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Review article: Biomedical intelligence

Vol. 144 No. 1516 (2014)

Biological agents in monotherapy for the treatment of rheumatoid arthritis

  • Cem Gabay
  • Paul Hasler
  • Diego Kyburz
  • Alexander So
  • Peter Villiger
  • Johannes von Kempis
  • Ulrich Walker
Cite this as:
Swiss Med Wkly. 2014;144:w13950


Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease, which results in joint destruction and permanent disability. The advent of disease-modifying antirheumatic drugs (DMARDs) has made a profound impact on the outcome and prognosis of RA. Methotrexate (MTX) is a central agent in RA therapy, and is used either alone or in combination with biological DMARDs. However, a large proportion of RA patients (20%–40%) either do not respond to or are unable to tolerate MTX or the alternative agents used in place of MTX (including leflunomide, sulfasalazine, azathioprine, hydroxycholoquine and combination DMARDs). For these patients, monotherapy with biological DMARDs is a key treatment option that balances tolerability with improved clinical outcomes. This article reviews the data for four biological agents approved for use as monotherapy in Switzerland (adalimumab, certolizumab pegol, etanercept and tocilizumab) in order to formulate a consensus statement on their roles in biologic monotherapy of RA.


  1. Spector TD. Rheumatoid arthritis. Rheum Dis Clin North Am. 1990;16:513–37.
  2. Wolfe F, Rasker JJ, Boers M, et al. Minimal disease activity, remission, and the long-term outcomes of rheumatoid arthritis. Arthritis Rheum. 2007;57:935–42.
  3. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7:429–42.
  4. Pincus T, Yazici Y, Sokka T, et al. Methotrexate as the “anchor drug” for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol. 2003;21:S179–S185.
  5. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 2009;68:1100–104.
  6. Jones G, Ding C. Tocilizumab: a review of its safety and efficacy in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2010;19:81–9.
  7. Kaneko A. Tocilizumab in rheumatoid arthritis: efficacy, safety and its place in therapy. Ther Adv Chronic Dis. 2013;4:15–21.
  8. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010;69:964–75.
  9. Brinker RR, Ranganathan P. Methotrexate pharmacogenetics in rheumatoid arthritis. Clin Exp Rheumatol. 2010;28:S33–S39.
  10. Gilani ST, Khan DA, Khan FA, et al. Adverse effects of low dose methotrexate in rheumatoid arthritis patients. J Coll Physicians Surg Pak. 2012;22:101–4.
  11. Breedveld FC, Combe B. Understanding emerging treatment paradigms in rheumatoid arthritis. Arthritis Res Ther. 2011;13(Suppl 1):S3–13.
  12. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2013; epub ahead of print.
  13. Nisar M, Ostor AJ. The role of tocilizumab monotherapy in the management of rheumatoid arthritis: a review. Int J Clin Rheumatol. 2012;7:9–19.
  14. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625–39.
  15. Choquette D, Thomas O, Arundine M. Lower Than Expected Levels of DMARD Acquisition Immediately Pre and Post Biologic Initiation in Rheumatoid Arthritis Patients. Arthritis Rheum. 2012;64(Suppl. 10):1841.
  16. Emery P, Sebba A, Huizinga TW. Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis. Ann Rheum Dis. 2013;72:1897–904.
  17. Voulgari PV, Kaltsonoudis E, Papagoras C, et al. Adalimumab in the treatment of rheumatoid arthritis. Expert Opin Biol Ther. 2012;12:1679–86.
  18. van de Putte LB, Atkins C, Malaise M, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis. 2004;63:508–16.
  19. 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;54:26–37.
  20. Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis. 2007;13:1323–32.
  21. Fleischmann R, Vencovsky J, van Vollenhoven RF, et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis. 2009;68:805–11.
  22. Weinblatt ME, Fleischmann R, Huizinga TW, et al. Efficacy and safety of certolizumab pegol in a broad population of patients with active rheumatoid arthritis: results from the REALISTIC phase IIIb study. Rheumatology (Oxford). 2012;51:2204214.
  23. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med. 1999;130:478–86.
  24. 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;343:1586–93.
  25. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al. 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. 2006;54:1063–74.
  26. 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;363:675–81.
  27. Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008;372:375–82.
  28. Emery P, Breedveld F, van der Heijde D, et al. Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis: a two-year, double-blind, randomized study. Arthritis Rheum. 2010;62:674–82.
  29. van Riel PL, Taggart AJ, Sany J, et al. Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: the ADORE study. Ann Rheum Dis. 2006;65:1478–83.
  30. Kameda H, Kanbe K, Sato E, et al. A merged presentation of clinical and radiographic data using probability plots in a clinical trial, the JESMR study. Ann Rheum Dis. 2013;72:310–2.
  31. Pope JE, Haraoui B, Thorne JC, et al. The Canadian Methotrexate and Etanercept Outcome Study: a randomised trial of discontinuing versus continuing methotrexate after 6 months of etanercept and methotrexate therapy in rheumatoid arthritis. Ann Rheum Dis. 2013; epub ahead of print.
  32. 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:R174.
  33. Combe B, Codreanu C, Fiocco U, et al. Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison. Ann Rheum Dis. 2006;65:1357–62.
  34. Mihara M, Kasutani K, Okazaki M, et al. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int Immunopharmacol. 2005;5:1731–40.
  35. Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:1761–9.
  36. Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66:1162–7.
  37. Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19:12–9.
  38. Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69:88–96.
  39. Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24–week symptomatic and structural results of a 2–year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72:43–50.
  40. Dougados M, Kissel K, Conaghan PG, et al. Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategy with and without methotrexate in rheumatoid arthritis: The ACT-RAY study. Arthritis Rheum. 2012;64:Abstract 2550.
  41. Huizinga T, Donky T, Conaghan PG, et al. Clinical and Radiographic Outcomes at Two Years and the Effect of Tocilizumab (TCZ) Discontinuation Following Sustained Remission in the Second Year of the ACT-RAY Study. Ann Rheum Dis. 2013;72(suppl. 3):43–50 (abstract).
  42. Takeuchi T, Kaneko Y, Atsumi T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in RA patients with inadequate response to methotrexate: 24–week results from a randomized controlled study (SURPRISE study). Ann Rheum Dis. 2013;72(suppl. 3):OP0040.
  43. Burmester G, Rigby W, van Vollenhoven RF, et al. Tocilizumab (TCZ) in combination and monotherapy versus methotrexate (MTX) in MTX-naive patients (pts) with early rheumatoid arthritis (RA): Clinical and radiographic outcomes from a randomised, placebo-controlled trial. Ann Rheum Dis. 2013;72(suppl. 3):OP0041.
  44. Gabay C, Emery P, van VR, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381:1541–50.
  45. Moreland LW, Alten R, Van den Bosch F, et al. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum. 2002;46:1470–9.
  46. Schiff M, Pritchard C, Huffstutter JE, et al. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis. 2009;68:1708–14.
  47. Nash P, Nayiager S, Genovese MC, et al. Immunogenicity, safety, and efficacy of abatacept administered subcutaneously with or without background methotrexate in patients with rheumatoid arthritis: results from a phase III, international, multicenter, parallel-arm, open-label study. Arthritis Care Res (Hoboken). 2013;65:718–28.
  48. Emery P, Fleischmann RM, Moreland LW, et al. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum. 2009;60:2272–83.
  49. Keystone EC, Genovese MC, Klareskog L, et al. Golimumab, a human antibody to tumour necrosis factor {alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis. 2009;68:789–96.
  50. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:2572–81.
  51. Owczarczyk K, Hellmann M, Fliedner G, et al. Clinical outcome and B cell depletion in patients with rheumatoid arthritis receiving rituximab monotherapy in comparison with patients receiving concomitant methotrexate. Ann Rheum Dis. 2008;67:1648–9.
  52. Listing J, Gerhold K, and Zink A. The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology (Oxford). 2013;52:53–61.
  53. Blumentals WA, Arreglado A, Napalkov P, et al. Rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective cohort study. BMC Musculoskelet Disord. 2012;13:158–13.
  54. Galloway JB, Hyrich KL, Mercer LK, et al. Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford). 2011;50:124–31.
  55. Askling J, Fored CM, Brandt L, et al. Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists. Ann Rheum Dis. 2007;66: 1339–44.
  56. Bongartz T, Sutton AJ, Sweeting MJ, et al. 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. 2006;295:2275–85.
  57. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011; CD008794.
  58. Wolfe F, Caplan L, and Michaud K. Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum. 2006;54:628–34.
  59. Genovese MC, Rubbert-Roth A, Smolen JS, et al. Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumulative analysis of up to 4.6 years of exposure. J Rheumatol. 2013;40:768–80.
  60. Hirao M, Hashimoto J, Tsuboi H, et al. Laboratory and febrile features after joint surgery in patients with rheumatoid arthritis treated with tocilizumab. Ann Rheum Dis. 2009;68:654–7.
  61. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448–54.
  62. Ruderman EM. Overview of safety of non-biologic and biologic DMARDs. Rheumatology (Oxford). 2012;51(Suppl 6):vi37–vi43.
  63. Woodrick RS, Ruderman EM. Safety of biologic therapy in rheumatoid arthritis. Nat Rev Rheumatol. 2011;7:639–52.
  64. Horton SC, Nam JL, Buch MH. Safety of biologics in rheumatoid arthritis. Int J Clin Rheumatol. 2012;7:425–51.
  65. Raaschou P, Simard JF, Holmqvist M, et al. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden. BMJ. 2013; epub ahead of print.
  66. Nishimoto N, Miyasaka N, Yamamoto K, et al. Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5–year extension study. Ann Rheum Dis. 2009;68:1580–4.
  67. Bartelds GM, Krieckaert CL, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305:1460–8.
  68. Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 2012;71:1914–5.
  69. Atzeni F, Talotta R, Salaffi F, et al. Immunogenicity and autoimmunity during anti-TNF therapy. Autoimmun Rev. 2013;12:703–8.
  70. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997;337:141–7.
  71. 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 metaanalysis. J Rheumatol. 2006;33:2398–408.
  72. http://www accessdata fda gov/drugsatfda_docs/label/2010/125276rems pdf. 2013;
  73. Bannwarth B, Richez C. Clinical safety of tocilizumab in rheumatoid arthritis. Expert Opin Drug Saf. 2011;10:123–31.
  74. Kerbleski JF, Gottlieb AB. Dermatological complications and safety of anti-TNF treatments. Gut. 2009;58:1033–9.
  75. Tanaka T, Ogata A, Narazaki M. Tocilizumab for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol. 2010;6:843–54.
  76. Stubenrauch K, Wessels U, Birnboeck H, et al. Subset analysis of patients experiencing clinical events of a potentially immunogenic nature in the pivotal clinical trials of tocilizumab for rheumatoid arthritis: Evaluation of an antidrug antibody ELISA using clinical adverse event-driven immunogenicity testing. Clin Ther. 2010;32:1597–609.
  77. Puxeddu I, Giori L, Rocchi V, et al. Hypersensitivity reactions during treatment with infliximab, etanercept, and adalimumab. Ann Allergy Asthma Immunol. 2012;108:123–4.
  78. Quercia O, Emiliani F, Foschi FG, et al. Adalimumab desensitization after anaphylactic reaction. Ann Allergy Asthma Immunol. 2011;106:547–8.
  79. Schiff MH, Kremer JM, Jahreis A, et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011;13:R141.
  80. Choy E, Sattar N. Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis. 2009;68:460–9.
  81. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44:2862–9.
  82. Ostensen M, Forger F. How safe are anti-rheumatic drugs during pregnancy? Curr Opin Pharmacol. 2013;13:470–5.
  83. Keating GM. Abatacept: A Review of its Use in the Management of Rheumatoid Arthritis. Drugs. 2013;73:1095–119.
  84. Chovel-Sella A, Karplus R, Sella T, et al. Clinical efficacy and adverse effects of golimumab in the treatment of rheumatoid arthritis. Isr Med Assoc J. 2012;14:390–4.
  85. Kavanaugh A, Rosengren S, Lee SJ, et al. Assessment of rituximab's immunomodulatory synovial effects (ARISE trial). 1: clinical and synovial biomarker results. Ann Rheum Dis. 2008;67:402–8.
  86. Kameda H, Kanbe K, Sato E, et al. Continuation of methotrexate resulted in better clinical and radiographic outcomes than discontinuation upon starting etanercept in patients with rheumatoid arthritis: 52–week results from the JESMR study. J Rheumatol. 2011;38:1585–92.
  87. Weinblatt ME, Kremer J, Cush J, et al. Tocilizumab as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs: Twenty-four-week results of an open-label, clinical practice study (ACT-STAR). Arthritis Care Res (Hoboken). 2013;65:362–71.
  88. Bykerk VP, Ostor AJ, Alvaro-Gracia J, et al. Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. Ann Rheum Dis. 2012;71:1950–4.

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