Skip to main content

Part of the book series: Progress in Inflammation Research ((PIR))

  • 808 Accesses

Abstract

Targeted therapeutic agents have changed the landscape of therapy in rheumatoid arthritis (RA). They have also provided valuable insights into the utility of animal models for development of targeted therapies, clinical trial design, pharmacodynamics, immunobiology and key pathogenic elements of disease. Studies of chimeric anti-CD4 monoclonal antibodies in RA demonstrated the need for pre-clinical studies to more closely approximate the human therapeutic paradigm as well as the importance of synovium as an appropriate pharmacodynamic window to predict efficacy and adverse side effects of the agents. Targeted therapies have been instructive in discerning the importance of TNF, IL-1, IL-6, IL-15 and RANKL in the pathological process themselves, such as the uncoupling of inflammation and structural damage. Current trends in the use of targeted therapeutics include aggressive earlier use, combination with methotrexate, use in moderate rather than severe disease, tight control as well as induration and maintenance regimes. Despite therapeutic advances with target therapies a number of unmet needs exist, including a low remission rate, cost and inadequate access as well as the lack of biomarkers to predict response and safety concerns. Despite this, target therapies have revolutionized the treatment of RA. In addition to having a substantial effect on clinical outcomes, a number of valuable lessons have been learned.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 289.00
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Keystone EC (2003) Abandoned therapies and unpublished trials in rheumatoid arthritis. Curr Opin Rheumatol 15: 253–258

    Article  PubMed  CAS  Google Scholar 

  2. Moreland LW, Pratt PW, Mayes MD, Postlethwaite A, Weisman MH, Schnitzer T, Lightfoot R, Calabrese L, Zelinger JJ, Woody N (1995) Double-blind placebo-controlled multicentre trial using chimeric monoclonal anti-CD4 antibody, CM-T412 in rheumatoid arthritis patients receiving concomitant methotrexate. Arthritis Rheum 38: 1581–8

    Article  PubMed  CAS  Google Scholar 

  3. Van der Lubbe PA, Dijkmans BA, Markusse HM, Nassander V, Breedveld FC (1995) A randomized double-blind placebo controlled study of CD4 monoclonal antibody therapy in early rheumatoid arthritis. Arthritis Rheum 38: 1097–1106

    Article  PubMed  Google Scholar 

  4. Horneff G, Burmester GR, Emmrich F, Kalden JR (1991) Treatment of rheumatoid arthritis with anti-CD4 monoclonal antibody. Arthritis Rheum 34: 129–140

    Article  PubMed  CAS  Google Scholar 

  5. Tak PP, van der Lubbe PA, Cauli A, Daha MR, Smeets TJ, Kluin PM, Meinders AE, Yanni G, Panayi GS, Breedveld FC (1995) Reduction of inflammation after anti-CD4 antibody treatment in early rheumatoid arthritis. Arthritis Rheum 38: 1456–1465

    Article  Google Scholar 

  6. Ruderman EM, Weinblatt ME, Thurmond LM, Pinkus GS, Gravallese EM (1995) Synovial tissue response to treatment with CAMPA TH-IH. Arthritis Rheum 38: 254

    Article  PubMed  CAS  Google Scholar 

  7. Choy EH, Pitzalis C, Cauli A, Bijl JA, Schantz A, Woody J, Kingsley GH, Panayi GS (1996) Percentage of anti-CD4 monoclonal antibody-coated lymphocytes in the rheumatoid joint is associated with clinical improvement. Arthritis Rheum 39: 52–56

    Article  PubMed  CAS  Google Scholar 

  8. Moreland LW, Pratt PW, Bucy RP, Jackson BS, Feldman JW, Koopman WJ (1994) Treatment of refractory rheumatoid arthritis with a chimeric anti-CD4 monoclonal antibody. Long term follow up of CD4+ T-cell counts. Arthritis Rheum 37: 854–858

    Article  Google Scholar 

  9. Suntharalingam, G. Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355, 1018–1028

    Article  PubMed  CAS  Google Scholar 

  10. Levy R, Weisman M, Wiesnehutter C et al (1996) Results of a placebo-controlled multicentre trial using a primatized non-depleting, anti-CD4 monoclonal antibody in the treatment of rheumatoid arthritis. Arthritis Rheum (Suppl): 122

    Google Scholar 

  11. Mason U, Aldric J, Breedveld F, Davis CB, Elliott M, Jackson M, Jorgensen C, Keystone E, Levy R, Tesser J (2002) CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized monoclonal anti-CD4 treatment of active rheumatoid arthritis. J Rheumatol 29, 220–229

    PubMed  CAS  Google Scholar 

  12. Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, Dougados M, Baldassare A, Ferraccioli G, Chubick A (2007) Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: An open-label extension analysis. Arthritis Rheum 56: 3896–3908

    Article  PubMed  CAS  Google Scholar 

  13. Emery P, Breedveld F, Martin-Mola E, Pavelka K, Szczepanski L, Kim D, Magrini F, Behrendt C, Kelman A (2006) Relationship between peripheral B Cell return and loss of EULAR response in RA patients treated with rituximab. Arthritis Rheum 54: S66

    Article  Google Scholar 

  14. Vos K, Thurlings RM, Wijbrandts CA, van Schaardenburg D, Gerlag DM, Tak PP (2007) Early effects of rituximab on the synovial cell infiltrate in patients with rheumatoid arthritis. Arthritis Rheum 56: 772–8

    Article  PubMed  CAS  Google Scholar 

  15. Thurlings RM, Vos K, Wijbrandts CA, Zwinderman AH, Gerlag DM, Tak PP (2008) Synovial tissue response to rituximab: Mechanism of action and identification of biomarkers of response. Ann Rheum Dis 67: 917–25

    Article  PubMed  CAS  Google Scholar 

  16. Gerlag DM, Tak PP (2008) Novel approaches for the treatment of rheumatoid arthritis: Lessons from the evaluation of synovial biomarkers in clinical trials. Best Pract Res Clin Rheumatol 22: 331–323

    Article  Google Scholar 

  17. Keystone EC, van der Heijde D, Mason D, Strand V, Landewe R, Combe B (2008) Centrolizumab pegol with methotrexate significantly decreases signs and symptoms and progression of joint damage in patients with active rheumatoid arthritis: 1-year results from the rapid 1 trial. Ann Rheum Dis 67(Suppl 11): 186

    Google Scholar 

  18. Smeets TJ, Kraan MC, van Loon ME, Tak PP (2003) Tumor necrosis factor alpha blockade reduces the synovial cell infiltrate early after initiation of treatment, but apparently not by induction of apoptosis in synovial tissue. Arthritis Rheum 48: 2155–62

    Article  PubMed  CAS  Google Scholar 

  19. Haringman JJ, Kraan MC, Smeets TJ, Zwinderman KH, Tak PP (2003) Chemokine blockade and chronic inflammatory disease: Proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis 62: 715–21

    Article  PubMed  CAS  Google Scholar 

  20. Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P (2004) Combination therapy with etanercept and anakina in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50: 1412–19

    Article  PubMed  CAS  Google Scholar 

  21. Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E (2006) Safety of the selective costimulatory modulator abatacept in rheumatoid arthritis patients receiving background biologic and monobiologic disease modifying antirheumatic drugs. A one year randomized placebo controlled study. Arthritis Rheum 54: 2807–16

    Article  PubMed  CAS  Google Scholar 

  22. Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, Vinh DC (2003) Anti-tumor necrosis factor agents and tuberculosis risk: Mechanisms of action and clinical management. Lancet Infect Dis 3: 148–155

    Article  PubMed  CAS  Google Scholar 

  23. Stone JH, Holbrook JT, Marriott MA, Tibbs AK, Sejismundo LP, Min YI, Specks U, Merkel PA, Spiera R, Davis JC (2006) Solid malignancies among patients in the Wegener’s Granulomatosus Etanercept Trial. Arthritis Rheum 54: 1608–18

    Article  PubMed  CAS  Google Scholar 

  24. Bongartz I, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295: 2275–85

    Article  PubMed  CAS  Google Scholar 

  25. Stuve O, Marra CM, Cravens PD, Singh MP, Hu W, Lovett-Racke A, Monson NL, Phillips JT, Tervaert JW, Nash RA et al (2007) Potential risk of progressive multifocal leukoencephalopathy with natalizumab therapy: Possible interventions. Arch Neurol 64: 169–76

    Article  PubMed  Google Scholar 

  26. Garcia-Suarez J, de Miguel D, Krsnik I, Banas H, Arribas I, Burgaleta C (2005) Changes in the natural history of progressive multifocal leukoencephalopahty in HIV negative lymphoproliferative disorders: Impact of novel therapies. Am J Hematol 80: 271–81

    Article  PubMed  CAS  Google Scholar 

  27. Strand V, Kimberly R, Isaacs JD (2007) Biologic therapies in rheumatology: Lessons learned, future directions. Nat Rev Drug Discov 6: 75–92

    Article  PubMed  CAS  Google Scholar 

  28. Maini R, St. Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P (1999) Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A randomized phase III trial. ATTRACT Study Group. Lancet 354: 1932–9

    Article  PubMed  CAS  Google Scholar 

  29. Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: A randomized, placebo-controlled, 52 week trial. Arthritis Rheum 50: 1400–11

    Article  PubMed  CAS  Google Scholar 

  30. Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, Weaver AL, Keystone EC, Furst DE, Mease PJ et al (1999) Etanercept therapy in rheumatoid arthritis. A randomized controlled trial. Ann Intern Med 130: 478–86

    PubMed  CAS  Google Scholar 

  31. Choy EH, Isenberg DA, Garrood T, Farrow S, Ioannou Y, Bird H, Cheung N, Williams B, Hazleman B, Price R et al (2002) Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: A randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 46: 3143–50

    Article  PubMed  CAS  Google Scholar 

  32. Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, van der Heijde D, Zhou L, Tsuji W, Newmark R et al (2008) Denosumab treatment effects on structural damage, bone mineral density and bone turnover in rheumatoid arthritis: A twelve month, multicenter double-blind, placebo controlled, phase II clinical trial. Arthritis Rheum 58: 1299–309

    Article  PubMed  CAS  Google Scholar 

  33. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoze C, Szechinski J, Li T, Ge Z, Becker JC, Westhovens R (2006) Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: A randomized trial. Ann Intern Med 144: 865–76

    PubMed  CAS  Google Scholar 

  34. Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, Keystone EC, Loveless JE, Burmester GR, Cravets MW et al (2006) REFLEX Trial Group. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54: 2793–806

    Article  PubMed  CAS  Google Scholar 

  35. Furst DE, Wallis R, Broder M, Beenhouwer DO (2006) Tumor necrosis factor antagonists: Different kinetics and/or mechanisms of action may explain differences in the risk for developing granulomatous infection. Semin Arthritis Rheum 36: 159–67

    Article  PubMed  CAS  Google Scholar 

  36. Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, Bernstein CN, Staun M, Thomsen OO, Innes A et al (2005) A randomized, placebocontrolled trial of certolizumab pegol (BDP870) for treatment of Crohn’s disease. Gastroenterology 129: 807–18

    Article  PubMed  CAS  Google Scholar 

  37. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S et al (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358: 676–88

    Article  PubMed  CAS  Google Scholar 

  38. Haraoui B, Cameron L, Ouellet M, White B (2006) Anti-infliximab antibodies in patients with rheumatoid arthritis who require higher doses of infliximab to achieve or maintain a clinical response. J Rheumatol 33: 31–6

    PubMed  CAS  Google Scholar 

  39. Wolbink GJ, Vis M, Lems W, Voskuyl AE, de Groot E, Nurmohamed MT, Stapel S, Tak PP, Arden L, Dijkmans B (2006) Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 54:711–715

    Article  PubMed  Google Scholar 

  40. Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, Dijkmans B, Tak PP, Wolbink GJ (2007) Clinical response to adalimumab: Relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis 66: 921–926

    Article  PubMed  CAS  Google Scholar 

  41. Keystone EC (2003) Abandoned therapies and unpublished trials in rheumatoid arthritis. Curr Opin Rheumatol 15: 253–8

    Article  PubMed  CAS  Google Scholar 

  42. Epstein WV (1996) Expectation bias in rheumatoid arthritis clinical trials. The anti-CD4 monoclonal antibody experience. Arthritis Rheum 39: 1773–80

    Article  PubMed  CAS  Google Scholar 

  43. van der Heijde D, Klareskog L, Rodriguez-Valverde V, Codreanu C, Bolosiu H, Melo-Gomes J, Tornero-Molina J, Wajdula J, Pedersen R, Fatenejad S et al (2006) Comparison of etanercept and methotrexate, alone and combined in the treatment of rheumatoid arthritis: Two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 54: 1063–74

    Article  PubMed  Google Scholar 

  44. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, Sharp J, Perez JL, Spencer-Green GT (2006) The PREMIER study: A multicenter randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate therapy. Arthritis Rheum 54: 26–37

    Article  PubMed  CAS  Google Scholar 

  45. Smolen JS, Han C, Bala M, Maini RN, Kalden JR, van der Heijde D, Breedveld FC, Furst DE, Lipsky PE, ATTRACT Study Group (2005) Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: A detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum 52: 1020–30

    Article  PubMed  CAS  Google Scholar 

  46. Goekoop-Ruit Erman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Peeters AJ, de Jonge-Bok JM, Mallée C et al (2007) Comparison of treatment strategies in early rheumatoid arthritis: A randomized trial. Ann Intern Med 146: 406–15

    Google Scholar 

  47. Klarenbeek NB, Guler-Yuksel M, van der Kooij, van der Heijde DM, Huizinga TW, Kerstens, PJ, Peeters AJ, Ronday HK, Westedt ML, Dijkmans BA et al (2008) Clinical outcomes of four different treatment strategies in patients with recent-onset rheumatoid arthritis: 5-year results of the best study. Ann Rheum Dis 66(Suppl 11): 192

    Google Scholar 

  48. von Dongen H, van Aken, Lard LR, Visser K, Ronday HK, Hulsmans HM, Speyer I, Westedt ML, Peeters AJ, Allaart CF et al (2007) Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double-blind, randomized placebo-controlled trial. Arthritis Rheum 56: 1424–32

    Article  PubMed  Google Scholar 

  49. Keystone E, Chon Y, Eickenhorst T (2005) Comparison of efficacy responses to etanercept treatment in rheumatoid arthritis patients with moderate versus severe disease. Ann Rheum Dis 64: 180

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Birkhäuser Verlag Basel/Switzerland

About this chapter

Cite this chapter

Keystone, E.C. (2009). Perspectives in targeted therapy. In: Tak, PP. (eds) New Therapeutic Targets in Rheumatoid Arthritis. Progress in Inflammation Research. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8238-4_12

Download citation

  • DOI: https://doi.org/10.1007/978-3-7643-8238-4_12

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-7643-8237-7

  • Online ISBN: 978-3-7643-8238-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics