Pathogenesis of rheumatoid arthritis

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SCIENCE & PRACTICE

Pathogenesis of rheumatoid arthritis

Rheumatoid arthritis is a common chronic inflammatory disorder involving the synovial membranes of multiple joints. Although rheumatoid arthritis is thought of as a prototypical autoimmune disease, its aetiology is unknown. Over time, enzyme release within the joint leads to varying degrees of destruction. During the past decade, the important contribution of immunogenetic predisposition to the initiation of arthritis and the central role of T cells in its maintenance have become clear. Further exploration of these influences is needed urgently because current therapies frequently fail to interrupt the established disease

expression of intercellular adhesion molecule-1(ICAM-1), which acts as a site of attachment for circulating mononuclear cells. ICAM-1 expression is enhanced by several cytokines, including interleukin-1 (IL-1), tumour necrosis factor a (TNF-ot), and interferon-y (INF-y). Synovial thickening (pannus formation) is accompanied by increased ICAM-1 expression.

process. 1-3 Animal models Several insights into rheumatoid arthritis have come from laboratory animal studies.’ If rats are sensitised against. epitopes on native cartilage collagen (type II) or on mycobacteria, collagen and adjuvant arthritis, respectively, are induced. In both models there is sustained proliferative synovitis with cartilage and bone destruction; these features make up the classic morphological triad of rheumatoid arthritis (fig 1). Although the role, if any, of collagenous or mycobacterial stimuli is unknown, these experimentally inducible conditions do have several parallels with human disease.

Initiation of joint

damage

The frequently abrupt onset, prominence of the inflammatory lesion (fig 2), and major histocompatibility complex (MHC) class II antigen linkage suggest that a single or limited set of antigens is the trigger for this autoimmune process. A likely candidate is an infectious agent such as a bacterium, mycoplasma, or virus. Human studies implicate the Epstein-Barr virus (EBV)whereas most laboratory animal work-eg, the development of an inflammatory arthropathy in mice transgenic for HTLV-16

-favours

a

Fig 1-Experimentally induced lesion in rheumatoid arthritis. Synovial thickening and inflammation, together with cartilage and bone destruction, following immunisation of a ratwith type II collagen. (From Trentham DE, Townes AS, Kang AH. J Exp Med 1977; 146: 857-68. Reproduced with permission.)

retroviral agent.

Histological examination of biopsy samples from human and animal synovia suggest that the earliest detectable lesion in rheumatoid arthritis is found in pericapillary sites beneath the synovial lining. In the collagen model, initial changes include migration of neutrophils into the juxtacapillary tissue, mast cell degranulation, and entry of CD4 cells into the synovial membrane. Even in these early stages there is evidence of a T-cell contribution to rheumatoid synovitis. In human specimens, endothelial cells of synovial capillaries have increased

Despite the expression of adhesion ligands and enhanced capillary permeability, T-cell migration into the joint is not random. T cells that leave the circulation have a distinct most intrasynovial T lymphocytes are CD4 +, CD45RO +, and CD29 "bright" .1,7 These markers indicate

phenotype;

Division of Rheumatology (K. L. Sewell, MD, D. E. Trentham, MD), Beth Israel Hospital and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.

ADDRESS

Correspondence to

Dr K L Sewell.

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to track T cells from an immunologically naive stage (CD45RA) through early memory (after encountering relevant antigen) to mature memory (CD45RO) cell stages. Rheumatoid synovitis is characterised by the presence of large numbers of mature memory cells,! which strongly suggests previous local exposure to antigen. Mature memory cells normally proliferate poorly and release only a small quantity of IL-2 during mitogen challenge. By

used

contrast, these cells promote monokine release and antibody production by B cells. Unlike many T cells, mature memory cells exert no negative feedback on immunoglobulin synthesis. Therefore it is not surprising that enormous quantities of immunoglobulin exist within the rheumatoid

joint. 2-"’Indium chloride Fig radioscintigraphy shows widespread joint involvement by rheumatoid arthritis in lower limbs. In this patient only the left knee was clinically swollen. (From de Sousa M, Bastos AL, Dynesius-Trentham R, et al. J Rheumatol 1986; 13: 1108-16. Reproduced with permission.)

subpopulation of helper T cells; memory T cells acquired antigen experience after leaving the thymus. Frequent T-cell surface display of HLA-DR, DQ, and DP antigens, together with positivity for an integrin, very late antigen type 1 (VLA-1),8 implies local activation and proliferation. These findings point to T cells, triggered by an unknown antigen or antigen-presenting cell (APC)/ peptide complex possibly within the joint, undergoing activation and leading to rheumatoid synovitis.

a

memory

have

T-cell mediation The evidence to support the role of T cells in the progression of joint destruction is substantial. CD4 cells are the dominant T-cell phenotype in pannus; T cells express several activation markers;3 the disease improves with T-cell targeted interventions such as thoracic duct drainage, total lymphoid irradiation, and cyclosporin; and active arthritis is less severe in AIDS patients who have CD4 cytopenia.9 Synovial T cells have slightly enhanced expression of classic markers of activation, the transferrin receptor and the high-affinity, heterodimeric a(3 receptor for interleukin-2 (IL-2R). Recent trials with DABIL-2, a human IL-2/ diphtheria toxin conjugate with striking specificity for the high-affinity IL-2R, have revealed in both adjuvant arthritisll and in patients with refractory rheumatoid arthritis12 that IL-2R-positive cells must contribute to these inflammatory synovitides. Not all investigators have detected increased numbers of intrasynovial IL-2R-positive cells; these propagating cells might be biologically potent but they are few in number. In the rat, only about 1000 type II collagen-reactive T cells, when injected into the joint cavity, create a florid and protracted arthritis.13 The observation that appreciable numbers of cells co-expressing CD4 and IL-2R exist in lymphocytic aggregates in subchondral bone specimens from patients with rheumatoid arthritis 14 could indicate that cells responsible for damage are not located exclusively in the synovium.

Localised autoantibody

production

CD45R is the extracellular domain of a T-cell membrane in the leukocyte common antigen (LCA/T200) As T cells mature or differentiate, they display different CD45 isoforms. Thus, CD45 isoform shifts can be

protein family.

Rheumatoid factors (autoantibodies mainly of the IgM isotype, which interact preferentially with determinants on the Fc portion of IgG) have received close attention in studies of rheumatoid arthritis. Localised intra-articular generation of rheumatoid factors may reflect in-situ release of interleukin-6 (IL-6), a monokine that promotes B-cell antibody production. One study showed that immunoglobulin production by synovial B-cell populations in 13 of 14 patients with rheumatoid arthritis was skewed towards anti-type-II-collagen reactivity.15 Likewise, synthesis by plasma cells of type-II-collagen antibodies was found in subchondral bone specimens from 19 patients with rheumatoid arthritis.’4 Thus, local production of antibodies to type II collagen may participate in established rheumatoid arthritis. Substantial quantities of immune deposits are present in articular cartilage of patients with rheumatoid arthritis. 16,17 Both antigen-antibody and intermolecular disulphide bonds seem to contribute to the adherence of antibody to the cartilage matrix.l’ With regard to their specificities, IgM and IgG rheumatoid factors, together with antibodies to type II and the minor cartilage collagens (types V, VI, and IX), have been detected.16 Binding of type-II-collagen antibodies to the cartilage surface was strikingly enhanced in an experimental model of arthritis and in test cartilage slices pre-incubated with neutrophil elastase; these findings suggest that degradation of superficial cartilage during an inflammatory response exposes additional type II collagen epitopes, thereby resulting in greater linkage.16 Cartilagebound immune complexes could augment joint inflammation by activating complement and inflammatory cells. Arthritogenic properties of IgG autoantibodies to type II collagen, isolated from the serum of a patient with rheumatoid arthritis and evaluated in a murine passive transfer experiment,18 are consistent with a similar process operating in human beings.

Cytokine networks The rheumatoid joint is exposed to a cytokine environment largely of macrophage origin. Substantial

of IL-l, TNF-a, granulocyte/macrophage-colony stimulating factor, and IL-6 are found, whereas only small quantities of T-cell products, such as IL-2 and INF-y, exist. The premise that articular destruction is driven by cells with a monocyte/macrophage lineage19 is compatible with biochemical findings and the notion that memory T cells are the underlying effector cell population. The mature memory population of T cells, perhaps in a dysfunctional or downregulated state, would explain the lack of T-cell cytokines in the rheumatoid joint. Three explanations might account for the seemingly quiescent T-cell state in rheumatoid synovitis. First, as for

amounts

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endogenous dampening. The roles of prostaglandins

and

leukotrienes still remain unresolved.

Genetic contribution A restricted set of genetically determined MHC class II molecules strongly predispose to rheumatoid arthritis. Increased risk for arthritis is associated with HLA-DR and especially with glutamine/lysine residues at aminoacids 70/71 of the HLA-DRpl chain.22 These findings are analogous to the use of antigens in experimental models of autoimmune disease, such as collagen arthritis and

Fig 3-Subunits

involved in

antigen recognition.

The T-cell receptor (TCR) consists of two disulphide-linked polypeptide chains designated a and 0, each of which contains a variable (Vfx and V[3) and constant (Ca and Cp) region. The two V regions interact to form a binding site that interdigitates with a two-fold structure comprised of a peptide, processed within the lysosomes of an antigen-presenting cell (APC) and residing in a cleft of the MHC, and the self-M H C complex. An M H C class I molecule, formed by an a heavy chain (with three domains designated of,, Ct.2’ and Ct.3) and &bgr;2-microglobulin, isshown. (From KumarV, Kono DH, Urban JL, Hood L. Annu Rev Immuno/1989, 7: 657-82. Reproduced with permission.)

the delayed-type hypersensitivity reactionthe genuine effector cell is extremely rare. Second, although memory T cells produce little IL-2/ even small amounts will support T-cell function if high-affinity IL-2R are expressed. Third, IL-2 production is ongoing but uptake by autocrine and paracrine pathways is also efficient, resulting in rapid turnover with little assayable IL-2."

Contributory pathways serious consequence of sustained rheumatoid synovitis is irreversible joint damage. Multiple processes, augmented in part by cytokines such as IL-1, are responsible for loss of joint integrity. Angiogenesis, promoted by angiogenin and several other factors, enhances both invasion of joint tissue by inflammatory cells and delivery of adequate amounts of nutrients to proinflammatory and proliferating cells.21 Neutrophils are drawn into the joint cavity by chemoattractants, including C5a, leukotriene B4, and platelet-activation factor (PAF), where they release enormous quantities of proteinases and additional chemotactic molecules. Plasmin, formed from plasminogen by plasminogen activator, could be a pivotal amplifier of proteinase release. Production of neutral proteinases by the synovial membrane, including collagenase and stromelysin, contribute substantially to both cartilage and bone erosions. By coating the synovium and cartilage with dense fibrin deposits, clotting cascades promote further injury. Although natural inhibitors of many of these mediators have been isolated, presumably the intensity and perhaps longevity of the inflammatory response in rheumatoid arthritis overwhelms any The

most

myelin-basic-protein-induced experimental allergic encephalomyelitis, which show close associations between disease susceptibility and specific MHC class II antigens.4 In patients with rheumatoid arthritis there seems to be a shared nucleotide sequence in a gene that encodes a key framework constituent of particular HLA-DR molecules. Structural predictions of class II MHC molecules, based on successful crystallographic visualisation of HLA class I counterparts, indicate that the crucial element encoded by the common sequence is the middle portion of the a-helix surrounding the antigen-binding groove of the HLA-DR molecule z3 Therefore, the structure associated with rheumatoid arthritis susceptibility resides on the cell surface adjacent to the T-cell receptor (TCR) molecule. How this disease determinant functions in rheumatoid arthritis is unclear. Two possible mechanisms are envisaged, both of which affect CD4 pathways. MHC class II molecules strongly influence selection events involved in T-cell maturation. For instance, negative intrathymic events eliminate cells with autoimmune potential and further maturation requires binding of the TCR to selfMHC molecules. At either stage, MHC molecules could fail to inhibit the emergence of autoreactive CD4 cells capable of sustaining arthritis. Alternatively, rheumatoid-arthritisspecific MHC molecules could facilitate disease-related antigen presentation, since mature T cells "recognise" antigen in a trimolecular topology involving the processed antigenic peptide, the TCR, and the MHC molecule (fig 3). Irrespective of the mechanism, the genetic susceptibility of rheumatoid arthritis virtually dictates an obligatory role for antigen-specific T cells in its pathogenesis.

T-cell receptors that The prospect rheumatoid-arthritis-specific HLA-DR determinants function as ligands for TCRs implies that responding CD4 cells might possess forms of the heterodimeric TCR with identical structural components. The elusive nature of the rheumatoid arthritis "antigen", coupled with new molecular technologies capable of dissecting the variability of the T-cell repertoire by TCR V (3 chain analysis, have prompted studies to determine whether CD4 effector cells in patients with arthritis are an oligoclonal population. Several reports suggest selective TCR use in synovially derived cells,22-24 but there has been no independent validation of these data.25 Four conclusions follow. First, such a notion may be incorrect since antigen-specific T-cell responses to a single large molecular weight antigen can be polyclonal; second, individual patient variability may account for these discordant results; third, the initial HLA-DR-associated antigen presentation event may be restricted and differ from subsequent antigen targets; or fourth, technical factors, such as an extremely low number of relevant cells, lead to lack of uniform outcomes.

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Immune

manipulations

The identity of the original antigenic stimulus is unknown but a theoretical view of how such a model operates is possible to derive. Type II collagen, a physically restricted, major structural component of cartilage, is arthritogenic in several animal species, including certain primates 4 Autoimmunity to type II collagen is frequently demonstrable within the joints of patients with rheumatoid arthritis .14,15,26 Not only does Epstein-Barr virus (EBV) possess homologous HLA-DR? chain epitopes implicated in rheumatoid arthritisbut it also shares with type II collagen a homologous a 1 (II) chain epitope.27 Accordingly, anti-collagen reactivity could arise in a HLA-susceptible host after EBV infection through molecular mimicry. Models of autoimmune disease, including experimental allergic encephalomyelitis and adjuvant arthritis, can be suppressed by feeding animals the relevant antigen, myelin basic protein and type II collagen, respectively.28 The simplicity and safety of this approach, designated oral tolerance, has led to the inception of clinical trials in multiple sclerosis and rheumatoid arthritis using these candidate

proteins.29 REFERENCES J, Lipsky PE. Cellular basis for rheumatoid inflammation. Clin Orthopaedics Rel Res 1991; 265: 9-12. 2. Harris ED Jr. Rheumatoid arthritis: pathophysiology and implications for therapy. N Engl J Med 1990; 322: 1277-89. 3. Panayi GS, Lanchbury JS, Kingsley GH. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. 1. Cush

Arthritis Rheum 1992; 35: 729-35. 4. Breedveld FC, Trentham DE. Progress in the understanding of inducible models of chronic arthritis. Rheum Dis Clin N Am 1987; 13: 531-44. 5. Roudier J, Petersen J, Rhodes GH, et al. Susceptibility to rheumatoid arthritis maps to a T-cell epitope shared by the HLA-Dw4 DR beta-1 chain and the Epstein-Barr virus glycoprotein gp 110. Proc Natl Acad Sci USA 1989; 86: 5104-08. 6. Iwakura Y, Tosu M, Yoshida E, et al. Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science 1991; 253: 1026-28. 7. Pitzalis C, Kingsley GH, Haskard DO, Panayi GS. The preferential accumulation of helper-inducer T lymphocytes in inflammatory lesions: evidence for regulation by selective endothelial and homotypic adhesion. Eur J Immunol 1988; 18: 1397-404. 8. Hemler ME, Glass D, Coblyn JS, Jacobson JG. Very late activation antigens on rheumatoid synovial fluid T lymphocytes: association with stages of T cell activation. J Clin Invest 1986; 78: 696-702. 9. Solinger AM, Hess EV. HIV and arthritis. Arthritis Rheum 1990; 17: 562. 10. Pitzalis C, Kingsley GH, Lanchbury JSS, Murphy J, Panayi GS. Expression of HLA-DR, DQ and DP antigens and IL-2 receptor on synovial fluid T lymphocyte subsets in rheumatoid arthritis: evidence for a "frustrated" activation. J Rheumatol 1987; 14: 662-66. 11. Bacha P, Forte SE, Perper SJ, Trentham DE, Nichols JC. Anti-arthritic effects demonstrated by an interleukin-2 receptor-targeted cytotoxin (DAB486IL-2) in rat adjuvant arthritis. Eur J Immunol 1992; 22: 1673-79. 12. Sewell KL, Trentham DE. Rapid improvement in refractory rheumatoid arthritis by an interleukin-2 receptor targeted immunotherapy. Clin Res 1991; 39: 314A (abstr). 13. Brahn E, Trentham DE. Experimental synovitis induced by collagenspecific T cell lines. Cell Immunol 1989; 118: 491-503. 14. Watson W, Tooms R, Carnesale P, Dutkowsky J. Subchondral bone and the erosive autoimmune origins of rheumatoid arthritis. Arthritis Rheum 1992; 35: S59 (abstr). 15. Tarkowski A, Klareskog L, Carlsten H, Herberts P, Koopman WJ. Secretion of antibodies to type I and type II collagen by synovial tissue cells in patients with rheumatoid arthritis. Arthritis Rheum 1989; 32: 1087-92. 16. Jason HE, Taurog JD. Mechanisms of disruption of the articular cartilage surface in inflammation: neutrophil elastase increases availability of collagen type II epitopes for binding with antibody on the surface of articular cartilage. J Clin Invest 1991; 87: 1531-36. 17. Trujillo PE, Mannik M. IgG is bound by antigen-antibody bonds and some IgG and albumin are bound by intermolecular disulfide bonds to cartilage in rheumatoid arthritis and osteoarthritis. Rheumatol Int 1992; 11: 225-34.

18. Wooley PH, Luthra HS, Singh SK, Huse AR, Stuart JM, David CS. Passive transfer of arthritis to mice by injection of human anti-type II collagen antibody. Mayo Clin Proc 1984; 59: 737-43. 19. Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum 1990; 33: 768-73. 20. Firestein GS, Xu WD, Townsend K, et al. Cytokines in chronic inflammatory 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 1988; 168: 1573-86. 21. Kock AE, Polverini PJ, Leibovich SJ. Stimulation of neovascularization by human rheumatoid synovial tissue macrophages. Arthritis Rheum 1986; 29: 471-79. 22. Williams WV, Fang Q, Demarco D, Vonfeldt J, Zurier RB, Weiner DB. Restricted heterogeneity of T cell receptor transcripts in rheumatoid synovium. J Clin Invest 1992; 90: 326-33. 23. Weyand CM, Oppitz U, Hicock K, Goronzy JJ. Selection of T cell receptor V&bgr; elements by HLA-DR determinants predisposing to rheumatoid arthritis. Arthritis Rheum 1992; 35: 990-98. 24. Paliard X, West SG, Lafferty JA, et al. Evidence for the effects of a superantigen in rheumatoid arthritis. Science 1991; 253: 325-29. 25. Moss PAH, Rosenberg WMC, Bell JI. The human T cell receptor in health and disease. Annu Rev Immunol 1992; 10: 71-96. 26. Londei M, Savill CM, Verhoef A, et al. Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis. Proc Natl Acad Sci USA 1989; 86: 636-40. 27. Birkenfeld P, Haratz N, Klein G, Sulitzeanu D. Cross-reactivity between the EBNA-1 p.107 peptide, collagen, and keratin: implications for the pathogenesis of rheumatoid arthritis. Clin Immunol Immunopathol 1990; 54: 14-25. 28. Zhang ZJ, Lee CSY, Lider O, Weiner HL. Suppression of adjuvant arthritis in Lewis rats by oral administration of type II collagen. J Immunol 1990; 145: 2489-93. 29. Marx J. Testing of autoimmune therapy begins. Science 1991; 252: 27-28.

Clinical management of rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory disease and other tissues, which has an annual incidence of between 2 and 4 per 10 000 adult population.’ The disease mainly involves the synovial joints but virtually every tissue in the body can be affected by the inflammatory process. Rheumatoid arthritis may present clinically in several ways, the most common being an insidious onset with symptoms developing over months. A few patients present with an acute onset of polyarthritis or disease that develops over a few weeks .2 Patients with rheumatoid arthritis tend to follow one of three courses (table I). Most patients, however, will have progressive disease with substantial morbidity and mortality. The diminished survival of these patients is similar to that seen for diabetes, Hodgkin’s disease, and three-vessel coronary artery disease; the median life expectancy is reduced by seven years for men and three years for women.3 For instance, a patient with rheumatoid arthritis attending an outpatient clinic has about a one in three chance of being severely disabled at 20 years while those requiring inpatient care have approximately an 80% chance.’ After 10 years of disease, fewer than 50% of patients can continue to work4 contributing to an annual cost of rheumatoid arthritis in the USA of over$1 billion. Since the exact cause and pathogenesis of rheumatoid arthritis are unknown, our therapies must be directed against the various components of the chronic inflammatory

affecting joints

ADDRESS:

Department of Medicine, St Vincent’s Hospital, University of New South Wales, Sydney, Australia (Prof Peter M Brooks, MD).