbrel). The probable mechanism of action for this drug is demonstrated in animation 13. . This biologic has been shown to be effective and safe in the treatment of RA (4) and will probably reach the marketplace within 6-12 months (approved in 1999).
In summary, I have gone over principles of inflammation and looked at the lesion in the synovium of patients with RA. Finally, I have described some of the most promising biologics. These biologics will be expensive. Novel approaches will be tried, such as combining biologics (anti-TNF and IL1ra in combination works well in animal models and are synergistic(note: it didn't work any better than just the anti-TNF agent alone, and there were more infections. Go figure?)). New terms will be uttered by those who treat RA, such as "induction therapy" and "maintenance therapy" and "re induction". I predict that these agents will allow for far more potent application of therapy, given their safer side-effect profile and specificity. Remissions will be far more common (author note: true). Long-term remissions will become a realit (note: not true), and there will be a new "four letter word" spoken where RA is treated.
If these predictions come true, then the expense will be justified in spades!
In summary, I have gone over principles of inflammation and looked at the lesion in the synovium of patients with RA. Finally, I have described some of the most promising biologics. These biologics will be expensive. Novel approaches will be tried, such as combining biologics (anti-TNF and IL1ra in combination works well in animal models and are synergistic(note: it didn't work any better than just the anti-TNF agent alone, and there were more infections. Go figure?)). New terms will be uttered by those who treat RA, such as "induction therapy" and "maintenance therapy" and "re induction". I predict that these agents will allow for far more potent application of therapy, given their safer side-effect profile and specificity. Remissions will be far more common (author note: true). Long-term remissions will become a reality (note: not true), and there will be a new "four letter word" spoken where RA is treated. If these predictions come true, then the expense will be justified in spades!
Slides, artwork and photos by Craig Wiesenhutter, M.D. unless indicated.
References:
1. Strand, V., Lipsky, P., Cannon, G. Calabrese, L., Wiesenhutter, C., Cohen, S., Olsen, N. and the CD5 Plus RA Investigators Group, Effects of Administration of an Anti-CD5 Immunoconjugate in Rheumatoid Arthritis: Results of Two Phase II Studies. Arthritis Rheumatism, 1993 May; 36(#5): p. 620-630
2a. Levy R., Weisman, M., Wiesenhutter, C., Yocum, D., Schnitzer, T., Goldman, A., Schiff, M., Breedveld, F., Solinger, A., MacDonald, B., and J. Lipani. Results of a Placebo-Controlled, Multicenter Trial Using a Primatized Non-depleting, Anti-CD4 Monoclonal Antibody in the Treatment of Rheumatoid Arthritis. Arthritis Rheumatism, 1996 Sept (Suppl), 39(#9): p. S123 Abstract #574
2b. Tesser, J.R., Wiesenhutter, C.W., Levy, R., Schiff, M., Lipani, J., Solinger, A., MacDonald, B., Elliott, M., and K. Singh. Treatment of Rheumatoid Arthritis with a Primatized anti-CD4 Monoclonal Antibody, SB-210396 (IDEC-CE9.1). Results of an Open Label Extension Study in Patients Responding to Induction Therapy. Arthritis Rheumatism, 1997 Sept (Suppl, 40(#9): p.S224 Abstract #1160
3. Maini R.N., Breedveld, F.c., Kalden J.R. et al Low Dose Methotrexate Suppresses Anti-Globulin reponses and potentiates efficacy of a chimeric Monoclonal anti-TNFalpha Antibody (cA2) given Repeatedly in Rheumatoid Arthritis Arthritis Rheumatism, 1997 Sept (Suppl, 40(#9): p.S126 Abstract #571
4. Weinblass, M., Moreland, L.W., Schiff, M.H. et all, Long-term and Phase III Treatment of DMARD Failing Rheumatoid Arthritis Patients with TNF Receptor P75 FC Fusion Protein (TNFR:FC, Enbrel.) Arthritis Rheumatism, 1997 Sept (Suppl, 40(#9): p.S126 Abstract #572
5. Nuki, George, Rozman, B., Pavelka, K. et al. Interleukin-1 Receptor Antagonist Continues to Demonstrate Clinical Improvement in Rheumatoid Arthritis Arthritis Rheumatism, 1997 Sept (Suppl, 40(#9): p.S224 Abstract #1159
6.Klippel, John H., and Paul A. Dieppe, Rheumatology, Second Edition. Mosby. This is the best textbook for this subject.
7. Kelly, Harris, Ruddy, and Sledge, Textbook of Rheumatology, Fifth Edition.