Pathogenesis of rheumatoid arthritis: Basis for future therapies

Pathogenesis of Rheumatoid Arthritis: Basis for Future Therapies By Robert L. Wortmann

Despite an increase in the number of rheumatologists in clinical practice over the past 15 years, the outcome for patients with rheumatoid arthritis (RA) remains relatively poor. The poor prognosis for patients with this disease is due to a lack of effective therapies. Better therapies will be developed only after the cause and pathogenesis of RA are better understood. Although the precise cause is unknown, a variety of evidence indicates that RA results from the presentation of a relevant antigen to an immunogeneticallysusceptible host.

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HEUMATOID ARTHRITIS (RA) is the disease most identified with the discipline of rheumatology. Unfortunately, despite an increasing number of rheumatologists, the treatment of this disease is too often ineffective. Only recently have we begun to appreciate the true and staggering morbidity of this condition.’ The extent of this morbidity is both surprising and disappointing. The number of rheumatologists has increased dramatically over the past 15 years; it was thought that patient outcomes would therefore improve because of more accurate, earlier diagnosis and the rational application of disease remitting agents. However, this has not been the case. It is appropriate, therefore, for us as rheumatologists to reassess the management of RA. It is clear that new therapeutic agents must be developed if we are to achieve better results for patients with this disease. New agents will probably not be discovered by accident; they will be designed and developed based on our understanding of the underlying pathobiology. Unfortunately, our understanding of this pathobiology is limited, and current schemes do not fully account for the complex and varied nature of the disease. Many questions remain unanswered. What is the pathophysiology that results in pannus formation and joint destruction? What causes the nonarticular and systemic features, including morning stiffness, anorexia, fatigue, anemia, and elevated levels of acute-phase reactants? Why does the disease vary from patient to patient? Why do only 75% of patients have rheumatoid factor in their sera? Why does the synovia become filled with Seminars in Arthriris and Rheumatism,

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This report reviews recognized potential antigens and known genetic variables affecting the immune response, as well as the various cellular and humoral immune responses that result from the antigen-host interaction. More successful therapy for RA will most certainly result from a better understanding of the pathobiology of the disease. Copyright 0 1991 by W.B. Saunders Company INDEX WORDS: Rheumatoid arthritis; etiology; immune response; immunogenetics.

lymphoid aggregates in some patients, but become diffusely infiltrated with lymphocytes or contain fibroblasts almost exclusively in others?2,3 The purpose of this review is to summarize our current knowledge of the pathobiology of RA to provide a basis for understanding future developments in this area. Today we believe that RA results from the presentation of a relevant antigen to an immunogenetically susceptible host. If so, then the clinical variation observed could be explained by different triggering antigens, by different host responses to a single antigen, or a combination of the two. Antigens that could potentially initiate an immune response that results in RA might be endogenous or exogenous. Possible endogenous antigens include collagens, mucopolysaccharides, and rheumatoid factors. Infectious agents lead the list of possible exogenous antigens. Infectious agents indicated as causing RA include mycoplasma, mycobacteria, spirochetes, and viruses. Mycoplasma can induce an RA-like illness in experimental animals. Mycobacteria express heat

From the Medical Service, Clement J. Zablocki Veterans Administration Medical Center, and the Department of Medicine, Medical College of Wisconsin, Milwaukee, WI. Robert L. Wortmann, MD: Chief Medical Service, Clement J. Zablocki VA Medical Center, Interim Chairman, Department of Medicine, Medical College of Wisconsin. Address reprint requests to Robert L. Wortmann, MD, Professor and Interim Chairman, Department of Medicine (1 I I), Medical College of Wisconsin, Milwaukee, WI 53295. Copyright 0 1991 by W.B. Saunders Company 0049-0172/91/2102-1005%5.00/O

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shock proteins, which are the same proteins critical to induction of adjuvant arthritis in rats.4 In addition, patients with RA have high levels of antibodies to heat shock proteins.5 The similarity between the synovial changes in Lyme disease and RA allows speculation that spirochetes could be involved. Epstein-Barr virus has received the most attention as a possible cause of RA. Circulating antibodies directed against Epstein-Barr antigens are found in 80% of patients with RA.6 EpsteinBarr virus causes B lymphocytes to overproduce immunoglobulins, including rheumatoid factors.7 Compared with healthy individuals, patients with RA have increased numbers of B lymphocytes infected with Epstein-Barr virus, as well as a diminished cytotoxic T-cell response to the virr~s.~Parvovirus, rubella virus, cytomegalovirus, herpes virus, and the type I human T-cell lymphotropic virus have also been implicated.‘,” Evidence for host variability or difference in genetics affecting susceptibility or disease manifestations is abundant. Individuals with RA who are anergic appear to have a different pattern of disease compared with those who are not anergic.3 Similarly, the disease manifests differently in individuals with anti-type II collagen antibodies compared with those without such antibodies I’ Perhaps the best example of host variation involves rheumatoid factor: only 70% to 80% of patients with RA have rheumatoid factor in their sera. However, those who do have rheumatoid factor tend to have more severe disease, with nodules and erosions. Interestingly, everyone possesses genes that encode for rheumatoid factor. ’ 2 Several observations provide evidence supporting the hypothesis that immunogenetics determine host susceptibility to RA. Individuals with a certain polymorphic component of the gene for a constant region of the K light chains of immunoglobulin G (IgG) have an increased relative risk of RA,13 and many rheumatoid factors from different individuals have light chains encoded by the same conserved variable region of the gene for the K light chainI Further support comes from our understanding of class-II major histocompatibility complex (MHC) molecules. The genes for these molecules encode for glycoproteins that combine with processed antigen and present them to helper T lymphocytes. These T cells express receptors for the MHC-antigen

ROBERT L. WORTMANN

complex. Most patients with RA have HLA-DR4, HLA-DR 1, or both. Those with HLA-DR4 tend to have more severe disease, while those who carry HLA-DR2/Dw2 have a milder di~ease.‘~ HLA-DR4 can be separated into five subtypes: Dw4, DwlO, Dw13, Dw14, and Dw15. Two of these, Dw4 and Dw 14, as well as HLA-DR 1, have been shown to promote susceptibility to RA. In fact, this susceptibility has been localized to a specific amino acid sequence in the third hypervariable region of the @,-chain of these MHC molecules. Interestingly, the same amino acid sequence is also found in gp 110, a major surface glycoprotein of Epstein-Barr viru~.‘~~‘~Consequently, T-cell recognition of gp 110 viral proteins might initiate RA in Dw4, Dw14, or HLADr l-positive individuals by the process of molecular mimicry. Alternatively, immune complexes containing a peptide that mimics these specific MHC molecules will be formed when Epstein-Barr virus is extruded from cells and complexed with antibodies directed against the surface glycoprotein. The resultant immune complexes containing a “selfpeptide” could be deposited in tissues or processed by any antigenpresenting cell, thereby initiating, sustaining, or amplifying an immune response that results in RA. Although much uncertainty persists conceming the cause of and host susceptibility to RA, the histopathologic changes that result once the disease process is under way are well described. Normal synovium is relatively acellular and avascular with a stroma consisting of fat and fibrous tissue incompletely limited by a lining one to two cells thick. The lining is composed of cells that can be separated into two categories. One category is monocyte-macrophage in nature and phagocytic. The other has characteristics of fibroblasts and has synthetic properties. The earliest changes observed in RA include endothelial cell damage, synovial edema, fibrin deposition, polymorphonuclear leukocyte invasion, and mild lining cell hyperplasia. ‘* These changes are followed closely by the perivascular accumulation of T and B lymphocytes. The primary causes of the endothelial damage and other changes are unknown, but are believed to result from the activity of cytokines, complement activation components, and arachidonic acid metabolites. Histamine and serotonin also play a role. Cytokines are small proteins produced

PATHOGENESIS

OF RHEUMATOID

ARTHRITIS

by macrophages, lymphocytes, and fibroblasts that trigger responses in cells that possess specific receptors. Interleukin- 1 (IL- 1) and tumor necrosis factor-alpha (TNF-a) are products of macrophages and fibroblasts and are recognized causes of endothelial adherence. The complement component C3a is a potent vasodilator, whereas C5a promotes endothelial adherence and is chemotactic for polymorphonuclear leukocytes. Prostaglandin E2 (PGE2), a cycle-oxygenase product of arachidonic acid, causes vasodilation and increased vascular permeability, whereas leukotriene B4 (LTBJ, a lipoxygenase product, promotes endothelial adherence and is chemotactic. Although the actual initiating event that results in the early changes of RA is unknown, it is believed to involve antigen presentation. Traditionally, attention has been focused on the macrophage as the antigen-presenting cell, but a variety of cell types are capable of this function. Endothelial cells, fibroblasts, and B cells can also process and present antigens. It may not matter which cell type initiates the process, because each participates in the pathology of RA. On the other hand, some of the interpatient variations might be accounted for by which cell(s) is primarily involved. The model of the macrophage as a major antigen-presenting cell is well recognized. After being taken up by the macrophage, the antigen is processed, or modified, and presented in complex with an MHC molecule to a T cell. Concomitantly, the macrophage releases a multitude of factors that can provoke and amplify the inflammatory response. These include IL- 1, TNF(Y,IL-6, colony-stimulating factors, coagulation factors, lysosomal enzymes, plasminogen activator, collagenases, LTB4, PGE2, and oxygenfree radicals. IL-l is an intriguing mediator within the scheme of RA. Released by macrophages and fibroblasts, this cytokine can bind to specific receptors on a variety of cell types with the capacity to not only initiate the immune response, but also to enhance it. IL 1, acting alone or in concert with TNF-a, is believed to play a major role in many of the systemic features of RA, including fever, sleep disturbances, weight loss, muscle wasting, and leukocytosis. I9 IL- 1, along with IL6, stimulates acute-phase reactant production in the liver. Furthermore, IL-1 can activate B cells, monocytes, and polymorphonuclear leukocytes;

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promote lining cell proliferation; stimulate prostaglandin production and matrix-degrading protease activity by chondrocytes and synovial fibroblasts; and activate osteoclast activity.*’ Thus, IL-l is probably a major participant in both the early phases of RA, as well as the chronic changes of pannus formation. Consequently, one could envision the macrophage as the major player or orchestrater of the inflammatory response that occurs in RA. A strong case can be made for lymphocytes having such a pivotal role as well. Large numbers of lymphocytes and plasma cells are found in rheumatoid synovia. Initially they are clustered around capillaries. I8As the disease progresses, the pannus formed often contains massive numbers of these cells. The T lymphocytes, especially those around macrophages, are CD4positive, or helper cells.*’ These cells are in an activated state with Ia antigens (products of MHC class II genes) expressed on their surfaces. Large amounts of Ia antigens are also expressed on the surfaces of macrophages and synovial lining cells. Ia antigens can be expressed in response to interferon gamma, a T-cell product. Activated T cells produce IL-2, IL-3, IL-4, B-cell growth factor (BCGF), and B-cell differentiation factor (BCDF) and express IL-2 receptors and transferrin on their surfaces.** The interaction of these cytokines and receptors causes T cells to enlarge and divide, and B cells to proliferate and differentiate into plasma cells that produce immunoglobulin and rheumatoid factors. Evidence for the critical role for T cells in the pathogenesis of RA is provided by the effectiveness of several experimental therapies that have been used to treat the disease. These include thoracic duct drainage, total-node irradiation, ricintagged anti-CD4 antibodies, and photopheresis. Although targeting the T cell for therapy may prove to be a successful strategy, the synovial changes of RA are probably not the result of a primary T-cell-driven immune response.23-25 The B cell, as an antigen-presenting cell, could take on a primary role in the pathogenesis of rheumatoid arthritis. Currently, more importance is given to the role of the B cell in perpetuating and amplifying the immune response, a role resulting from the secretion of rheumatoid factor. In addition to being activated by antigens, B cells can respond to a variety of macrophage (IL-l, TNF-a, interferon alpha) and T-lymphocyte-de-

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ROBERT L. WORTMANN

’

Collagenase PGE2

-0

T Cell

B cell growth factor S cell differentiation

Lysosomal enzymes

Fig Differentiates into plasma cell Secretes rheumatoid factor which: - forms immune complexes - activates complement

Collagenase PGE2

The

synovial

and

systemic

manifestations

of RA re-

sult from the complex interaction of many different cell types, cytokines, and

Lysosomal enzymes Oxygen radicals PGE2, LTS4

rived (interferon gamma, IL-2, IL-4, BCGF, BCDF) cytokines. The rheumatoid factors produced can form immune complexes that enhance the immune response by several mechanisms. First, large rheumatoid factor complexes can activate the complement cascade.26 Second, rheumatoid factor can precipitate out with IgG in the superficial layers of cartilage initiating locally damaging events. 27 Finally, the complexes can be taken up, processed, and presented by antigenpresenting cells, perpetuating the disease process that might have been triggered by another antigen. Synovial lining cells and chondrocytes must also be viewed as active participants in the rheumatoid process. Synovial macrophages and fibroblasts are capable of secreting factors that activate adjacent cells and induce proliferation. They are also capable of releasing inflammatory mediators like collagenase and prostaglandins.28 Chondrocytes can release metalloproteinases, collagenase, and PGE2 when stimulated with IL1.29Furthermore, these cells could be activated

1:

changes

inflammatory

mediators.

by basic calcium phosphate or apatite crystals released as a result of cartilage and bone destruction. Both synovial lining cells and chondrocytes release proteolytic enzymes, collagenase, and PGE2 after endocytosis of these crystals.30,31 Thus, the pathologic changes that occur in rheumatoid arthritis appear to result from the complex interactions of multiple cell types (Fig 1). The order in which various cell types become involved and the cytokines and inflammatory mediators that are most critical to the process are uncertain. The ultimate treatment for RA may well await the resolution of these uncertainties. However, some exciting therapies are under investigation: antagonists to IL 1 receptors,32 ricintagged anti-(CDS) T-cell antibodies,33 and photopheresis34 are all strategies that may prove beneficial. Yet, until these or others are proven effective, we must continue to focus on making the diagnosis as soon as possible and using the mediations that are available in more effective ways.

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antigen and synovial tissue immunohistologic characteristic. J Clin Invest 74:1173-l 185, 1984 4. Van Eden W, Thole JW, VanderZee R, et al: Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 331:171-173, 1988 5. Tsoulfa Cl, Rook GA, Van-Embden JD, et al: Raised serum IgG and IgA antibodies to mycobacterial antigens in rheumatoid arthritis. Ann Rheum Dis 48: 118-l 23, 1989

PATHOGENESIS OF RHEUMATOID ARTHRITIS

6. Alspaugh MA, Henle G, Lennette ET, et al: Elevated levels of antibodies to Epstein-Barr virus antigens in sera and synovial fluids of patients with rheumatoid arthritis. J Clin lnvest67:1134-1140, 1981 7. Slaughter L, Carson DA, Jensen FC, et al: In vitro effects of Epstein-Barr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects. J Exp Med 148:1429-1434, 1978 8. Yao QY, Rickinson AB, Gaston JS, et al: Disturbance of the Epstein-Barr virus-host balance in rheumatoid arthritis patients: A quantitative study. Clin Exp Immunol 64:302310, 1986 9. Phillips PE: Evidence implicating infectious agents in rheumatoid arthritis and juvenile rheumatoid arthritis. Clin Exp Rheumatol6:87-94, 1988 10. Venables PJW: Infection and rheumatoid arthritis. Curr Opin Rheumatol 1:15-20, 1989 11. Stuart JM, Huffstutter EH, Towens AS, et al: Incidence and specificity of antibodies to types I, II, IV and V collagen in rheumatoid arthritis and other rheumatic diseases as measured by ‘251-radioimmunoassay. Arthritis Rbeum 26:832-840, 1983 12. Carson DA, Chen PP, Kipps TJ, et al: Idiopathic and genetic studies of human rheumatoid factors. Arthritis Rheum 30:1321-1325, 1987 13. Moxley G: DNA polymorphism of immunoglobulin kappa confers risk of rheumatoid arthritis. Arthritis Rheum 32634-637, 1989 14. Silverman GJ, Goldfien RD, Chen P, et al: Idiopathic and subgroup analysis of human monoclonal rheumatoid factors: Implications for structural and genetic basis of autoantibodies in humans. J Clin Invest 82:469-475, 1988 15. Young A, Jaraquemade D, Awad J, et al: Association of HLA-DR4/Dw4 and DR2/Dw2 with radiologic changes in a small prospective study of patients with rheumatoid arthritis Preferential relationship with HLA-Dw rather than HLA-DR specificities. Arthritis Rheum 27:20-25, 1984 16. Roudier J, Rhodes G, Petersen J, et al: The EpsteinBarr virus glycoprotein gp 110, a molecular link between HLA DR4, HLA DR 1, and rheumatoid arthritis. Stand J Immunol 27:367-37 1, 1988 17. Roudier J, Petersen J, Rhodes GH, et al: Susceptibility to rheumatoid arthritis maps to a T cell epitope shared by HLA-DW4 beta- 1 chain and the Epstein-Barr virus glycoprotein gp 110. Proc Nat1 Acad Sci USA 86:5104-5108, 1989 18. Schumacher HR, Kitridou RC: Synovitis of recent onset. A clinicopatbologic study during the first month of disease. Arthritis Rheum 15:465-485, 1972 19. Kunkel SL, Spengler M, Kwon G, et al: Production and regulation of tumor alpha. A cellular and molecular analysis. Methods Achiev Exp Path01 13:240-259, 1988 20. Dinarelio CA: Interleukin-1. Dig Dis Sci 33:258-358, 1988 (suppl3) 2 1. Knottinen YT, Reitamo S, Ranki A, et al Characterization of the immunocompetent cells of rheumatoid syno-

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vium from tissue sections and eluates. Arthritis Rheum 24: 71-79, 1983 22. Burmester GR, Jahn B, Gramatzki M: Activated T cells in vivo and in vitro: Divergents and expression of Tat and la antigens in the nonbastoid small T ceils of inIlammation and normal T cells activated in vitro. J Immunol 133:12301234, 1984 23. Kurosaaka M, Ziff M: Immunoelectron microscopic study of the distribution of T cell subsets in rheumatoid synovium. J Exp Med 158:1191-1210, 1983 24. Firestein GS, Zvaifler NJ: Peripheral blood and synovial fluid monocyte activation in innammatory arthritis. II. Low levels of synovial fluid and synovial tissue interferon suggest gamma-interferon is not the primary MAF in arthritis. Arthritis Rheum 30:864-87 1, 1987 25. Firestein GS, Xu W-D, Townsend K, et al: Cytokines in chronic inllammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J Exp Med 168:1573-1586, 1988 26. Pope RM, Teller DC, Mannik M: The molecular basis of self-association of antibodies to IgG (rheumatoid factor) in rheumatoid arthritis. Proc Nat1 Acad Sci USA 7 1:517-521, 1974 27. Shiozawa S, Jasin HE, Ziff M: Absence of immunoglobulins in rheumatoid cartilage-pannus junctions. Arthritis Rheum 23:816-821, 1980 28. Dayer JM, de Rochemonteix B, Bums B, et al: Human recombinant interleukin- 1 stimulates collagenase and prostaglandin E2 production by human synovial celIs. J Chn Invest 77:645-648, 1986 29. Shinmei J, Masuda K, Kikuchi T, et al: The role of cytokines in chondrocyte mediated cartilage degradation. J Rheumatol 16:32-34, 1989 (suppl 18) 30. Cheung HS, McCarty DJ: Biological effects of calcium containing crystals on synoviocytes, in Rubin RP, Weiss GB (eds): Calcium in Biological Systems. New York, NY, Plenum, 1985, pp 719-724 3 1. Cheung HS, Halverson PB, McCarty DJ: Phagocytosis of hydroxapatite on calcium pyrophosphate dihydrate crystals by rabbit articular chondrocytes stimulates release of collagenase, neutral protease and prostaglandin E2 and Fz. Proc Sot Exp Biol Med 173:181-189, 1983 32. Carter DB, Deibel Jr MR, Dunn CJ, et al: Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature 344:633-638, 1990 33. Strand V, Fishwild D, XOMA Arthritis Investigators Group: Treatment of rheumatoid arthritis with anti-CD5 immunoconjugate: Clinical and immunologic findings and preliminary results of re-treatment. Arthritis Rheum 33:S25, 1990 (suppl) 34. Malawista SE, Track D, Edelson R: Treatment of rheumatoid arthritis by extracorporeal photochemotherapy (ECP): A pilot study. Arthritis Rheum 33:S155, 1990 (suppl)