BioDrugs

, Volume 23, Issue 2, pp 111–124

Biologic Therapy for Rheumatoid Arthritis

Clinical Efficacy and Predictors of Response
  • Laura J. Gibbons
  • Kimme L. Hyrich
Therapy Review

Abstract

Rheumatoid arthritis (RA) is a chronic, disabling disease of the synovial joints, thought to be autoimmune in origin. The emergence of biologic therapies has proven to be highly successful in effectively treating RA in the majority of cases. However, the cost of these agents is high and some patients do not respond to these drugs, or they suffer from adverse events. This article will review the currently available data on efficacy and the clinical, genetic, and biomarkers of response to these biologic therapies in RA.

The anti-tumour necrosis factor-alpha (anti-TNFα) agents, adalimumab, etanercept and infliximab, act to neutralize the pro-inflammatory cytokine. Response to these agents is higher in patients receiving concurrent disease modifying anti-rheumatic drugs or non-steroidal anti-inflammatory drugs, in those with lesser disability, and in non-smokers. Many genetic predictors of response have been investigated, such as the shared epitope, the TNF gene and its receptors, but none have been absolutely confirmed. Synovial expression of TNFα has been suggested as a biomarker of response, while anti-cyclic citrullinated peptide antibody and rheumatoid factor (RF)-positivity predict poor response. Newer biologic agents include the interleukin (IL)-1 receptor antagonist anakinra, the B-cell depleting agent rituximab, the selective costimulation modulator abatacept, and the anti-IL-6 receptor monoclonal antibody tocilizumab. No genetic studies of response to these agents have been performed to date. However, it has been reported that low synovial infiltration of B cells and complete B-cell depletion after the first rituximab infusion are predictors of good response to this agent.

References

  1. 1.
    Klareskog L, Van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004 Feb 28; 363(9410): 675–81PubMedCrossRefGoogle Scholar
  2. 2.
    Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000 Nov 30; 343(22): 1586–93PubMedCrossRefGoogle Scholar
  3. 3.
    Breedveld FC, Weisman MH, Kavanaugh AF, et al. 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 treatment. Arthritis Rheum 2006 Jan; 54(1): 26–37PubMedCrossRefGoogle Scholar
  4. 4.
    St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004 Nov; 50(11): 3432–43PubMedCrossRefGoogle Scholar
  5. 5.
    O’Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med 2004 Jun 17; 350(25): 2591–602PubMedCrossRefGoogle Scholar
  6. 6.
    Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001 Mar 22; 344(12): 907–16PubMedCrossRefGoogle Scholar
  7. 7.
    Feldmann M, Maini RN. Discovery of TNF-α as a therapeutic target in rheumatoid arthritis: preclinical and clinical studies. Joint Bone Spine 2002; 69(1): 12–8PubMedCrossRefGoogle Scholar
  8. 8.
    Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999 Mar 16; 130(6): 478–86PubMedGoogle Scholar
  9. 9.
    Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003 Jan; 48(1): 35–45PubMedCrossRefGoogle Scholar
  10. 10.
    Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999 Jan 28; 340(4): 253–9PubMedCrossRefGoogle Scholar
  11. 11.
    Lipsky PE, Van der Heijde DMFM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000; 343(22): 1594–602PubMedCrossRefGoogle Scholar
  12. 12.
    Nixon R, Bansback N, Brennan A. The efficacy of inhibiting tumour necrosis factor alpha and interleukin 1 in patients with rheumatoid arthritis: a meta-analysis and adjusted indirect comparisons. Rheumatology (Oxford) 2007 Jul; 46(7): 1140–7PubMedCrossRefGoogle Scholar
  13. 13.
    Hochberg MC, Tracy JK, Hawkins-Holt M, et al. Comparison of the efficacy of the tumour necrosis factor alpha blocking agents adalimumab, etanercept, and infliximab when added to methotrexate in patients with active rheumatoid arthritis. Ann Rheum Dis 2003 Nov; 62Suppl. 2: ii13–16PubMedGoogle Scholar
  14. 14.
    Chen YF, Jobanputra P, Barton P, et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess 2006 Nov; 10 (42): iii–iv, xi–xiii, 1-229Google Scholar
  15. 15.
    Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995 Jun; 38(6): 727–35PubMedCrossRefGoogle Scholar
  16. 16.
    Goekoop-Ruiterman YP, De Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2008 Feb; 58(2 Suppl.): S126–35PubMedGoogle Scholar
  17. 17.
    Van der Bijl AE, Goekoop-Ruiterman YP, De Vries-Bouwstra JK, et al. Infliximab and methotrexate as induction therapy in patients with early rheumatoid arthritis. Arthritis Rheum 2007 Jul; 56(7): 2129–34PubMedCrossRefGoogle Scholar
  18. 18.
    Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFα blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford) 2005 Feb; 44(2): 157–63PubMedCrossRefGoogle Scholar
  19. 19.
    Zink A, Strangfeld A, Schneider M, et al. Effectiveness of tumor necrosis factor inhibitors in rheumatoid arthritis in an observational cohort study: comparison of patients according to their eligibility for major randomized clinical trials. Arthritis Rheum 2006 Nov; 54(11): 3399–407PubMedCrossRefGoogle Scholar
  20. 20.
    Kievit W, Fransen J, Oerlemans AJ, et al. The efficacy of anti-TNF in rheumatoid arthritis, a comparison between randomised controlled trials and clinical practice. Ann Rheum Dis 2007 Nov; 66(11): 1473–8PubMedCrossRefGoogle Scholar
  21. 21.
    Greenberg JD, Kishimoto M, Strand V, et al. Tumor necrosis factor antagonist responsiveness in a United States rheumatoid arthritis cohort. Am J Med 2008 Jun; 121(6): 532–8PubMedCrossRefGoogle Scholar
  22. 22.
    Gomez-Reino JJ, Carmona L. Switching TNF antagonists in patients with chronic arthritis: an observational study of 488 patients over a four-year period. Arthritis Res Ther 2006; 8(1): R29PubMedCrossRefGoogle Scholar
  23. 23.
    Zink A, Joachim L, Kary S, et al. Treatment continuation in patients receiving biological agents or conventional DMARD therapy. Ann Rheum Dis 2005; 64: 1274–9PubMedCrossRefGoogle Scholar
  24. 24.
    Kristensen LE, Saxne T, Nilsson JA, et al. Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis: results from a six-year observational study in southern Sweden. Arthritis Res Ther 2006; 8(6): R174PubMedCrossRefGoogle Scholar
  25. 25.
    Hyrich KL, Watson KD, Silman AJ, et al. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 2006 Dec; 45(12): 1558–65CrossRefGoogle Scholar
  26. 26.
    Hyrich KL, Symmons DP, Watson KD, et al. Comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another disease-modifying antirheumatic drug in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2006 Jun; 54(6): 1786–94PubMedCrossRefGoogle Scholar
  27. 27.
    Finckh A, Dehler S, Gabay C. The effectiveness of leflunomide as a co-therapy of tumour necrosis factor inhibitors in rheumatoid arthritis: a population-based study. Ann Rheum Dis 2009 Jan; 68 (1): 33-9Google Scholar
  28. 28.
    Kristensen LE, Kapetanovic MC, Gulfe A, et al. Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology (Oxford) 2008 Apr; 47(4): 495–9PubMedCrossRefGoogle Scholar
  29. 29.
    Radovits BJ, Kievit W, Fransen J, et al. Influence of age on the outcome of anti-TNFalphatherapy in rheumatoid arthritis. Ann Rheum Dis Epub 2008 Nov 19Google Scholar
  30. 30.
    Fernandez-Nebro A, Irigoyen MV, Urena I, et al. Effectiveness, predictive response factors, and safety of anti-tumor necrosis factor (TNF) therapies in anti-TNF-naive rheumatoid arthritis. J Rheumatol 2007 Dec; 34(12): 2334–42PubMedGoogle Scholar
  31. 31.
    Geborek P, Crnkic M, Petersson IF, et al. Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden. Ann Rheum Dis 2002; 61(9): 793–8PubMedCrossRefGoogle Scholar
  32. 32.
    Fitzcharles M-A, Clayton D, Menard HA. The use of infliximab in academic rheumatology practice: an audit of early clinical experience. J Rheumatol 2002; 29(12): 2525–30PubMedGoogle Scholar
  33. 33.
    Scott DL, Steer S. The course of established rheumatoid arthritis. Best Pract Res Clin Rheumatol 2007 Oct; 21(5): 943–67PubMedCrossRefGoogle Scholar
  34. 34.
    van Zeben D, Breedveld FC. Prognostic factors in rheumatoid arthritis. J Rheumatol Suppl 1996 Mar; 44: 31–3PubMedGoogle Scholar
  35. 35.
    Anderson JJ, Wells G, Verhoeven AC, et al. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum 2000 Jan; 43(1): 22–9PubMedCrossRefGoogle Scholar
  36. 36.
    Martinez A, Salido M, Bonilla G, et al. Association of the major histo-compatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum 2004 Apr; 50(4): 1077–82PubMedCrossRefGoogle Scholar
  37. 37.
    Criswell LA, Lum RF, Turner KN, et al. The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum 2004 Sep; 50(9): 2750–6PubMedCrossRefGoogle Scholar
  38. 38.
    Kang CP, Lee KW, Yoo DH, et al. The influence of a polymorphism at position −857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in rheumatoid arthritis. Rheumatology (Oxford) 2005 Apr; 44(4): 547–52CrossRefGoogle Scholar
  39. 39.
    Marotte H, Pallot-Prades B, Grange L, et al. The shared epitope is a marker of severity associated with selection for, but not with response to, infliximab in a large rheumatoid arthritis population. Ann Rheum Dis 2006 Mar; 65(3): 342–7PubMedCrossRefGoogle Scholar
  40. 40.
    Miceli-Richard C, Comets E, Verstuyft C, et al. A single tumour necrosis factor haplotype influences the response to adalimumab in rheumatoid arthritis. Ann Rheum Dis 2008 Apr; 67(4): 478–84PubMedCrossRefGoogle Scholar
  41. 41.
    Potter C, Hyrich KL, Tracey A, et al. Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis. Ann Rheum Dis 2009 Jan; 68(1): 69–74PubMedCrossRefGoogle Scholar
  42. 42.
    Mugnier B, Balandraud N, Darque A, et al. Polymorphism at position −308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 2003 Jul; 48(7): 1849–52PubMedCrossRefGoogle Scholar
  43. 43.
    Padyukov L, Lampa J, Heimburger M, et al. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis 2003 Jun; 62(6): 526–9PubMedCrossRefGoogle Scholar
  44. 44.
    Cuchacovich M, Soto L, Edwardes M, et al. Tumour necrosis factor (TNF)alpha −308 G/G promoter polymorphism and TNFalpha levels correlate with a better response to adalimumab in patients with rheumatoid arthritis. Scand J Rheumatol 2006 Nov; 35(6): 435–40PubMedCrossRefGoogle Scholar
  45. 45.
    Lee YH, Rho YH, Choi SJ, et al. Association of TNF-alpha −308 G/A polymorphism with responsiveness to TNF-alpha-blockers in rheumatoid arthritis: a meta-analysis. Rheumatol Int 2006 Dec; 27(2): 157–61PubMedCrossRefGoogle Scholar
  46. 46.
    Seitz M, Wirthmuller U, Moller B, et al. The −308 tumour necrosis factor-alpha gene polymorphism predicts therapeutic response to TNFalpha-blockers in rheumatoid arthritis and spondyloarthritis patients. Rheumatology (Oxford) 2007 Jan; 46(1): 93–6CrossRefGoogle Scholar
  47. 47.
    Guis S, Balandraud N, Bouvenot J, et al. Influence of −308 A/G polymorphism in the tumor necrosis factor alpha gene on etanercept treatment in rheumatoid arthritis. Arthritis Rheum 2007 Dec 15; 57(8): 1426–30PubMedCrossRefGoogle Scholar
  48. 48.
    Marotte H, Arnaud B, Diasparra J, et al. Association between the level of circulating bioactive tumor necrosis factor alpha and the tumor necrosis factor alpha gene polymorphism at −308 in patients with rheumatoid arthritis treated with a tumor necrosis factor alpha inhibitor. Arthritis Rheum 2008 May; 58(5): 1258–63PubMedCrossRefGoogle Scholar
  49. 49.
    Maxwell JR, Potter C, Hyrich KL, et al. Association of the tumour necrosis factor-308 variant with differential response to anti-TNF agents in the treatment of rheumatoid arthritis. Hum Mol Genet 2008 Nov 15; 17(22): 3532–8PubMedCrossRefGoogle Scholar
  50. 50.
    Fabris M, Tolusso B, Di Poi E, et al. Tumor necrosis factor-alpha receptor II polymorphism in patients from southern Europe with mild-moderate and severe rheumatoid arthritis. J Rheumatol 2002 Sep; 29(9): 1847–50PubMedGoogle Scholar
  51. 51.
    Rooryck C, Barnetche T, Richez C, et al. Influence of FCGR3A-V212F and TNFRSF1B-M196R genotypes in patients with rheumatoid arthritis treated with infliximab therapy. Clin Exp Rheumatol 2008 Mar; 26(2): 340–2PubMedGoogle Scholar
  52. 52.
    Toonen EJ, Coenen MJ, Kievit W, et al. The tumour necrosis factor receptor superfamily member 1b 676T>G polymorphism in relation to response to infliximab and adalimumab treatment and disease severity in rheumatoid arthritis. Ann Rheum Dis 2008 Aug; 67(8): 1174–7PubMedCrossRefGoogle Scholar
  53. 53.
    Kastbom A, Bratt J, Ernestam S, et al. Fcgamma receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis. Arthritis Rheum 2007 Feb; 56(2): 448–52PubMedCrossRefGoogle Scholar
  54. 54.
    Schotte H, Schluter B, Drynda S, et al. Interleukin 10 promoter microsatellite polymorphisms are associated with response to long term treatment with etanercept in patients with rheumatoid arthritis. Ann Rheum Dis 2005 Apr; 64(4): 575–81PubMedCrossRefGoogle Scholar
  55. 55.
    Radstake TR, Fransen J, Toonen EJ, et al. Macrophage migration inhibitory factor polymorphisms do not predict therapeutic response to glucocorticoids or to tumour necrosis factor alpha-neutralising treatments in rheumatoid arthritis. Ann Rheum Dis 2007 Nov; 66(11): 1525–30PubMedCrossRefGoogle Scholar
  56. 56.
    Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987 Nov; 30(11): 1205–13PubMedCrossRefGoogle Scholar
  57. 57.
    Chatzikyriakidou A, Georgiou I, Voulgari PV, et al. Combined tumour necrosis factor-alpha and tumour necrosis factor receptor genotypes could predict rheumatoid arthritis patients’ response to anti-TNF-alpha therapy and explain controversies of studies based on a single polymorphism. Rheumatology (Oxford) 2007 Jun; 46(6): 1034–5CrossRefGoogle Scholar
  58. 58.
    Hinks A, Barton A, John S, et al. Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene. Arthritis Rheum 2005 Jun; 52(6): 1694–9PubMedCrossRefGoogle Scholar
  59. 59.
    Tutuncu Z, Kavanaugh A, Zvaifler N, et al. Fcgamma receptor type IIIA polymorphisms influence treatment outcomes in patients with inflammatory arthritis treated with tumor necrosis factor alpha-blocking agents. Arthritis Rheum 2005 Sep; 52(9): 2693–6PubMedCrossRefGoogle Scholar
  60. 60.
    Wijbrandts CA, Dijkgraaf MG, Kraan MC, et al. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium. Ann Rheum Dis 2008 Aug; 67(8): 1139–44PubMedCrossRefGoogle Scholar
  61. 61.
    Fabre S, Dupuy AM, Dossat N, et al. Protein biochip array technology for cytokine profiling predicts etanercept responsiveness in rheumatoid arthritis. Clin Exp Immunol 2008 Aug; 153(2): 188–95PubMedCrossRefGoogle Scholar
  62. 62.
    Pachot A, Arnaud B, Marrote H, et al. Increased tumor necrosis factor-alpha mRNA expression in whole blood from patients with rheumatoid arthritis: reduction after infliximab treatment does not predict response. J Rheumatol 2007 Nov; 34(11): 2158–61PubMedGoogle Scholar
  63. 63.
    Buch MH, Reece RJ, Quinn MA, et al. The value of synovial cytokine expression in predicting the clinical response to TNF antagonist therapy (infliximab). Rheumatology (Oxford) 2008 Oct; 47(10): 1469–75CrossRefGoogle Scholar
  64. 64.
    Marotte H, Maslinski W, Miossec P. Circulating tumour necrosis factor-alpha bioactivity in rheumatoid arthritis patients treated with infliximab: link to clinical response. Arthritis Res Ther 2005; 7(1): R149–55PubMedCrossRefGoogle Scholar
  65. 65.
    Braun-Moscovici Y, Markovits D, Zinder O, et al. Anti-cyclic citrullinated protein antibodies as a predictor of response to anti-tumor necrosis factor-alpha therapy in patients with rheumatoid arthritis. J Rheumatol 2006 Mar; 33(3): 497–500PubMedGoogle Scholar
  66. 66.
    Morozzi G, Fabbroni M, Bellisai F, et al. Low serum level of COMP, a cartilage turnover marker, predicts rapid and high ACR70 response to adalimumab therapy in rheumatoid arthritis. Clin Rheumatol 2007 Aug; 26(8): 1335–8PubMedCrossRefGoogle Scholar
  67. 67.
    Gonzalez-Alvaro I, Ortiz AM, Tomero EG, et al. Baseline serum RANKL levels may serve to predict remission in rheumatoid arthritis patients treated with TNF antagonists. Ann Rheum Dis 2007 Dec; 66(12): 1675–8PubMedCrossRefGoogle Scholar
  68. 68.
    Lequerre T, Jouen F, Brazier M, et al. Autoantibodies, metalloproteinases and bone markers in rheumatoid arthritis patients are unable to predict their responses to infliximab. Rheumatology (Oxford) 2007 Mar; 46(3): 446–53CrossRefGoogle Scholar
  69. 69.
    Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002 Mar; 46(3): 614–24PubMedCrossRefGoogle Scholar
  70. 70.
    Cohen SB, Strand V, Aguilar D, et al. Patient-versus physician-reported outcomes in rheumatoid arthritis patients treated with recombinant interleukin-1 receptor antagonist (anakinra) therapy. Rheumatology (Oxford) 2004 Jun; 43(6): 704–11CrossRefGoogle Scholar
  71. 71.
    Konttinen L, Kankaanpaa E, Luosujarvi R, et al. Effectiveness of anakinra in rheumatic disease in patients naive to biological drugs or previously on TNF blocking drugs: an observational study. Clin Rheumatol 2006 Nov; 25(6): 882–4PubMedCrossRefGoogle Scholar
  72. 72.
    Gartlehner G, Hansen RA, Jonas BL, et al. The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and meta-analysis. J Rheumatol 2006 Dec; 33(12): 2398–408PubMedGoogle Scholar
  73. 73.
    Genovese MC, Cohen S, Moreland L, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2004 May; 50(5): 1412–9PubMedCrossRefGoogle Scholar
  74. 74.
    National Institute for Clinical Excellence. The management of adults with rheumatoid arthritis [online]. Available from URL: http://www.nice.org.uk/nicemedia/pdf/CG79NICEGuideline.pdf [Accessed 2009 Apr 14]
  75. 75.
    Kalliolias GD, Liossis SN. The future of the IL-1 receptor antagonist anakinra: from rheumatoid arthritis to adult-onset Still’s disease and systemic-onset juvenile idiopathic arthritis. Expert Opin Investig Drugs 2008 Mar; 17(3): 349–59PubMedCrossRefGoogle Scholar
  76. 76.
    Dass S, Vital EM, Emery P. Rituximab: novel B-cell depletion therapy for the treatment of rheumatoid arthritis. Expert Opin Pharmacother 2006 Dec; 7(18): 2559–70PubMedCrossRefGoogle Scholar
  77. 77.
    Cheson BD, Leonard JP. Monoclonal antibody therapy for B-cell non-Hodgkin’s lymphoma. N Engl J Med 2008 Aug 7; 359(6): 613–26PubMedCrossRefGoogle Scholar
  78. 78.
    Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006 May; 54(5): 1390–400PubMedCrossRefGoogle Scholar
  79. 79.
    Cohen SB, Emery P, Greenwald MW, et al. 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 2006 Sep; 54(9): 2793–806PubMedCrossRefGoogle Scholar
  80. 80.
    Rituxan (rituximab) injection for intravenous use: highlights of US prescribing information [online]. Available from URL: http://www.gene.com/gene/products/information/pdf/rituxan-prescribing.pdf [Accessed 2009 Apr 17]
  81. 81.
    Leandro MJ, Cambridge G, Ehrenstein MR, et al. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 2006 Feb; 54(2): 613–20PubMedCrossRefGoogle Scholar
  82. 82.
    Teng YK, Levarht EW, Hashemi M, et al. Immunohistochemical analysis as a means to predict responsiveness to rituximab treatment. Arthritis Rheum 2007 Dec; 56(12): 3909–18PubMedCrossRefGoogle Scholar
  83. 83.
    Dass S, Rawstron AC, Vital EM, et al. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthritis Rheum 2008 Oct; 58(10): 2993–9PubMedCrossRefGoogle Scholar
  84. 84.
    Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006 Jun 20; 144(12): 865–76PubMedGoogle Scholar
  85. 85.
    Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005 Sep 15; 353(11): 1114–23PubMedCrossRefGoogle Scholar
  86. 86.
    Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 2008 Aug; 67(8): 1096–103PubMedCrossRefGoogle Scholar
  87. 87.
    Weinblatt M, Schiff M, Goldman A, et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann Rheum Dis 2007 Feb; 66(2): 228–34PubMedCrossRefGoogle Scholar
  88. 88.
    Maini RN, Taylor PC, Szechinski J, et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006 Sep; 54(9): 2817–29PubMedCrossRefGoogle Scholar
  89. 89.
    Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008 Mar 22; 371(9617): 987–97PubMedCrossRefGoogle Scholar
  90. 90.
    Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008 Nov; 67(11): 1516–23PubMedCrossRefGoogle Scholar
  91. 91.
    RoActemra: European public assessment report [online]. Available from URL: http://www.emea.europa.eu/humandocs/Humans/EPAR/RoActemra/RoActemra.htm [Accessed 2009 Apr 17]

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Laura J. Gibbons
    • 1
  • Kimme L. Hyrich
    • 1
  1. 1.ARC Epidemiology Unit, Epidemiology Research Group, School of Translational Medicine, Stopford BuildingUniversity of ManchesterManchesterUK

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