Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a common human autoimmune disease with a prevalence of about 1%. While there has been progress in defining its etiology and pathogenesis, these are still incompletely understood (35Ziff M Rheumatoid arthritis - Its present and future.J. Rheumatol. 1990; 17: 127-133PubMed Google Scholar). Like many autoimmune diseases it is more frequent in women, suggesting a role for sex hormones. Rheumatoid arthritis is characterized by a chronic inflammation of the synovial joints and infiltration by blood-derived cells, chiefly memory T cells, macrophages, and plasma cells, all of which show signs of activation, (14Janossy, G., Panayai, G., Duke, O., Bofill, M., Poulter, L.W., and Goldstein, G. (1981). Rheumatoid arthritis: a disease of T-lymphocyte/macrophage immunoregulation. The Lancet 839–841.Google Scholar, 4Cush J.J Lipsky P.E Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis.Arthritis Rheum. 1988; 31: 1230-1238Crossref PubMed Scopus (225) Google Scholar). This leads in most cases to progressive destruction of cartilage and bone, which occurs after invasion of these tissues by the cellular synovial tissue and is believed to be mainly mediated by cytokine induction of destructive enzymes, chiefly matrix metalloproteinases. There is also prominent development of new vessels and evidence of systemic inflammation, for example, upregulated acute phase proteins. In more severe cases there is involvement of vessels and other organs. Mortality is increased in patients with severe rheumatoid arthritis (23Pincus T Callahan L.F What is the natural history of rheumatoid arthritis?.Rheum. Dis. Clin. North Am. 1993; 19: 123-151PubMed Google Scholar). A diseased joint showing the major cell types and sites of joint destruction is illustrated in Figure 1. Twin and other genetic studies have demonstrated that a major genetic contribution to disease predisposition resides in the HLA-DR locus (28Stasny P Association of the B cell alloantigen DRW4 with rheumatoid arthritis.N. Engl. J. Med. 1978; 298: 869-871Crossref PubMed Scopus (907) Google Scholar). More than 80% of caucasian rheumatoid patients express DR1 or DR4 subtypes which share an epitope mapping to amino acids 70-74 of the DRβ chain, in the polymorphic region lining the peptide binding groove (12Gregersen P.K Silver J Winchester R.J The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.Arthritis Rheum. 1987; 30: 1205-1213Crossref PubMed Scopus (2099) Google Scholar). As the only known function of DR is to present peptides to CD4+ T cells, this genetic association clearly implicates a role for T cells at some stage in the disease pathogenesis. However, it is not known which stage that may be. It could be in defining the T cell repertoire of antigen receptors or in the presentation of an inducing extrinsic antigen (e.g., pathogen) involved in the induction of the disease process. However, the most popular concept is that the pathogenic role for CD4+ T cells is in presentation of an autoantigen (30Todd J.A Acha-Orbea H Bell J.I Chao N Fronek Z Jacob C.O McDermott M Sinha A.A Timmerman L Steinman L McDevitt H.O A molecular basis for MHC class II associated autoimmunity.Science. 1988; 240: 1003-1009Crossref PubMed Scopus (605) Google Scholar). There is recent evidence that the genetically susceptible HLA-DR4 (e.g., DR0401) alleles bind different peptides in their peptide binding groove than the nonsusceptible (e.g., DR0402) alleles. Susceptible alleles bind a negatively charged amino acid at the p4 pocket of the binding groove, (34Woulfe S.L Bono C.P Zacheis D.A Kirschmann T.A Baudino C.S Karr R.W Schwartz B.D Negatively charged residues interacting with the p4 pocket confer binding specificity to DRB1*0401.Arthritis Rheum. 1995; 38: 1744-1753Crossref PubMed Scopus (33) Google Scholar). Mutation analysis revealed that position 71 of the DRβ chain in particular correlates with the genetic linkage of RA susceptibility (13Hammer J Gallazzi F Bono E Karr R.W Guenot J Valsasnini P Nagy Z.A Sinigaglia F Peptide binding specificity of HLA-DR4 molecules Correlation with rheumatoid arthritis association.J. Exp. Med. 1995; 181: 1847-1855Crossref PubMed Scopus (281) Google Scholar). How this eventually leads to a pro-inflammatory response remains to be determined. To obtain clues about the important antigens recognized, T cell receptor expression in RA joints has been extensively studied, but early reports of restricted T cell receptor usage have not been confirmed. The nature of the autoantigens recognized by autoantigen reactive T cells in rheumatoid arthritis are not known, although collagen type II (26Ronnelid J Lysholm J Engstrom-Laurent A Klareskog L Heyman B Local anti-type II collagen antibody production in rheumatoid arthritis synovial fluid. Evidence for an HLA-DR4-restricted IgG response.Arthritis Rheum. 1994; 37: 1023-1029Crossref PubMed Scopus (105) Google Scholar), a major protein of hyaline cartilage, and other chondrocyte/cartilage proteins, as well as the heat shock protein HSP70 have been suggested. Much progress will become possible when the important T cell epitopes are defined, as it will open up the possibility of inducing antigen specific therapy, such as immunological tolerance. However, the role of T lymphocytes in established RA is incompletely understood. Based on the lack of T cell proliferation and low levels of T cell derived cytokines detectable in RA joints10Firestein G.S Zvaifler N.J How important are T cells in chronic rheumatoid synovitis?.Arthritis Rheum. 1990; 33: 768-773Crossref PubMed Scopus (449) Google Scholar suggested that T cells may not be important in perpetuating disease at the late stages. This possibility is supported by the disappointing results of therapeutic trials of agents designed to diminish T cell function in late-stage RA patients: depleting antibodies to CD4, CDW52, and CD7, as well as immunotoxins directed to IL-2 receptor or CD5 expressing cells (e.g.,31van der Lubbe P.A Dijkmans B.A.C Markusse H.M Nassander U Breedveld F.C A randomised, double-blind, placebo-controlled study of CD4 monoclonal antibody therapy in early rheumatoid arthritis.Arthritis Rheum. 1995; 38: 1097-1106Crossref PubMed Scopus (147) Google Scholar, 17Kirkham B.W Thien F Pelton B.K Pitzalis C Amlot P Denman A.M Panayi G.S Chimeric CD7 monoclonal antibody therapy in rheumatoid arthritis.J. Rheumatol. 1992; 19: 1348-1352PubMed Google Scholar, 19Moreland L.W Sewell K.L Trentham D.E Bucy R.P Sullivan W.F Schrohenloher R.E Shmerling R.H Parker K.C Swartz W.G Woodworth T.G Koopman W.J Interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis a double-blind, placebo-controlled trial with open-label extension.Arthritis Rheum. 1995; 38: 1177-1186Crossref PubMed Scopus (62) Google Scholar, 22Olsen N.J Cush J.J Lipsky P.E Sinclair E.W Cannon G McCune W.J Strand V Lorenz T Multicenter trial of an anti-CD5 immunoconjugate in rheumatoid arthritis (RA).Arthritis Rheum. 1994; 37: S295Google Scholar) have only yielded moderate or no benefit in placebo controlled studies. Since there are two major subsets of of helper (CD4+) T cell function (Th1 cells producing the pro-inflammatory mediators IL-2 and IFNγ and Th2 cells producing IL-4, which has anti-inflammatory properties20Mosmann T.R Coffman R.L Th1 and Th2 cells Different patterns of lymphokine secretion lead to different functional properties.Annu. Rev. Immunol. 1989; 7: 145-173Crossref PubMed Scopus (6854) Google Scholar), it is possible that nonspecific T cell directed immunotherapy, such as those listed above, may be ineffective because both pathogenic and protective T cell functions would be downregulated. In view of the clear cut role of T cells in driving immune responses and in animal models of autoimmunity, including the collagen type II and other models of arthritis, it is on balance likely that T cells are involved both in disease induction and in disease maintenance. The most likely reason for their reduced function in active disease is the inhibitory cytokine environment, with augmented IL-10 and TGFβ (8Fava R Olsen N Keski-Oja J Moses H Pincus T Active and latent forms of transforming growth factor β activity in synovial effusions.J. Exp. Med. 1989; 169: 291-296Crossref PubMed Scopus (210) Google Scholar, 32Wahl S.M Transforming growth factor β The Good, the Bad, and the Ugly.J. Exp. Med. 1994; 180: 1587-1590Crossref PubMed Scopus (434) Google Scholar, 15Katsikis P Chu C.Q Brennan F.M Maini R.N Feldmann M Immunoregulatory role of interleukin-10 (IL-10) in rheumatoid arthritis.J. Exp. Med. 1994; 179: 1517-1527Crossref PubMed Scopus (497) Google Scholar). The role of B lymphocytes in RA has been extensively studied since the discovery that most patients have IgM autoantibodies termed rheumatoid factors (RF) which recognize the Fc region of IgG. However, RF are not present in all RA patients and are also present in other diseases, such as Sjogren's syndrome. The DNA sequences encoding RF have been extensively studied to seek clues concerning the pathogenesis of RA. Both IgM and the less frequent IgG RF differ from the germ line sequence, the latter extensively, suggesting the presence of an antigen driven process (21Olee T Lu E.W Huang D.F Soto-Gil R.W Deftos M Kozin F Carson D.A Chen P.P Genetic analysis of self-associating immunoglobulin G rheumatoid factors from two rheumatoid synovia implicates an antigen-driven response.J. Exp. Med. 1992; 175: 831-842Crossref PubMed Scopus (92) Google Scholar). How RF factor contributes to the disease process is still not understood, but current concepts include a role in facilitating antigen presentation. Immune complexes of RF and IgG may contribute to disease activity by activating complement and stimulating cytokine synthesis. Augmented numbers of CD5+ B lymphocytes have been detected in patients with RA (24Plater-Zyberk C Maini R.N Lam K Kennedy T.D Janossy G A rheumatoid arthritis B cell subset expresses a phenotype similar to that in chronic lymphocytic leukemia.Arthritis Rheum. 1985; 28: 971-976Crossref PubMed Scopus (205) Google Scholar). Abnormal glycosylation of IgG in active RA has been reported and may be important because it would favor immune complex formation. Other autoantibodies are also present in RA, including those reacting to filaggrin (27Sebbag M Simon M Vincent C Masson-Bessiere C Girbal E Jean-Jacques D Serre E The anti-perinuclear factor and the so-called anti-keratin antibodies are the same rheumatoid arthritis-specific autoantibodies.J. Clin. Invest. 1995; 95: 2672-2679Crossref PubMed Scopus (308) Google Scholar). As cytokines are important mediators of the immune and inflammatory systems, establishing their role in autoimmune diseases was of interest, especially in view of the hypothesis we had proposed in 1983 which linked cytokine induced upregulation of antigen presentation to the development of autoimmunity. For this purpose RA, with its accessible lesions, was the ideal disease study. Several groups, including our own, have investigated cytokine mRNA and protein expression in synovium (e.g.,5Di Giovine F.S Nuki G Duff G.W Tumour necrosis factor in synovial exudates.Ann. Rheum. Dis. 1988; 47: 768-772Crossref PubMed Scopus (212) Google Scholar; reviewed by10Firestein G.S Zvaifler N.J How important are T cells in chronic rheumatoid synovitis?.Arthritis Rheum. 1990; 33: 768-773Crossref PubMed Scopus (449) Google Scholar, 1Arend W.P Dayer J.-M Inhibition of the production and effects of interleukin-1 and tumor necrosis factor α in rheumatoid arthritis.Arthritis Rheum. 1995; 38: 151Crossref PubMed Scopus (930) Google Scholar, 9Feldmann M Brennan F.M Maini R.N Role of cytokines in rheumatoid arthritis.Annu. Rev. Immunol. 1996; 14: 397-440Crossref PubMed Scopus (2294) Google Scholar). Despite differences in duration, severity of disease, or treatment, all RA operative samples and biopsies expressed the same broad range of pro-inflammatory cytokines, suggesting that synovial cytokine expression in a diseased tissue was prolonged, unlike the transient cytokine production induced by mitogen. This hypothesis was tested by enzymatically dissociating synovium and culturing the cells without extrinsic stimulation. These cultures produced cytokines such as IL-1 and TNFα for a prolonged period of time, indicating that the signals driving cytokine production were present, and so could be studied in vitro. By adding anti-TNFα antibodies, it was found that synovial production of other pro-inflammatory cytokines such as IL-1 (2Brennan F.M Chantry D Jackson A Maini R Feldmann M Inhibitory effect of TNFα antibodies on synovial cell interleukin-1 production in rheumatoid arthritis.Lancet. 1989; 2: 244-247Abstract PubMed Scopus (822) Google Scholar), GM-CSF, IL-6, and IL-8 was greatly reduced. Blocking IL-1, using the IL-1 receptor antagonist reduced IL-6 and IL-8 production, but not that of TNFα (reviewed by9Feldmann M Brennan F.M Maini R.N Role of cytokines in rheumatoid arthritis.Annu. Rev. Immunol. 1996; 14: 397-440Crossref PubMed Scopus (2294) Google Scholar). These results indicated that the pro-inflammatory cytokines were linked in a network or cascade. It suggested that blocking TNFα would also diminish the actions of many other pro-inflammatory mediators, and hence, that TNFα may be a good therapeutic target. Analogous studies have evaluated the expression of anti-inflammatory cytokines in rheumatoid joints. TGFβ is abundant, both in latent and active form (8Fava R Olsen N Keski-Oja J Moses H Pincus T Active and latent forms of transforming growth factor β activity in synovial effusions.J. Exp. Med. 1989; 169: 291-296Crossref PubMed Scopus (210) Google Scholar, 32Wahl S.M Transforming growth factor β The Good, the Bad, and the Ugly.J. Exp. Med. 1994; 180: 1587-1590Crossref PubMed Scopus (434) Google Scholar), as is IL-10 (15Katsikis P Chu C.Q Brennan F.M Maini R.N Feldmann M Immunoregulatory role of interleukin-10 (IL-10) in rheumatoid arthritis.J. Exp. Med. 1994; 179: 1517-1527Crossref PubMed Scopus (497) Google Scholar). In contrast, IL-4 is not usually found, suggesting that the T cells involved in RA joints are chiefly of the Th1 type. Cytokine inhibitors such as the IL-1 receptor antagonist and soluble TNF receptors are also upregulated in rheumatoid joints (reviewed by9Feldmann M Brennan F.M Maini R.N Role of cytokines in rheumatoid arthritis.Annu. Rev. Immunol. 1996; 14: 397-440Crossref PubMed Scopus (2294) Google Scholar). Current views of the cytokine network in rheumatoid joints, and probably in other chronic inflammatory sites, thus involve two key concepts. First, that TNFα is at the apex of a pro-inflammatory cytokine cascade, as illustrated simplistically in Figure 2. Second, that in a chronic inflammatory site there is also upregulation of multiple anti-inflammatory mediators. Hence the rheumatoid synovium can be envisaged as an equilibrium, just tilted towards the pro-inflammatory side (Figure 3). A TNFα dependent cytokine cascade is also found in normal immune responses, such as in experimental gram negative infections, in which blocking TNFα also reduced IL-1 and IL-6 expression (11Fong Y Tracey K.J Moldawer L.L Hesse D.G Manogue K.B Kenney J.S Lee A.T Kuo G.C Allison A.C Lowry S.F Cerami A Antibodies to cachectin/tumor necrosis factor reduce interleukin 1β and interleukin 6 appearance during lethal bacteremia.J. Exp. Med. 1989; 170: 1627-1633Crossref PubMed Scopus (535) Google Scholar).Figure 3Cytokine Disequilibrium in Rheumatoid ArthritisView Large Image Figure ViewerDownload Hi-res image Download (PPT) Injecting genetically susceptible strains of mice with cartilage constituents such as collagen type II in complete Freund's adjuvant induces an arthritis with synovitis and erosions histologically resembling RA (3Courtenay J.S Dallman M.J Dayan A.D Martin A Mosedale B Immunisation against heterologous type II collagen induces arthritis in mice.Nature. 1980; 283: 666-668Crossref PubMed Scopus (883) Google Scholar). Both T cell and B cell activation is important in collagen induced arthritis. Cytokines of both Th1 (IFNγ secreting) and Th2 cells (IL-4 secreting) are produced, and at disease onset a Th1 profile predominates. By serendipity, another informative model of arthritis was developed by G. Kollias and colleagues (16Keffer J Probert L Cazlaris H Georgopoulos S Kaslaris E Kioussis D Kollias G Transgenic mice expressing human tumour necrosis factor a predictive genetic model of arthritis.EMBO J. 1991; 10: 4025-4031Crossref PubMed Scopus (1342) Google Scholar). A human TNFα transgene was generated in which the AU rich 3′ UT region (which shortens mRNA half life) was replaced by the stable β globin 3′ UT, resulting in overexpression of TNFα. Multiple lines of these mice were found to develop a chronic erosive arthritis. This transgenic model directly demonstrates the concept that TNFα is of importance in the arthritic process, as does the therapeutic benefit of treatment with anti-TNFα antibody in the DBA/1 collagen induced arthritis model (29Thorbecke G.J Shah R Leu C.H Kuruvilla A.P Hardison A.M Palladino M.A Involvement of endogenous tumour necrosis factor α and transforming growth factor β during induction of collagen type II arthritis in mice.Proc. Natl. Acad. Sci. USA. 1992; 89: 7375-7379Crossref PubMed Scopus (328) Google Scholar, 33Williams R.O Mason L.J Feldmann M Maini R.N Synergy between anti-CD4 and anti-TNF in the amelioration of established collagen-induced arthritis.Proc. Natl. Acad. Sci. USA. 1994; 91: 2762-2766Crossref PubMed Scopus (196) Google Scholar). Subsequently it has been found that virtually all animal models of arthritis are ameliorated by anti-TNFα, including human-TNFα transgenic arthritis, adjuvant arthritis, streptococcal cell-wall arthritis, and antigen induced arthritis in rabbits (reviewed by9Feldmann M Brennan F.M Maini R.N Role of cytokines in rheumatoid arthritis.Annu. Rev. Immunol. 1996; 14: 397-440Crossref PubMed Scopus (2294) Google Scholar). Histological analysis has demonstrated that anti-TNFα therapy, after disease onset protected the joints from destruction induced by the inflammatory process (e.g.,33Williams R.O Mason L.J Feldmann M Maini R.N Synergy between anti-CD4 and anti-TNF in the amelioration of established collagen-induced arthritis.Proc. Natl. Acad. Sci. USA. 1994; 91: 2762-2766Crossref PubMed Scopus (196) Google Scholar). The downregulation of pro-inflammatory cytokines by anti-TNFα antibody in RA joint cultures in vivo and the benefit of anti-TNFα in collagen induced arthritis provided the rationale for clinical trials of anti-TNFα antibody in longstanding RA patients with active disease. The results of multiple clinical trials of anti-TNFα antibody performed with cA2, a chimeric anti-TNFα antibody (mouse Fv, human IgG1), have revealed a marked benefit in all assessable aspects of the disease. There was very rapid improvement, within days, and for an antibody the benefit lasted a long time, ranging from 8-26 weeks in the first trial (7Elliott M.J Maini R.N Feldmann M Long-Fox A Charles P Katsikis P Brennan F.M Walker J Bijl H Ghrayeb J Woody J Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to TNFα.Arthritis Rheum. 1993; 36: 1681-1690Crossref PubMed Scopus (1004) Google Scholar). After these patients relapsed, retreatment with cA2 on further occasions ameliorated disease on each occasion, indicating that the pro-inflammatory cascade remains TNFα dependent. The clinical efficacy of anti-TNFα has been verified in randomized double-blind placebo-controlled trials (6Elliott M.J Maini R.N Feldmann M Kalden J.R Antoni C Smolen J.S Leeb B Breedveld F.C Macfarlane J.D Bijl H Woody J.N Randomised double blind comparison of a chimaeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis.Lancet. 1994; 344: 1105-1110Abstract PubMed Scopus (1661) Google Scholar). These results have triggered clinical trials with other anti-TNFα reagents, a different anti-TNFα antibody of IgG4 isotype (25Rankin E.C.C Choy E.H.S Kassimos D Kingsley G.H Sopwith S.M Isenberg D.A Panayi G.S The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody (CD571) in rheumatoid arthritis.Br. J. Rheumatol. 1995; 34: 334-342Crossref PubMed Scopus (237) Google Scholar), and TNF receptor IgG fusion proteins, which have also been successful. The success of these clinical trials indicates that while there may be diversity of immune responses, as suggested by some HLA-DR heterogeneity in different populations, there is little heterogeneity in terms of cytokine mechanisms. These results emphasize that cytokines may be good therapeutic targets in other inflammatory/autoimmune diseases as well. The clinical trials have provided an opportunity to learn more about the disease process and the mechanism by which anti-TNFα antibody works in humans. First, it was shown that the elevated serum IL-6 levels fall rapidly, normalizing in a day or so. This verifies that a TNFα dependent cytokine cascade operates in vivo (7Elliott M.J Maini R.N Feldmann M Long-Fox A Charles P Katsikis P Brennan F.M Walker J Bijl H Ghrayeb J Woody J Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to TNFα.Arthritis Rheum. 1993; 36: 1681-1690Crossref PubMed Scopus (1004) Google Scholar). Histological analysis of joints after anti-TNFα therapy revealed diminished numbers of cells in joints as well as diminished expression of endothelial adhesion molecules. Soluble E-selectin and ICAM-1 in serum were down regulated and counts of long-lived blood cells such as lymphocytes were rapidly augmented after anti-TNFα treatment. These results suggest that anti-TNFα antibody may exert a prolonged benefit because of diminished cell recruitment into joints (18Maini R.N Elliott M.J Brennan F.M Williams R.O Chu C.Q Paleolog E Charles P.J Taylor P.C Feldmann M Monoclonal anti-TNFα antibody as a probe of pathogenesis and therapy of rheumatoid disease.Immunol. Rev. 1995; 144: 195-223Crossref PubMed Scopus (173) Google Scholar). However, anti-TNFα therapy of rheumatoid arthritis is not a cure, and other therapeutic approaches are needed. In collagen induced arthritis in DBA/1 mice, there is marked synergy between anti-TNF antibody therapy and therapy targeted at T cells, for example with anti-CD4 antibody, suggesting that synergistic approaches targeting these two key aspects of the pathogenesis may be the best approach towards attempting a cure (33Williams R.O Mason L.J Feldmann M Maini R.N Synergy between anti-CD4 and anti-TNF in the amelioration of established collagen-induced arthritis.Proc. Natl. Acad. Sci. USA. 1994; 91: 2762-2766Crossref PubMed Scopus (196) Google Scholar). There is much yet to learn about the etiology, pathogenesis, and therapy of rheumatoid arthritis. For example, the non-HLA genetic predisposition, which may include cytokine polymorphism and a tendency to generate relatively too many Th1 cells, may yield new clues for therapy. There is debate as to whether the process of joint destruction is directly driven by the inflammatory process, or whether the basic process of joint destruction, with proliferation of fibroblasts and other cells is driven independently. Certainly in the animal models, anti-TNFα prevents or abrogates joint destruction, suggesting that inflammation and joint destruction are linked. What drives the production of the excessive TNFα in RA joints and why the anti-inflammatory mechanisms cannot fully downregulate its effects are tantalizing questions. What is the major cause of new capillary growth (neovascularization) needed to sustain the augmented cell mass in the synovium? As unravelling the pathogenesis of RA has already led to therapeutic advances, it is very likely that answers to the remaining questions will help generate new treatment approaches.