New And Emerging Therapies For Rheumatoid Arthritis


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Rheumatoid Arthritis (RA) is a common rheumatological disorder. Many drugs including Anti TNF agents have been used for the treatment of this condition. The result hitherto, have been excellent, but shortcomings and the absence of complete remissions even in Anti TNF treated patients, makes the trial of newer agents, targeted to novel pathophysiologic molecules, all the more important and urgent. New insights in the pathogens of RA and three new biologics for RA have been discussed.

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New And Emerging Therapies For Rheumatoid Arthritis

  1. 1. New And Emerging Therapies For Rheumatoid Arthritis
  2. 2. Review Article NEW AND EMERGING THERAPIES FOR RHEUMATOID ARTHRITIS Sundeep Kumar Upadhyaya Senior Consultant, Rheumatology Immunology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. e-mail:, Rheumatoid Arthritis (RA) is a common rheumatological disorder. Many drugs including Anti TNF agents have been used for the treatment of this condition. The result hitherto, have been excellent, but shortcomings and the absence of complete remissions even in Anti TNF treated patients, makes the trial of newer agents, targeted to novel pathophysiologic molecules, all the more important and urgent. New insights in the pathogens of RA and three new biologics for RA have been discussed. Key words: Abatacept, Emerging therapies, Rheumatoid arthritis, Rituximab, Tocilizumab. INTRODUCTION persistent inflammatory reaction is established in the joint, sustained remissions despite drug therapy are the exception rather than the rule. It is likely that current therapies are targeting common inflammatory pathways downstream of the inciting events. These pathways therefore appear not to be unique to RA but are common to several autoimmune inflammatory diseases. Many such diseases thus also respond to DMARDs and biologics used for the treatment of RA (e.g. ulcerative colitis). That, anti TNF- products are extremely effective proves the fact that TNF- is an important pro-inflammatory cytokine driving the inflammatory response in RA [4]. It is noteworthy that anti IL-1 products have yielded disappointing results. Therefore, not all cytokines expressed in the rheumatoid synovium are necessarily viable therapeutic targets. However, the results from clinical trials in the management of RA using anti IL-6 and anti IL-15 are encouraging. Thus, targeting these cytokines for the management of RA is logical. Although, anti-CD4, anti-CD5 and anti-CD52 products have failed to produce significant benefits in RA management (indicating that curbing T-cell activity alone is not the solution), abatacept or CTLA4-Ig which blocks the stimulation of naïve T cells, has been found to be extremely effective in RA treatment. Activated T cells have been seen in contact with macrophages; this cell-cell contact has been shown in vitro to induce synovial fibroblast and macrophages to secrete damaging cytokines [5] (Fig.1). The B-cell is also a therapeutic target largely based on the success of Rituximab therapy for RA [6]. About 50% of patients who have RA, B-cells, T-cells and dendritic cells organize themselves into follicular structures resembling germinal centres [7]. When rheumatoid synovitis is reconstituted in special mouse models of RA, B-cell depletion disrupts the ANTI-TUMOR necrosis factor agents for the treatment of rheumatoid arthritis (RA) have been in use both clinically and in trials for more than ten years. They are extremely effective and have hitherto been used in patients who have failed multiple conventional DMARDs like Methotrexate and Leflunomide. They achieve ACR 50 and ACR 70 clinical responses in a sizable number of patients and are widely available in all developing countries including India. Radiographic joint damage occurs in patients with rheumatoid arthritis (RA) in nearly 75% within the first 2 years of disease [1]. Currently RA treatment approaches are focused on early intensive therapy with multiple disease modifying drugs (DMARDs). Methotrixate (MTX) is the first choice DMARD and often the anchor drug for combination regimens. An increasing proportion of patients are receiving newer DMARDs like leflunomide and biologics like anti TNF- products (etanercept and infliximab) since the response rates with MTX alone are poor. Indeed, combined use of MTX and an anti TNFproduct is among the most potent treatments for RA. Yet, clinical trials of early RA treatment show that this combination generates ACR70 responses of only 35-45% [2,3]. The desired role of DMARD therapy is thus not realized in most treatment regimens and these shortcomings of currently approved therapies highlight the need for investigating new strategic approaches and novel drugs. This article reviews the new biologic therapeutic agents available for treatment in India. New insights into RA pathogenesis The failures and successes of new drugs evaluated for the treatment of RA have provided new insights into the mechanisms underlying the disease pathogenesis. Once a 51 Apollo Medicine, Vol. 6, No. 1, March 2009
  3. 3. Review Article Fig.1. Role of T cells in rheumatoid arthritis pathogenesis. Antigen-presenting cells (ACPs) present processed peptide to the TCR, which recognizes the peptide within the context of the MHC molecule. Other receptors must also be activated for full T-cell activation to happen; these are represented by the molecules schematically depicted on the surface of ACPs, T cells synovicytes, and B cells. (Adapted from J.M. Kremer). Fig.2 tertiary lymphoid micro-structure and diminishes T-cell activity/response [8]. Thus B-cell depletion may reduce Tcell activation and is a very important method for controlling inflammation in RA. to receive either placebo (n=119) or abatacept, 2mg/kg (n=105) or 10mg/kg (n=115), intravenously, at days 1, 15 and 30 and monthly thereafter for 12 months [9,10]. At six months, the group receiving 10mg/kg of abatacept had a bigger ACR 20 response rate than the placebo group (60% vs.35%). These responses were maintained at 12 months. However, the ACR 20 responses in the 2mg/kg group were not different from the placebo, indicating that 10mg/kg per dose is the optimal dose for the treatment of RA. Targeting the T-cell: Cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig): Abatacept CTLA4-Ig represents a new class of molecules that blocks the second stimulus for T-cell activation. Resting Tcells require two separate signals for full stimulation. The first signal is the interaction of the processed peptide in the major histo-compatibility (MHC) with the T cell receptor (TCR). The second signal is the engagement of the CD-28 on T-cells with the CD80/86 (B7-1 or B7-2) on the surface of the antigen presenting cell (Fig.2). CTLA 4 is a second, high affinity receptor for both CD80 and CD86, binding up-to a 1000 times as avidly to the B7 members as CD 28. The binding of CTLA 4-Ig to the B7 molecule thus prevents the interaction between CD80/86 and CD28, essentially blocking the second signal for T-cell activation (Fig. 2). In another recent trial, 393 patients who had an inadequate response to anti TNF- therapy plus MTX/ other DMARD, were randomized in a ratio of 2:1 to receive a fixed dose of abatacept (500mg, 750mg, or 1000mg) at days 1, 15, 29, and then every 28 days through day 141 [11]. At six months, the abatacept group was superior to the placebo group (ACR 20) was 50.4% vs.19.5%; P<0.001). Abatacept may also be used in patients who have had an inadequate response to MTX mono-therapy. In a study involving 652 patients on stable MTX doses, patients were randomly allocated in a 2:1 ratio to receive abatacept in a fixed dose of 10mg/kg on days 1, 15, 29 and then every 28 days through day 141 [12]. At 12 months, ACR 20, 50 and 70 response rates were higher in the abatacept group than the placebo group (80% vs. 60%, 53.3% vs. 33.8%, and 26.7% vs. 12.7%, respectively; P<0.001 for all comparisons between abatacept and placebo groups). There was also data generated to show a reduced radiographic progression in the abatacept group [13]. CTLA4-Ig or Abatacept is the fusion protein consisting of cytotoxic T-lymphocyte associated antigen 4 (CTLA 4) covalently linked to the Fc region of a human IgG1 molecule (Fig.3). Several large clinical trials have proven the efficacy of CTLA4-Ig in the treatment of RA. In one early study, 339 patients who had active RA despite receiving optimal doses of MTX, were randomly allocated Apollo Medicine, Vol. 6, No. 1, March 2009 Mechanism of action of the CTLA4-Ig molecule. Because CTLA4 binds to CD80/CD86 with much greater avidity than CD28 (and CD28 binds to both CTLA4 and CD80/CD86), the presence of the artificial construct molecule will also selectively bind CD28, thus preventing full T-cell activation as well as subsequent B cell activation. (Adapted from J.M. Kremer) 52
  4. 4. Review Article Fig 3. Schematic representation of the structure of the CTLA4 molecule. A human CTLA4(CD152) transmembrane protein is fused with an IgGI Fc molecule to make the CTLA4-Ig, which is given intravenously. Fig. 4. Articular effects of IL-6. The toxicity profile of abatacept has been very favorable [14]. IL-6 inhibition is clinically achieved by blocking the IL-6 receptor (IL-6R). In a placebo controlled trial using a recombinant, humanized, monoclonal antibody against the IL-6R receptor (tocilizumab). In patients with refractory RA, ACR20 and ACR50 responses were achieved in 78 and 40% respectively [17]. Mild elevations of cholesterol and moderate elevations of liver enzymes were observed in the tocilizumab group. In another study patients with disease duration of less than 5 years were randomly allocated to receive either tocilizumab, 8mg/kg, intravenously every 4 weeks or another conventional DMARD (MTX but not leflunomide/biologics) [18]. At 52 weeks the tocilizumab group showed less radiographic progression than the conventional DMARD group. The ACR20, ACR50 and ACR70 responses were 89%, 70% and 47% vs. 35%, 14% and 6% in the tocilizumab and DMARD groups, respectively. Targeting the B-cell: Rituximab (anti CD20 monoclonal antibody) CD20 is expressed on the B-cells from the pre-B cell through the mature stage, but is absent on stem cells and plasma cells. Rituximab eleminates B-cells by binding to CD20, and causes an antibody-dependent cellular cytotoxicity, which finally leads to a transient depletion of CD20 positive B-cells. Several large clinical trials have proven the efficacy and safety of Rituximab for RA. In one early clinical trial (randomized, double blind, controlled study) involving rituximab alone, MTX alone, rituximab + cyclophospha-mide, and rituximab + MTX, most of the ACR20 and ACR 50 responses were significantly lesser in the MTX only group vs. all the other rituximab groups [6]. Adverse events in the form of hypotension, hypertension, cough, pruritis and rash were related to the first inflammations in the rituximab groups. SUMMARY The new anti rheumatic/biologic drugs will bring new therapeutic possibilities and challenges for the treatment of RA. These new agents will allow the clinician to use novel induction regimens, combination therapies, and tailor-made therapies for the individual RA patient. New potent induction regimens may allow drug free holidays to become a realistic goal, thus mitigating the possible side effects of long term immuno suppressive drugs. For e.g. in the BeST study 56% of 120 patients who started the treatment of early RA with infliximab in combination with MTX were able to maintain a low disease activity even after stopping infliximab [19]. These and other encouraging results will provide motivation for similar induction regimens in early RA. Rituximab has also been investigated as an option for RA patients who have failed anti TNF- therapy. In one clinical trial patients who had failed concomitant MTX (10-25mg/wk) and anti TNF- therapy, subjects were randomized to receive rituximab or placebo [15]. ACR20 and ACR 50 responses were significantly better in the rituximab group. Targeting a tocilizumab specific cytokine: Anti IL-6, IL-6 is another cytokine which plays an important role in the pathogenesis of RA (Fig.4). IL-6 is abundantly expressed on T-cell, macrophages and fibroblasts in the rheumatoid synovium. More importantly, serum IL-6 concentrations have been shown to correlate with disease activity and radiological joint damage [16]. MTX monotherapy may not survive as the acceptable standard of care for the treatment of RA since most recent studies feature combination regimens. Pioneering 53 Apollo Medicine, Vol. 6, No. 1, March 2009
  5. 5. Review Article treatments for early and moderate RA are no just emerging therapies for this condition, they qualify as current therapies. rheumatoid arthritis refractory to tumor necrosis factor inhibition.N Engl J Med 2005; 353: 1114-1123. 12. Russell A, Shergy W, Numah I, et al. Abatacept treatment demonstrates rapid, consistent and sustained increases in ACR response rates over 1 year in patients with active rheumatoid arthritis. Presented at EULAR 2005. Vienna, Austria, June 8-11, 2005. Available at:http:// Accessed January 2, 2006. REFERENCES 1. Wolfe F, Sharp JT. Radiographic outcome of recentonset rheumatoid arthritis: a 19 year study of radiographic progression. Arthritis Rheum 1998; 41: 1571-1582. 13. Genant H, Peterfy C, Paira S, et al. Abatacept significantly inhibits structural damage progression as assessed by the Genant-modified Sharp scoring system in rheumatoid arthritis patients with inadequate methotrexate responses. Ann Rheum Dis 2005; 64(Suppl III): 56. 2. St. Clair EW, Van der Heijde DMFM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis. A randomized, controlled trial. Arthritis Rheum 2004;50: 3432-3443. 3. Breedveld F,Weisman M, Kavanaugh A, et al. Adalimumab plus methotrexate versus methotrexate or adalimumab alone in methotrexate-naïve patients with early aggressive rheumatoid arthritis: results of the PREMIER study. Arthritis Rheum 2006; 54: 26-37. 14. Weinblatt M, Combe B, White A, et al. Safety of abatacept in patients with active rheumatoid arthritis receiving background non-biologic and biologic DMARDs: 1-year results of the ASSURE trial. Ann Rheum Dis 2005; 64(Suppl III): 60. 4. McInnes IB, Gracie JA. Targeting cytokines beyond tumor necrosis factor- and interleukin-1 in rheumatoid arthritis.Curr Rheumatol Rep 2004; 6: 336-342. 15. Cohen SB, Greenwald M, Dougdas MR, et al. Efficacy and safety of rituximab in active RA patients who experience an adequate response to one or more antiTNF- therapies (REFLEX study). Arthritis Rheum 2005; 52(Suppl): S677. 5. Firestein GS.Evolving concepts of rheumatoid arthritis. Nature 2003; 423: 356-361. 6. Edwards JCW, Szczepanski L, Szczepanski J, et al. Efficacy of B-cell targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-2581. 16. Choy E. Clinical experience with inhibition of interleukin6. Rheum Dis Clin North Am 2004; 30: 405-415. 17. Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody. A multicenter, double-blind, placebocontrolled, dose-escalation trial.Arthritis Rheum 2004; 50: 1761-1769. 7. Goronzy JJ, Weyand CM. Rheumatoid arthritis.Immunol Rev 2005; 204: 55-73. 8. Takemura S, Klimiuk PA, Braun A, et al. T cell activation in rheumatoid synovium in B cell dependent. J Immunol 2001;167: 4710-4718. 18. Nishimoto N, Hashimoto J, Miyasaka N, et al. Blocking interlukin-6 (IL-6) by tocilizumab (a humanized antiinterlukin-6 receptor monoclonal antibody) monotherapy reduces joint damage in active rheumatoid arthritis (RA): evidence from X-ray reader-blinded randomized controlled trial [abstract]. Arthritis Rheum 2005; 62: 51-54. 9. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907-1915. 10. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve month results of phase IIb double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005; 52: 2263-2271. 19. van der Bijl AE, Goekoop-Ruiterman YP, Breedveld FC, et al. Initial combination therapy with infliximab and methotrexate can suppress rheumatoid arthritis after infliximab discontinuation. Arthritis Rheum 2005; 52(Suppl): S346. 11. Genovese MC, Becker J-C, Schiff M, et al. Abatacept for Apollo Medicine, Vol. 6, No. 1, March 2009 54
  6. 6. A o oh s i l ht:w wa o o o p a . m/ p l o p a : t / w .p l h s i lc l ts p / l ts o T ie: t s / ie. m/o p a A o o wt rht :t t r o H s i l p l t p /w t c ts l Y uu e ht:w wy uu ec m/p l h s i ln i o tb : t / w . tb . a o o o p a i a p/ o o l ts d F c b o : t :w wfc b o . m/h A o o o p a a e o k ht / w . e o k o T e p l H s i l p/ a c l ts Si s ae ht:w wsd s aen t p l _ o p a l e h r: t / w .i h r.e/ o o H s i l d p/ le A l ts L k d : t :w wl k d . m/ mp n /p l -o p a i e i ht / w . e i c c a y o oh s i l n n p/ i n no o a l ts Bo : t :w wl s l e l . / l ht / w . t a h a hi g p/ e tk t n