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Treatment of rheumatoid arthritis: Tightening the noose
EDITORIALS Treatment of rheumatoid arthritis: Tightening the noose Abbreviations: APC = antigen-presenting cell; IL = interleukin; RA = rheumatoid arthritis; RF = rheumatoid factor; TNF = tumor necrosis factor
R
heumatoid arthritis affects more than 2 million Americans. Because the peak onset is during the most productive years between the ages of 20 and 45, costs associated with this disease (direct and indirect) reached $65 billion in 1992.1 Over the years, the discovery and development of effective therapies for RA has paralleled our understanding of the pathophysiology of the disease. In the early part of the 20th century, when RA was hypothesized to have an infectious pathogenesis, treatments were aimed at infectious causes. Forestier2 pioneered the use of gold salts for RA because of his belief that the disease resembled mycobacterial infections, for which gold was effective. Sulfasalazine was designed specifically for the treatment of RA, incorporating both a salicylate moiety and a sulfa moiety, thereby utilizing both the known efficacy of aspirin and the antibiotic properties of sulfa.3 Some early reports suggested chloroquine was tried because of the possibility that RA represented a form of amebic infection.4 Later, tetracyclines were touted for their efficacy against mycoplasma. Although the mechanism of action of these drugs is poorly understood, their efficacy is probably not related to the original hypotheses. However, all of these treatments have since been demonstrated to be effective in randomized controlled trials. Later, as autoimmunity was better understood, treatments were aimed at generalized immunosuppression. Fifty years ago the Nobel Prize was awarded for the isolation and characterization of adrenocortical hormones. The description of their dramatic effect on RA was an important part of this discovery.5 As the longterm side effects of corticosteroids became evident, other means of immunosuppression such as nitrogen
J Lab Clin Med 2001;138:5-7. Copyright © 2001 by Mosby, Inc. 0022-2143/2001 $35.00 + 0 5/1/115937 doi:10.1067/mlc.2001.115937
mustard, azathioprine, 6-mercaptopurine, chlorambucil, and cyclophosphamide were used.6,7 When aspirin, long known to be an effective treatment for RA, was found to inhibit prostaglandins, key mediators of inflammation, non-steroidal antiinflammatory drugs were developed. Methotrexate, an antimetabolite that has become the anchor in most RA treatment regimens, was initially used for its antiinflammatory properties as well as for its antiproliferative and subtle immune-modulating properties.8 Much of its anti-inflammatory and immune-modulating effect is thought to be due to its ability to produce an accumulation of extracellular adenosine, which has many anti-inflammatory effects. Other molecular and cellular effects are still being investigated.9 The histopathology of rheumatoid synovium is remarkable for lymphoid follicles that contain both Tand B-lymphocytes in abundance. Although the pathogenic importance of T cells is accepted, the role of the B cells is not as certain. These B cells are polyclonally activated and trigger production of an autoantibody specific for immunoglobulin, RF. Several autoantibodies are seen in RA, with RF being the most abundant, but none seem to be truly pathogenic. Other autoantibodies such as anticitrullin have been shown to be predictive of disease but not clearly pathogenic.10 Although RF is present in up to 90% of individuals with RA and is a good predictor of the severity of disease, it is neither necessary nor sufficient for the development of RA. It is present in a variety of other conditions as well as in normal individuals. Currently, the function of RF in RA is felt to be similar to that in the normal immune response: to aid B cells in antigen presentation and for the stabilization and clearance of immune complexes. Although effective immunosuppressive and anti-inflammatory treatments for RA tend to lower RF levels, treatments such as plasmapheresis aimed specifically at lowering RF levels have never been successful. As the study of rheumatoid disease focused on the 5
6 Editorial
CD4+T lymphocyte as the perpetuator of disease, more-specific immunosuppressive therapies were sought. Cyclosporin A, originally an anti-rejection drug that is a T cell inhibitor, was found to be effective for RA, especially when used in combination with methotrexate.11 Multiple anti-T cell treatments aimed at depleting T cell subsets have been tried unsuccessfully in RA.12 Monoclonal antibodies directed against various T cell markers have been used, with some conjugated to toxins and others designed as depleting antibodies. IL-2 conjugated to diphtheria toxin has also been tested. None has been successful in modifying disease activity in RA, and some have been associated with unacceptable side effects. Depletion of CD4 cells with monoclonal antibodies has produced profound long-lasting immunosuppression, but it has still failed to improve disease. In spite of these failures, much has been learned about the development and implementation of this new concept of drug therapy, the biologics. Even efforts to identify and deplete arthritogenic T cell clones bearing specific T cell receptors have met with limited success. The effectiveness of T cell receptor vaccination in experimentally induced animal models of autoimmunity, in which the antigen-specific pathogenic T cell can be easily identified, has led to the search for similar treatments for human patients with RA. A human cartilage antigen, gp-39, has been identified as a possible causative antigen for RA, but the presence of T cell receptors specific for this antigen has not been confirmed experimentally.13 In RA, as in spontaneous animal models of autoimmunity, T cell receptor usage is varied. Clonal expansions of multiple different T cell receptors can be found in rheumatoid synovium and peripheral blood. Although no particular subset appears to dominate, vaccination with three of the more common T cell receptor V beta peptides found to be preferentially expanded in the synovium of many RA patients has yielded encouraging results, but larger clinical studies will be necessary to demonstrate efficacy convincingly.14 The mechanism by which immunomodulation occurs with TCR immunization is complex and has not been completely defined. The focus of investigation into the pathophysiology of RA for some has shifted to APCs such as dendritic cells and macrophages.15 This has occurred partly because of the importance of APCs in the activation of T cells and partly because of the lack of success with treatments targeting the T cell. These APCs are efficient producers of cytokines such as TNF-α, the most recent therapeutic target in the treatment of RA, and IL-1β. TNF-α has been implicated in the pathogenesis of RA for more than a decade.16 It is synthesized by monocytes and macrophages present in the joint, stimulates production of other inflammatory mediators such as
J Lab Clin Med July 2001
prostaglandin E2, and promotes joint destruction by inducing collagenase production and fibroblast proliferation. It induces the production of IL-1, which acts with TNF-α to produce bony erosions and joint destruction. Thalidomide, although rarely used, has been resurrected as a therapy for RA because of its ability to inhibit TNF-α production by macrophages. Etanercept and Infliximab, two biologic agents, are both now approved by the FDA for use in RA. Etanercept is a fusion protein of the ligand-binding region of the 75kd (p75) TNF receptor that is linked to the Fc portion of human immunoglobulin G1. Infliximab is a chimeric (humanized mouse) monoclonal antibody against TNFα. Etanercept has recently been shown to be better than methotrexate alone in early RA in its ability to delay joint damage and control symptoms.17 Although longterm data on efficacy and toxicity are lacking for TNFα inhibitors, to date they have produced few serious side effects. Injection site reactions are common with etanercept, and infliximab can produce hypersensitivity reactions. Serious life-threatening infections can occur, and the presence of chronic, recurrent, or active infections is a contraindication for the use of TNF-α inhibitors. IL-1β, produced in large amounts by APCs, is also a therapeutic target for biologic agents. A soluble IL-1 receptor antagonist (Anakinra) is currently awaiting FDA approval for use in RA. Although these new biologic agents are potent and seem relatively safe, their use is currently limited by cost, which is in the range of $10,000 to $12,000 per year. These therapies do not induce long-term remissions, so treatment must be continued indefinitely. Long-term data regarding their effect on disability and its costs are needed before any conclusions regarding cost effectiveness can be made. On the horizon, IL-10, a cytokine that is produced by both T cells and macrophages and has immunosuppressive and anti-inflammatory properties, is being investigated for use in RA. Novel new delivery systems for these biologic agents that use gene therapy are also being developed. Although new therapies for RA are more abundant and more exciting than at any time in the past 15 years, a cure is still needed. As our understanding of the pathophysiology of RA reaches the molecular level, the opportunity for more and more precise therapeutic tools presents itself. In the current issue of the Journal, Urayama et al18 describe the effect of a newly developed disease-modifying antirheumatic drug, KE-298, on activated T cells. This compound has already been shown to suppress development of disease in a wide variety of animal models of arthritis. The ability of this compound to target only activated T cells solves the problem of antigenic diversity in RA. Theoretically, this drug would
J Lab Clin Med Volume 138 Number 1
target all the T cells that are currently activated without regard to their specificity yet leave the immune system relatively intact to respond to any infectious threats to the organism. Importantly, these authors show that KE298 produces apoptosis of activated T cells, thereby eliminating the offending clones permanently. If our understanding of the mechanisms of autoimmunity in RA is correct, the elimination of T cells that have become activated and are driving the disease could be an important step toward finding the long-awaited but elusive cure. But experience has taught us that the immune system is incredibly plastic and redundant, and that controlling an immune response gone astray is a difficult thing. Even so, understanding the various mechanisms of action of effective therapies will move us closer to treatment strategies that will effectively eliminate disease. HOLLIS E. KRUG, MD Rheumatology Division Department of Medicine University of Minnesota Medical School Minneapolis VA Medical Center Minneapolis, MN 55417
REFERENCES
1. American College of Rheumatology. Rheumatoid arthritis. www.rheumatology.org/patients/factsheet/ra.html. 2000. 2. Forestier J. Rheumatoid arthritis and its treatment by gold salts. J Lab Clin Med 1935;20:827-40. 3. Svartz N. Salazopyrin, a new sulfanilamide preparation. Acta Med Scand 1942;60:577-98. 4. Bunim JJ. Antimalarial compounds in rheumatoid arthritis. Bull Rheum Dis 1957;8:149-52. 5. Hench PS, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Mayo Clin Proc 1949;24:181-97. 6. Jimenez Diaz C, Lopez Garcia E, Merchante A, Perianes J.
Editorial
7.
8.
9. 10. 11.
12.
13.
14.
15. 16.
17.
18.
7
Treatment of rheumatoid arthritis with nitrogen mustard. JAMA 1951;147:1418-9. Mason M, Currey HLF, Barnes CG, Dunne JF, Hazleman BL, Strickland ID. Azathioprine in rheumatoid arthritis. Br Med J 1969;1:420-2. Gubner R. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951;122:176-82. Seitz M. Molecular and cellular effects of methotrexate. Curr Opin Rheumatol 1999;11:226-32. Smolen JS, Steiner G. Are autoantibodies active players or epiphenomena? Curr Opin Rheumatol 1998;10:201-6. Tugwell P, Pincus T, Stein M, Gluck O, Kraag G, McKendry R, et al. Combination therapy with cyclosprine and methotrexate in severe rheumatoid arthritis: The MethotrexateCyclosporin Combination Study Group. N Engl J Med 1995; 333:137-41. Choy EHS, Kingsley GH, Panayi GS. Immunotherapies. In: Rheumatology. Klippel JH, Dieppe PA, editors. London: Mosby; 1998. p. 3.10.1-3.10.5. Kotzin BL, Falta MT, Crawford F, Rosloniec EF, Bill J, Marrack P, et al. Use of soluble peptide-DR4 tetramers to detect synovial T cells specific for cartilage antigens in patients with rheumatoid arthritis. Proc Natl Acad Sci USA 2000;97: 291-6. Moreland LW, Morgan EE, Adamson TC, Fronek Z, Calabrese LH, Cash JM, et al. T cell receptor peptide vaccination in rheumatoid arthritis: a placebo-controlled trial using a combination of Vbeta3, Vbeta14, and Vbeta17 peptides. Arthritis Rheum 1998;41:1906-10. Thomas R, Lipsky P. Presentation of self peptides by dendritic cells. Arthritis Rheum 1996;39:183-90. Arend WP, Dayer JM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 1990;33: 305-15. Bathon J, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and metho-trexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586-93. Urayama S, Kawakami A, Nakashima T, Yamasaki S, Hida A, Ida H, et al. A new disease-modifying antirheumatic drug, 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298), selectively augments activation-induced T cell death. J Lab Clin Med 2001;138:11-7.
R
heumatoid arthritis affects more than 2 million Americans. Because the peak onset is during the most productive years between the ages of 20 and 45, costs associated with this disease (direct and indirect) reached $65 billion in 1992.1 Over the years, the discovery and development of effective therapies for RA has paralleled our understanding of the pathophysiology of the disease. In the early part of the 20th century, when RA was hypothesized to have an infectious pathogenesis, treatments were aimed at infectious causes. Forestier2 pioneered the use of gold salts for RA because of his belief that the disease resembled mycobacterial infections, for which gold was effective. Sulfasalazine was designed specifically for the treatment of RA, incorporating both a salicylate moiety and a sulfa moiety, thereby utilizing both the known efficacy of aspirin and the antibiotic properties of sulfa.3 Some early reports suggested chloroquine was tried because of the possibility that RA represented a form of amebic infection.4 Later, tetracyclines were touted for their efficacy against mycoplasma. Although the mechanism of action of these drugs is poorly understood, their efficacy is probably not related to the original hypotheses. However, all of these treatments have since been demonstrated to be effective in randomized controlled trials. Later, as autoimmunity was better understood, treatments were aimed at generalized immunosuppression. Fifty years ago the Nobel Prize was awarded for the isolation and characterization of adrenocortical hormones. The description of their dramatic effect on RA was an important part of this discovery.5 As the longterm side effects of corticosteroids became evident, other means of immunosuppression such as nitrogen
J Lab Clin Med 2001;138:5-7. Copyright © 2001 by Mosby, Inc. 0022-2143/2001 $35.00 + 0 5/1/115937 doi:10.1067/mlc.2001.115937
mustard, azathioprine, 6-mercaptopurine, chlorambucil, and cyclophosphamide were used.6,7 When aspirin, long known to be an effective treatment for RA, was found to inhibit prostaglandins, key mediators of inflammation, non-steroidal antiinflammatory drugs were developed. Methotrexate, an antimetabolite that has become the anchor in most RA treatment regimens, was initially used for its antiinflammatory properties as well as for its antiproliferative and subtle immune-modulating properties.8 Much of its anti-inflammatory and immune-modulating effect is thought to be due to its ability to produce an accumulation of extracellular adenosine, which has many anti-inflammatory effects. Other molecular and cellular effects are still being investigated.9 The histopathology of rheumatoid synovium is remarkable for lymphoid follicles that contain both Tand B-lymphocytes in abundance. Although the pathogenic importance of T cells is accepted, the role of the B cells is not as certain. These B cells are polyclonally activated and trigger production of an autoantibody specific for immunoglobulin, RF. Several autoantibodies are seen in RA, with RF being the most abundant, but none seem to be truly pathogenic. Other autoantibodies such as anticitrullin have been shown to be predictive of disease but not clearly pathogenic.10 Although RF is present in up to 90% of individuals with RA and is a good predictor of the severity of disease, it is neither necessary nor sufficient for the development of RA. It is present in a variety of other conditions as well as in normal individuals. Currently, the function of RF in RA is felt to be similar to that in the normal immune response: to aid B cells in antigen presentation and for the stabilization and clearance of immune complexes. Although effective immunosuppressive and anti-inflammatory treatments for RA tend to lower RF levels, treatments such as plasmapheresis aimed specifically at lowering RF levels have never been successful. As the study of rheumatoid disease focused on the 5
6 Editorial
CD4+T lymphocyte as the perpetuator of disease, more-specific immunosuppressive therapies were sought. Cyclosporin A, originally an anti-rejection drug that is a T cell inhibitor, was found to be effective for RA, especially when used in combination with methotrexate.11 Multiple anti-T cell treatments aimed at depleting T cell subsets have been tried unsuccessfully in RA.12 Monoclonal antibodies directed against various T cell markers have been used, with some conjugated to toxins and others designed as depleting antibodies. IL-2 conjugated to diphtheria toxin has also been tested. None has been successful in modifying disease activity in RA, and some have been associated with unacceptable side effects. Depletion of CD4 cells with monoclonal antibodies has produced profound long-lasting immunosuppression, but it has still failed to improve disease. In spite of these failures, much has been learned about the development and implementation of this new concept of drug therapy, the biologics. Even efforts to identify and deplete arthritogenic T cell clones bearing specific T cell receptors have met with limited success. The effectiveness of T cell receptor vaccination in experimentally induced animal models of autoimmunity, in which the antigen-specific pathogenic T cell can be easily identified, has led to the search for similar treatments for human patients with RA. A human cartilage antigen, gp-39, has been identified as a possible causative antigen for RA, but the presence of T cell receptors specific for this antigen has not been confirmed experimentally.13 In RA, as in spontaneous animal models of autoimmunity, T cell receptor usage is varied. Clonal expansions of multiple different T cell receptors can be found in rheumatoid synovium and peripheral blood. Although no particular subset appears to dominate, vaccination with three of the more common T cell receptor V beta peptides found to be preferentially expanded in the synovium of many RA patients has yielded encouraging results, but larger clinical studies will be necessary to demonstrate efficacy convincingly.14 The mechanism by which immunomodulation occurs with TCR immunization is complex and has not been completely defined. The focus of investigation into the pathophysiology of RA for some has shifted to APCs such as dendritic cells and macrophages.15 This has occurred partly because of the importance of APCs in the activation of T cells and partly because of the lack of success with treatments targeting the T cell. These APCs are efficient producers of cytokines such as TNF-α, the most recent therapeutic target in the treatment of RA, and IL-1β. TNF-α has been implicated in the pathogenesis of RA for more than a decade.16 It is synthesized by monocytes and macrophages present in the joint, stimulates production of other inflammatory mediators such as
J Lab Clin Med July 2001
prostaglandin E2, and promotes joint destruction by inducing collagenase production and fibroblast proliferation. It induces the production of IL-1, which acts with TNF-α to produce bony erosions and joint destruction. Thalidomide, although rarely used, has been resurrected as a therapy for RA because of its ability to inhibit TNF-α production by macrophages. Etanercept and Infliximab, two biologic agents, are both now approved by the FDA for use in RA. Etanercept is a fusion protein of the ligand-binding region of the 75kd (p75) TNF receptor that is linked to the Fc portion of human immunoglobulin G1. Infliximab is a chimeric (humanized mouse) monoclonal antibody against TNFα. Etanercept has recently been shown to be better than methotrexate alone in early RA in its ability to delay joint damage and control symptoms.17 Although longterm data on efficacy and toxicity are lacking for TNFα inhibitors, to date they have produced few serious side effects. Injection site reactions are common with etanercept, and infliximab can produce hypersensitivity reactions. Serious life-threatening infections can occur, and the presence of chronic, recurrent, or active infections is a contraindication for the use of TNF-α inhibitors. IL-1β, produced in large amounts by APCs, is also a therapeutic target for biologic agents. A soluble IL-1 receptor antagonist (Anakinra) is currently awaiting FDA approval for use in RA. Although these new biologic agents are potent and seem relatively safe, their use is currently limited by cost, which is in the range of $10,000 to $12,000 per year. These therapies do not induce long-term remissions, so treatment must be continued indefinitely. Long-term data regarding their effect on disability and its costs are needed before any conclusions regarding cost effectiveness can be made. On the horizon, IL-10, a cytokine that is produced by both T cells and macrophages and has immunosuppressive and anti-inflammatory properties, is being investigated for use in RA. Novel new delivery systems for these biologic agents that use gene therapy are also being developed. Although new therapies for RA are more abundant and more exciting than at any time in the past 15 years, a cure is still needed. As our understanding of the pathophysiology of RA reaches the molecular level, the opportunity for more and more precise therapeutic tools presents itself. In the current issue of the Journal, Urayama et al18 describe the effect of a newly developed disease-modifying antirheumatic drug, KE-298, on activated T cells. This compound has already been shown to suppress development of disease in a wide variety of animal models of arthritis. The ability of this compound to target only activated T cells solves the problem of antigenic diversity in RA. Theoretically, this drug would
J Lab Clin Med Volume 138 Number 1
target all the T cells that are currently activated without regard to their specificity yet leave the immune system relatively intact to respond to any infectious threats to the organism. Importantly, these authors show that KE298 produces apoptosis of activated T cells, thereby eliminating the offending clones permanently. If our understanding of the mechanisms of autoimmunity in RA is correct, the elimination of T cells that have become activated and are driving the disease could be an important step toward finding the long-awaited but elusive cure. But experience has taught us that the immune system is incredibly plastic and redundant, and that controlling an immune response gone astray is a difficult thing. Even so, understanding the various mechanisms of action of effective therapies will move us closer to treatment strategies that will effectively eliminate disease. HOLLIS E. KRUG, MD Rheumatology Division Department of Medicine University of Minnesota Medical School Minneapolis VA Medical Center Minneapolis, MN 55417
REFERENCES
1. American College of Rheumatology. Rheumatoid arthritis. www.rheumatology.org/patients/factsheet/ra.html. 2000. 2. Forestier J. Rheumatoid arthritis and its treatment by gold salts. J Lab Clin Med 1935;20:827-40. 3. Svartz N. Salazopyrin, a new sulfanilamide preparation. Acta Med Scand 1942;60:577-98. 4. Bunim JJ. Antimalarial compounds in rheumatoid arthritis. Bull Rheum Dis 1957;8:149-52. 5. Hench PS, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Mayo Clin Proc 1949;24:181-97. 6. Jimenez Diaz C, Lopez Garcia E, Merchante A, Perianes J.
Editorial
7.
8.
9. 10. 11.
12.
13.
14.
15. 16.
17.
18.
7
Treatment of rheumatoid arthritis with nitrogen mustard. JAMA 1951;147:1418-9. Mason M, Currey HLF, Barnes CG, Dunne JF, Hazleman BL, Strickland ID. Azathioprine in rheumatoid arthritis. Br Med J 1969;1:420-2. Gubner R. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951;122:176-82. Seitz M. Molecular and cellular effects of methotrexate. Curr Opin Rheumatol 1999;11:226-32. Smolen JS, Steiner G. Are autoantibodies active players or epiphenomena? Curr Opin Rheumatol 1998;10:201-6. Tugwell P, Pincus T, Stein M, Gluck O, Kraag G, McKendry R, et al. Combination therapy with cyclosprine and methotrexate in severe rheumatoid arthritis: The MethotrexateCyclosporin Combination Study Group. N Engl J Med 1995; 333:137-41. Choy EHS, Kingsley GH, Panayi GS. Immunotherapies. In: Rheumatology. Klippel JH, Dieppe PA, editors. London: Mosby; 1998. p. 3.10.1-3.10.5. Kotzin BL, Falta MT, Crawford F, Rosloniec EF, Bill J, Marrack P, et al. Use of soluble peptide-DR4 tetramers to detect synovial T cells specific for cartilage antigens in patients with rheumatoid arthritis. Proc Natl Acad Sci USA 2000;97: 291-6. Moreland LW, Morgan EE, Adamson TC, Fronek Z, Calabrese LH, Cash JM, et al. T cell receptor peptide vaccination in rheumatoid arthritis: a placebo-controlled trial using a combination of Vbeta3, Vbeta14, and Vbeta17 peptides. Arthritis Rheum 1998;41:1906-10. Thomas R, Lipsky P. Presentation of self peptides by dendritic cells. Arthritis Rheum 1996;39:183-90. Arend WP, Dayer JM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 1990;33: 305-15. Bathon J, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and metho-trexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586-93. Urayama S, Kawakami A, Nakashima T, Yamasaki S, Hida A, Ida H, et al. A new disease-modifying antirheumatic drug, 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298), selectively augments activation-induced T cell death. J Lab Clin Med 2001;138:11-7.